Resuscitation with whole blood or blood components improves survival and lessens the pathophysiological burden of trauma and haemorrhagic shock in a pre-clinical porcine model.

PURPOSE: In military trauma, disaster medicine, and casualties injured in remote locations, times to advanced medical and surgical treatment are often prolonged, potentially reducing survival and increasing morbidity. Since resuscitation with blood/blood components improves survival over short pre-surgical times, this study aimed to evaluate the quality of resuscitation afforded by blood/blood products or crystalloid resuscitation over extended 'pre-hospital' timelines in a porcine model of militarily relevant traumatic haemorrhagic shock. METHODS: This study underwent local ethical review and was done under the authority of Animals (Scientific Procedures) Act 1986. Forty-five terminally anaesthetised pigs received a soft tissue injury to the right thigh, haemorrhage (30% blood volume and a Grade IV liver injury) and fluid resuscitation initiated 30 min later [Group 1 (no fluid); 2 (0.9% saline); 3 (1:1 packed red blood cells:plasma); 4 (fresh whole blood); or 5 (plasma)]. Fluid (3 ml/kg bolus) was administered during the resuscitation period (maximum duration 450 min) when the systolic blood pressure fell below 80 mmHg. Surviving animals were culled with an overdose of anaesthetic. RESULTS: Survival time was significantly shorter for Group 1 compared to the other groups (P < 0.05). Despite the same triggers for resuscitation when compared to blood/blood components, saline was associated with a shorter survival time (P = 0.145), greater pathophysiological burden and significantly greater resuscitation fluid volume (P < 0.0001). CONCLUSION: When times to advanced medical care are prolonged, resuscitation with blood/blood components is recommended over saline due to the superior quality and stability of resuscitation achieved, which are likely to lead to improved patient outcomes.

Serological responses to Anthrax Vaccine Precipitated (AVP) increase with time interval between booster doses.

We undertook a Phase 4 clinical trial to assess the effect of time interval between booster doses on serological responses to AVP. The primary objective was to evaluate responses to a single booster dose in two groups of healthy adults who had previously received a complete 4-dose primary course. Group A had received doses on schedule while Group B had not had one for ≥2 years. Secondary objectives were to evaluate the safety and tolerability of AVP booster doses, and to gain information on correlates of protection to aid future anthrax vaccine development. Blood samples were taken on Day 1 before dosing, and on Days 8, 15, 29 and 120, to measure Toxin Neutralisation Assay (TNA) NF50 values and concentrations of IgG antibodies against Protective Antigen (PA), Lethal Factor (LF) and Edema Factor (EF) by ELISA. For each serological parameter, fold changes from baseline following the trial AVP dose were greater in Group B than Group A at every time-point studied. Peak responses correlated positively with time since last AVP dose (highest values being observed after intervals of ≥10 years), and negatively with number of previous doses (highest values occurring in individuals who had received a primary course only). In 2017, having reviewed these results, the Joint Committee on Vaccination and Immunisation (JCVI) updated UK anthrax vaccination guidelines, extending the interval between routine AVP boosters from one to 10 years. Booster doses of AVP induce significant IgG responses against the three anthrax toxin components, particularly PA and LF. Similarly high responses were observed in TNA, a recognised surrogate for anthrax vaccine efficacy. Analysis of the 596 TNA results showed that anti-PA and anti-LF IgG make substantial independent contributions to neutralisation of anthrax lethal toxin. AVP may therefore have advantages over anthrax vaccines that depend on generating immunity to PA alone.

Establishment of a Novel Oral Murine Model of Ricin Intoxication and Efficacy Assessment of Ovine Ricin Antitoxins.

Ricin, produced from the castor beans of Ricinus communis, is a cytotoxin that exerts its action by inactivating ribosomes and causing cell death. Accidental (e.g., ingestion of castor beans) and/or intentional (e.g., suicide) exposure to ricin through the oral route is an area of concern from a public health perspective and no current licensed medical interventions exist to protect from the action of the toxin. Therefore, we examined the oral toxicity of ricin in Balb/C mice and developed a robust food deprivation model of ricin oral intoxication that has enabled the assessment of potential antitoxin treatments. A lethal oral dose was identified and mice were found to succumb to the toxin within 48 h of exposure. We then examined whether a despeciated ovine F(ab')2 antibody fragment, that had previously been demonstrated to protect mice from exposure to aerosolised ricin, could also protect against oral intoxication. Mice were challenged orally with an LD99 of ricin, and 89 and 44% of mice exposed to this otherwise lethal exposure survived after receiving either the parent anti-ricin IgG or F(ab')2, respectively. Combined with our previous work, these results further highlight the benefit of ovine-derived polyclonal antibody antitoxin in providing post-exposure protection against ricin intoxication.

A prospective observational study of acute traumatic coagulopathy in traumatic bleeding from the battlefield.

BACKGROUND: Acute trauma coagulopathy (ATC) after military trauma has not been comprehensively studied. ATC is defined as a prolonged prothrombin time ratio (PTr) or reduced clot amplitude (A5) in viscoelastic testing. Compared to civilian trauma, military trauma has more injuries from explosions and gunshot wounds (GSWs), potentially leading to a different pathophysiology for traumatic coagulopathy. This study aimed to characterize military ATC on admission to a military hospital in Afghanistan and to explore any differences due to the mechanism of injury. METHODS: Severely injured military casualties were enrolled in the study. Blood samples were taken on admission and after routine testing, waste plasma was prepared, frozen, and transported to the United Kingdom for in-depth hemostatic analysis. RESULTS: Seventy-seven percent of casualties had ATC defined by a PTr greater than 1.2 and 19% when defined by rotational thromboelastometry (ROTEM) A5 less than 36 mm. Coagulation factor depletion correlated with degree of shock, particularly factor V (p < 0.01), factor X (p < 0.01), and fibrinogen levels (p < 0.01). Thrombin generation was well preserved. Fibrinolytic biomarkers were raised correlating with the degree of shock (p < 0.01), and 8% of casualties had hyperfibrinolysis on ROTEM analysis. Plasmin-antiplasmin complexes (p < 0.01) and d-dimer levels (p = 0.01) were higher and clot firmness lower (p = 0.02) in those injured by explosion compared to GSW's. CONCLUSIONS: ATC was present and correlated with shock, similar to civilian trauma. Thrombin generation remained adequate. Fibrinogen and factor V levels were disproportionately low but still sufficient to allow clot formation. Fibrinolysis is a key feature, probably due to a tissue plasminogen activator surge at the time of injury. Blast injuries are associated with a greater activation of fibrinolysis than GSWs.

Closed chest compressions reduce survival in an animal model of haemorrhage-induced traumatic cardiac arrest.

Closed chest compressions (CCC) are recommended for medical cardiac arrest, but there is little evidence to support their inclusion for traumatic cardiac arrest (TCA). This laboratory study evaluated CCC following haemorrhage-induced TCA and whether resuscitation with blood improved survival compared to saline. The study was conducted with the authority of UK Animals (Scientific Procedures) Act 1986 (received institutional ethical approval and a Home Office Licence) using 39 terminally anesthetised, instrumented, juvenile Large White pigs. Following baseline measurements, animals underwent captive bolt injury to the right thigh and controlled haemorrhage (30% blood volume). Sixty minutes later there was a further haemorrhage to a MAP of 20 mmHg. The randomised resuscitation protocol was initiated within 5 min: CCC (Group 1); IV whole blood (Group 2); IV 0.9% saline (Group 3); IV whole blood + CCC (Group 4); and IV saline + CCC (Group 5). Fluid was administered as 3 × 10 ml/kg boluses using the Belmont® Rapid Infuser. The LUCAS™ II Chest Compression System delivered CCC. Primary Outcome was attainment of return of spontaneous circulation (ROSC MAP ≥ 50 mmHg) at Study End (fifteen minutes post-resuscitation) and secondary outcomes included haemodynamics. Mortality (MAP≤10 mmHg) was significantly higher in Group 1 compared to Groups 2 and 3 (P < 0.0001). Resuscitation with whole blood was significantly better than saline (P = 0.0069), no animals in Group 3 attained ROSC. The addition of chest compressions to fluid resuscitation resulted in a significantly worse outcome with saline resuscitation (P = 0.0023) but not with whole blood (P = 0.4411). Cardiovascular variables at the end of the Resuscitation Phase and Study End were significantly worse for Group 5 compared to Group 3. Some significant differences were present at the end of the Resuscitation Phase for Group 4 versus Group 2 but these differences were no longer present by Study End. CCC were associated with increased mortality and compromised haemodynamics compared to intravenous fluid resuscitation. Whole blood resuscitation was better than saline.

Production, Characterisation and Testing of an Ovine Antitoxin against Ricin; Efficacy, Potency and Mechanisms of Action.

Ricin is a type II ribosome-inactivating toxin that catalytically inactivates ribosomes ultimately leading to cell death. The toxicity of ricin along with the prevalence of castor beans (its natural source) has led to its increased notoriety and incidences of nefarious use. Despite these concerns, there are no licensed therapies available for treating ricin intoxication. Here, we describe the development of a F(ab')2 polyclonal ovine antitoxin against ricin and demonstrate the efficacy of a single, post-exposure, administration in an in vivo murine model of intoxication against aerosolised ricin. We found that a single dose of antitoxin afforded a wide window of opportunity for effective treatment with 100% protection observed in mice challenged with aerosolised ricin when given 24 h after exposure to the toxin and 75% protection when given at 30 h. Treated mice had reduced weight loss and clinical signs of intoxication compared to the untreated control group. Finally, using imaging flow cytometry, it was found that both cellular uptake and intracellular trafficking of ricin toxin to the Golgi apparatus was reduced in the presence of the antitoxin suggesting both actions can contribute to the therapeutic mechanism of a polyclonal antitoxin. Collectively, the research highlights the significant potential of the ovine F(ab')2 antitoxin as a treatment for ricin intoxication.

Alcohol Use Disorder Treatment: The Association of Pretreatment Use and the Role of Drinking Goal.

BACKGROUND: In a recent study conducted in a family medicine setting, the medication acamprosate was found not to be efficacious in the treatment of alcohol dependence, but a drinking goal of abstinence was found to have positive effects on alcohol use outcomes. The purpose of this secondary analysis was to further understand which patients with an alcohol use disorder may be most successfully treated in a primary care setting. METHODS: The study was exploratory and used a trajectory-based approach based on data from the acamprosate treatment trial of 100 participants (recruited mostly by advertisement) who were randomly assigned to receive either acamprosate or a matching placebo. Post hoc trajectories of alcohol use before treatment were identified to examine whether trajectory classes and their interactions with treatment arm (acamprosate or placebo), pretreatment drinking goal (abstinence or a reduction), and time predicted alcohol use outcomes. RESULTS: Three distinct trajectory classes were identified: frequent drinkers, nearly daily drinkers, and consistent daily drinkers. Consistent daily drinkers with a goal of abstinence significantly improved over time on the primary outcome measure of percent days abstinent when compared with frequent and nearly daily drinkers. In addition, all participants with a goal of abstinence, regardless of trajectory class, significantly reduced their percentage of heavy drinking days over time. CONCLUSIONS: Patients with an alcohol use disorder who have a drinking goal of abstinence, in particular consistent daily drinkers, may maximally benefit from alcohol use disorder treatment, including the use of medication, in a primary care setting.

Evaluation of Prehospital Blood Products to Attenuate Acute Coagulopathy of Trauma in a Model of Severe Injury and Shock in Anesthetized Pigs.

Acute trauma coagulopathy (ATC) is seen in 30% to 40% of severely injured casualties. Early use of blood products attenuates ATC, but the timing for optimal effect is unknown. Emergent clinical practice has started prehospital deployment of blood products (combined packed red blood cells and fresh frozen plasma [PRBCs:FFP], and alternatively PRBCs alone), but this is associated with significant logistical burden and some clinical risk. It is therefore imperative to establish whether prehospital use of blood products is likely to confer benefit. This study compared the potential impact of prehospital resuscitation with (PRBCs:FFP 1:1 ratio) versus PRBCs alone versus 0.9% saline (standard of care) in a model of severe injury. Twenty-four terminally anesthetised Large White pigs received controlled soft tissue injury and controlled hemorrhage (35% blood volume) followed by a 30-min shock phase. The animals were allocated randomly to one of three treatment groups during a 60-min prehospital evacuation phase: hypotensive resuscitation (target systolic arterial pressure 80 mmHg) using either 0.9% saline (group 1, n = 9), PRBCs:FFP (group 2, n = 9), or PRBCs alone (group 3, n = 6). Following this phase, an in-hospital phase involving resuscitation to a normotensive target (110 mmHg systolic arterial blood pressure) using PRBCs:FFP was performed in all groups. There was no mortality in any group. A coagulopathy developed in group 1 (significant increase in clot initiation and dynamics shown by TEG [thromboelastography] R and K times) that persisted for 60 to 90 min into the in-hospital phase. The coagulopathy was significantly attenuated in groups 2 and 3 (P = 0.025 R time and P = 0.035 K time), which were not significantly different from each other. Finally, the volumes of resuscitation fluid required was significantly greater in group 1 compared with groups 2 and 3 (P = 0.0067) (2.8 ± 0.3 vs. 1.9 ± 0.2 and 1.8 ± 0.3 L, respectively). This difference was principally due to a greater volume of saline used in group 1 (P = 0.001). Prehospital PRBCs:FFP or PRBCs alone may therefore attenuate ATC. Furthermore, the amount of crystalloid may be reduced with potential benefit of reducing the extravasation effect and later tissue edema.

Stuck in a moment: an ex ante analysis of patient complaints in plastic surgery, used to predict malpractice risk profiles, from a large cohort of physicians in the patient advocacy reporting system.

INTRODUCTION: Unsolicited patient complaints (UPCs) serve as a powerful predictor of increased risk of malpractice claims, and reductions in UPCs, through targeted physician interventions, lower incidence of lawsuits and decrease cost of risk management. We analyzed UPCs, verified by trained counselors in patient relations, to determine the malpractice risk of plastic surgeons, compared to dermatologists, all surgeons, and all physicians, from a national patient complaint registry. METHODS: We examined the patient complaint profiles and risk scores of 31,077 physicians (3935 surgeons, 338 plastic and reconstructive surgeons, and 519 dermatologists), who participated in the Patient Advocacy Reporting System, a national registry of UPCs. Patient complaint data were collected from 70 community and academic hospitals across 29 states, from 2009 to 2012. In addition to determining the specific complaint mix for plastic surgery compared to all physicians, each physician was assigned a patient complaint risk score, based on a proprietary weighted-sum algorithm, with a score higher than 70, indicative of high risk for malpractice claims. Patient complaint profiles and risk scores were compared between all groups, using Wilcoxon rank and χ analysis. P values less than 0.05 were assigned statistical significance. RESULTS: Over this 4-year period, the majority of plastic surgeons (50.8%) did not generate any patient complaints, but those who did received an average of 9.8 complaints from 4.8 patients. The percentage of physicians at high risk for malpractice claims, based upon the Patient Advocacy Reporting System index score of patient complaints, was as follows: all physicians, 2.0%; all surgeons, 4.1%; plastic and reconstructive surgeons, 2.4%; dermatologists, 1.4%. Physicians (from 2012 only) who were identified by their sponsoring institutions as "reconstructive" plastic surgeons (n = 41) were 5 times as likely to have a high risk score, compared to physicians who were identified as "plastic" surgeons (n = 233), and were more likely to practice within an academic health care system that had a level 1 trauma center and a plastic surgery residency program. The overall mix of patient complaints from plastic and reconstructive surgeons was nearly the same as the national cohort of all physicians: care and treatment, 49%; communication, 19%; accessibility and availability, 14%; money or payment issues, 9%; and concern for patient/family, 9%. CONCLUSIONS: "Reconstructive" plastic surgeons are at increased risk for UPCs, compared to most physicians, especially dermatologists. Because UPCs are a robust proxy for malpractice risk, targeted interventions to decrease patient complaints may improve patient satisfaction and reduce malpractice claims and risk management activity. Monitoring UPCs may permit early identification of high-risk surgeons before malpractice claims accumulate.

Efficacy of acamprosate for alcohol dependence in a family medicine setting in the United States: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Acamprosate has been found to enhance rates of complete abstinence and to increase percent days abstinent (PDA) from alcohol relative to placebo treatment. As most U.S. clinical trials of acamprosate have been conducted in alcohol and other drug specialty clinics, there is a need to examine the efficacy of acamprosate in generalist settings. This study tested the efficacy of acamprosate versus placebo on the primary study outcome of PDA in the treatment of alcohol-dependent patients in a family medicine setting. Secondary study outcomes included percent heavy drinking days (%HDD) and gamma glutamyltransferase level (normal or high). METHODS: A randomized, double-blind, placebo-controlled, parallel group design of acamprosate was conducted in 2 family medicine settings (North Carolina and Wisconsin). One hundred volunteers were recruited primarily by advertisement, and participants were assigned to 666 mg (2 pills) oral acamprosate 3 times daily (1,998 mg/d) or matching placebo over a 12-week period. All participants concomitantly received 5 sessions of a brief behavioral intervention from a family/primary care physician. RESULTS: No significant treatment effect of acamprosate was found on PDA or the secondary outcomes. Significant treatment goal by time interaction effects was found on PDA and %HDD. Participants who had an initial goal of abstinence versus a reduction in alcohol use improved on average over time in PDA and had less %HDD from baseline to the end of treatment. CONCLUSIONS: This clinical trial did not find evidence of efficacy for acamprosate compared to placebo among alcohol-dependent individuals recruited primarily by advertisement as studied in a primary care setting. Drinking outcomes significantly improved regardless of medication condition. A goal of abstinence was significantly associated with improved drinking outcomes, suggesting that alcohol-dependent patients with such a goal may do particularly well with counseling in a family medicine setting.

Ecological network analysis: an application to the evaluation of effects of pesticide use in an agricultural environment.

Ecological network analysis is used to evaluate the impact of pesticide use on ecological systems in the context of agricultural farmland environments. The aim is to provide support for the design of effective and minimally damaging pest control strategies. The ecological network analysis can identify species that are important to the integrity of the ecological network. The methodology can be used to monitor the impact of shifts in terms of types of pesticide used on the ecological system. The authors' intention is to use this methodology to provide supporting evidence for the UK Voluntary Initiative programme aimed at convincing farmers voluntarily to make improved choices in the use of a wide range of pesticides.

Evaluation of barrier creams against sulphur mustard: (II) In vivo and in vitro studies using the domestic white pig.

Previous studies in our laboratory have demonstrated that barrier creams, comprising perfluorinated polymers, are effective against the chemical warfare agent sulphur mustard (SM) when evaluated using human skin in vitro. The purpose of this follow-up study was to further evaluate three candidate (perfluorinated) barrier creams against SM (vapour) using the domestic white pig. The severity and progression of the resulting skin lesions were quantified daily for three weeks post-exposure using biophysical measurements of transepidermal water loss (TEWL) and skin reflectance spectroscopy (SRS). Skin biopsies obtained post-mortem were evaluated by light microscopy and additional skin samples were obtained from adjacent (unexposed) skin sites for a comparative in vitro skin absorption study. Samples of SM vapour within the dosing chambers were measured ex vivo to ascertain the exposure dose (Ct). The three creams were highly effective against SM in vivo (Ct approximately 5000 mg.min.m(-3)): After 3 weeks, barrier cream pre-treated sites were not significantly different from control (unexposed) skin when evaluated by TEWL, SRS or histology. In contrast, skin exposed to SM without pre-treatment showed evidence of persistent damage that was consistent with the slow healing time observed in humans. The amount of SM absorbed in vitro in untreated pig skin was similar to that required to cause comparable lesions in human skin (8-20 and 4-10 microg.cm(-2), respectively), further validating the use of pigs as a toxicologically-relevant dermal model for SM exposure.

Evidence-based and population-based medicine: national implementation under the UME-21 project.

BACKGROUND AND OBJECTIVES: The Undergraduate Medical Education for the 21st Century (UME-21) project developed and implemented innovations to medical school curricula at medical schools across the country. This report describes the development and implementation of innovative approaches to improving instruction in evidence-based medicine with a population-based perspective. METHODS: Each school participating in the UME-21 project designed, implemented, and evaluated its own unique curriculum initiatives. We examined these initiatives using data abstracted from written reports submitted to the project Executive Committee. Additional data were obtained by personal communication with project directors and evaluators at the various schools, student and preceptor comments, internal program evaluation at each school, and external evaluation by the UME-21 project leadership. The Association of American Medical Colleges Graduation Questionnaire was also used. RESULTS: Fourteen of 18 participating schools implemented a broad range of curricula to facilitate teaching and learning about evidence-based and population-based medicine. Common themes included the application of evidence to patient care, use of clinical practice guidelines and pathways, and the general incorporation of evidence-based techniques (literature searching, critical appraisal, etc) into the teaching of other content, such as clinical science and managed care. Teaching approaches included Web-based and other computer-based education, an emphasis on active and self-directed learning, use of small groups and workshops, and distribution of this content over multiple years. As an alternative to full-length evidence-based medicine courses, many schools incorporated an evidence-based approach into existing courses and clerkships. Data demonstrated an upward trend in student satisfaction with how topics were presented at UME-21 schools. CONCLUSIONS: These innovations successfully demonstrated that evidence-based and population-based medicine content can be introduced into medical school curricula. Introducing these constructs in ways that demonstrate their relevance to patient care facilitates student learning.