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OBJECTIVE To utilize the geometry of superficial anatomic landmarks to guide incisional location and orientation for peripheral lymphadenectomy, document deep anatomic landmarks for lymphocentrum identification, and develop novel surgical approaches to the superficial cervical, axillary, and superficial inguinal lymphocentrums in dogs. ANIMALS 12 canine cadavers. PROCEDURES 2 cadavers were used for a pilot investigation to determine optimal body positioning, select superficial anatomic landmarks for lymphocentrum identification, and evaluate novel surgical approaches to the 3 lymphocentrums. These lymphocentrums were then dissected in 10 additional cadavers using these novel surgical approaches. Measurements of the distances from lymphocentrum to landmark and between landmarks were obtained for each lymphocentrum. Deep anatomic landmarks were recorded for each dissection. The mean and SD were calculated for each measurement and used to develop geometric guidelines for estimating the location of each lymphocentrum for these surgical approaches. RESULTS Each peripheral lymphocentrum was found in the same location relative to the respective, predetermined, superficial, anatomic boundaries in all cadavers. Briefly, the superficial landmarks to each lymphocentrum were as follows: (1) superficial cervical: wing of atlas, acromion process of scapula, greater tubercle of humerus; (2) axillary: caudal border of transverse head of superficial pectoral muscle, caudal triceps muscle, ventral midline; and (3) superficial inguinal: origin of pectineus muscle, ipsilateral inguinal mammary gland, ventral midline. The proposed superficial and deep surgical landmarks were identified within every cadaver. The previously undescribed surgical approaches were effective for lymphocentrum identification. CLINICAL RELEVANCE Anatomic landmarks provided in this study may help reduce surgical time and tissue trauma during peripheral lymphadenectomy in dogs. This study was also the first to describe a surgical approach to the superficial inguinal lymphocentrum and ventral approaches to the superficial cervical and axillary lymphocentrums and provided previously unpublished anatomic landmarks for a lateral approach to the superficial cervical lymphocentrum.

Background There are benefits to choosing deep sedation over general anesthesia as an intraoperative anesthetic for shoulder surgery. Deep sedation, however, may be challenging in patients with risk factors for hypoxemia. Methods We conducted a retrospective case control study comparing patients who underwent shoulder surgery using deep sedation and interscalene block versus general anesthesia and cervical paravertebral or interscalene block. A non-invasive positive pressure system (SuperNO2VA mask; Vyaire Medical, Mettawa, IL, USA) was utilized as an airway adjunct in patients undergoing deep sedation. Results Sixty patients were included in the study (20 patients with block with sedation and 40 patients with general anesthesia). No patient who received deep sedation required conversion to general anesthesia or additional airway support measures. Induction- and emergence-related anesthesia times were lower for those who received deep sedation than those who received general anesthesia (39 [CI 31–48] vs 17 [CI 8–27] minutes; p Conclusions This retrospective study showed that non-invasive positive pressure ventilation facilitated the performance of deep sedation for shoulder surgery with an interscalene block for both shoulder arthroscopic procedures and shoulder arthroplasty. This technique was associated with avoidance of mechanical ventilation, decreased anesthesia time, use of vasopressors, and need for urinary catheter placement.

To improve rigor and reproducibility of animal research, the recently released NIH Advisory Committee report recommends major improvements in investigator statistical training and practice. The IACUC can serve as important gatekeepers of research quality by ensuring that simple statistically based reproducibility criteria are addressed in animal use protocols.

Objectives The objective of this study was to quantify the effects of owner separation and physical examination location on fear, anxiety and stress (FAS) behavioral indicators in cats. Methods The study was a prospective, non-blinded, randomized, two-period, two-treatment crossover trial. Healthy adult cats presenting for wellness or dental evaluations at a single veterinary teaching hospital received three physical examinations: a baseline assessment (owner present) followed by physical examinations in both a treatment area (owner absent [TAOA]) and an examination room (owner present [EROP]). The physical examination sequence order was randomized. Low-stress handling techniques were used for all examinations. The primary endpoints were heart rate (HR; beats per min [bpm]) and total FAS scores. HR was measured by auscultation, and FAS by five specific behaviors scored as 0/1 and summed for each assessment period. Results Twenty-one healthy cats were enrolled. HR measured at entry (baseline) was a significant determinant of subsequent HR readings. HR measured during examinations conducted in both EROP and TAOA were elevated to levels indicative of stress (>180 bpm). HR was significantly higher for TAOA relative to EROP (30 bpm, 95% confidence interval 18–43; P Conclusions and relevance Owner separation coupled with physical examination location can result in clinically significant increases in perceived stress in cats, and compromise vital sign assessments. Whenever possible, physical examinations and procedures should take place with the owner present with separation from unfamiliar dogs and cats.

OBJECTIVETo investigate the predictive value of right axis deviation of the mean electrical axis (MEA) in assessing the severity of pulmonic stenosis (PS) in dogs.ANIMALSRecords for 218 client-owned dogs diagnosed between 2014 and 2020 with PS as determined by Doppler echocardiography.PROCEDURESUniversity of Florida Small Animal Clinic medical records were reviewed, and signalment and clinical risk variables (murmur grade and clinical signs) were extracted. MEA was determined from ECG records by use of leads I and III. Predictive potential of MEA and associated risk factors to diagnose PS severity (mild [< 50 mm Hg], moderate, or severe [> 75 mm Hg]) were assessed by receiver-operating characteristic curve analysis and quantile regression.RESULTSRecords for 88 dogs were eligible for analysis. Greater PS severity was associated with smaller breeds presenting with ECG abnormalities, overt clinical signs, and high-category murmur grades (IV and V). Mean MEA increased with stenosis severity category, with an average of 62° for mild, 113° for moderate, and 157° for severe. Each 10° increase in MEA corresponded to an approximately 5–mm Hg increase in PG. Increasing PS severity was associated with MEA right axis deviation > 100° and the more severe cases (PG > 75 mm Hg) with MEA right axis deviation > –180°.CLINICAL RELEVANCEMean electrical axis right axis deviation may be a useful screening metric for dogs with suspected moderate to severe PS.

Non-aversive handling is a well-documented refinement measure for improving rodent welfare. Because maternal stress is related to reduced productivity, we hypothesized that welfare benefits associated with non-aversive handling would translate to higher production and fewer litters lost in a laboratory mouse breeding colony. We performed a randomized controlled trial to examine the effects of a standard method of handling (tail-lift with forceps) versus non-aversive handling with transfer tunnels (‘tunnel-handled’) on breeding performance in 59 C57BL/6J mouse pairs. Intervention assignments could not be concealed from technicians, but were concealed from assessors and data analyst. An operationally significant effect of tunnel-handling (large enough differences to warrant programmatic change) was defined before study initiation as a 5% increase in productivity, or one extra pup over the reproductive lifetime of each pair. Pairs were randomly allocated to handling intervention and cage rack location, and monitored over an entire 6-month breeding cycle. For each group, we measured number of pups born and weaned, and number of entire litters lost prior to weaning. Differences between transfer methods were estimated by two-level hierarchical mixed models adjusted for parental effects and parity. Compared to tail-lift mice, tunnel-handled mice averaged one extra pup per pair born (+1.0; 95% CI 0.9, 1.1; P = 0.41) and weaned (+1.1, 95% CI 0.9, 1.2; P = 0.33). More tunnel-handled pairs successfully weaned all litters produced (13/29 pairs, 45% vs 4/30 pairs, 13%; P = 0.015), averaged fewer litter losses prior to weaning (11/29 pairs [38%] vs 26/30 pairs [87%]; P

IntroductionHemorrhage control is the top priority in far-forward care. Preclinical studies are essential for determining safety and efficacy before novel therapeutics can be tested in humans. Unfortunately, poor methodological quality jeopardizes translational potential.MethodsWe systematically reviewed 136 recent publications describing swine models of hemostasis and hemorrhage reduction to assess compliance with established standards for scientific reporting. Quality measures were summarized by descriptive statistics; randomization was assessed by using baseline group differences to test the uniform distribution assumption for observed P-values.ResultsMost articles did not report information essential to assess study validity and reliability of experimental results. Studies claiming random allocation showed clear evidence of systematic bias. Sample sizes were small, but nearly all studies reported statistically significant effects in the direction of “benefit.” Excessive hypothesis testing increased the risk of false positives.ConclusionsMethodological quality was poor. Although funding agencies actively promote good scientific practice, investigators have been slow to comply. Poorly executed and reported animal research is an ethical and translational issue, wasting animals and potentially harming patients. To properly assess the therapeutic benefit of novel interventions, investigators must rely less on rote hypothesis testing, develop skills in experimental design and quantitative analysis, and comply with best-practice reporting guidelines.

Translation of animal-based preclinical research is hampered by poor validity and reproducibility issues. Unfortunately, preclinical research has ‘fallen between the stools’ of competing study design traditions. Preclinical studies are often characterised by small sample sizes, large variability, and ‘problem’ data. Although Fisher-type designs with randomisation and blocking are appropriate and have been vigorously promoted, structured statistically-based designs are almost unknown. Traditional analysis methods are commonly misapplied, and basic terminology and principles of inference testing misinterpreted. Problems are compounded by the lack of adequate statistical training for researchers, and failure of statistical educators to account for the unique demands of preclinical research. The solution is a return to the basics: statistical education tailored to non-statistician investigators, with clear communication of statistical concepts, and curricula that address design and data issues specific to preclinical research. Statistics curricula should focus on statistics as process: data sampling and study design before analysis and inference. Properly-designed and analysed experiments are a matter of ethics as much as procedure. Shifting the focus of statistical education from rote hypothesis testing to sound methodology will reduce the numbers of animals wasted in noninformative experiments and increase overall scientific quality and value of published research.

All animal protocols need quantitative justification of animal numbers, but not all will need power calculations.

OBJECTIVES To quantify the effects of wellness examinations conducted in the common treatment area on fear, anxiety and stress indicators in client-owned dogs. MATERIALS AND METHODS The study was a prospective, non-blinded, randomised, two-period two-treatment crossover trial. Client-owned healthy adult dogs presenting for wellness or dental evaluations at a single veterinary teaching hospital received three consecutive rapid assessment exams; a baseline exam (owner present), followed by two identical physical exams differing in location and presented in random order (isolated exam room with owner present versus common treatment area, owner absent). Primary endpoints were a cumulative fear, anxiety and stress score for five standardised behaviours and heart rate (bpm) measured for each exam. RESULTS Forty-four dogs were enrolled. Modal fear, anxiety and stress score at baseline was 1 of 5, indicating none to mild stress. Both fear, anxiety and stress and heart rates measured in the common treatment area were clinically elevated relative to assessments conducted in the exam room. Relative to baseline, animals examined in the common treatment area showed increased fear, anxiety and stress (+2.6 units, se 0.5; P

The ARRIVE (Animals in Research: Reporting In Vivo Experiments) guidelines were endorsed by the Shock Society in 2012, but to date there has been no systematic evaluation of research reporting quality for Shock. We systematically assessed 100 randomly selected animal-based research articles published between 2014 and 2018 for reporting quality and statistical practice, compared with 40 pre-ARRIVE studies. More than half of surveyed papers omitted verifiable ethical oversight information and basic animal descriptive information. Few papers reported best-practice methods, such as sample size justification (10%), randomization (43%), randomization method (7%), blinding (23%). Only one paper reported effect sizes to interpret study results. Most troubling was inadequate reporting of welfare-related information (anesthesia, analgesia, humane endpoints, euthanasia). Almost a decade after ARRIVE endorsement, our findings show that reporting deficiencies have persisted with little sign of correction. There is a clear need for investigators to increase transparency of research methods reporting, and drastically improve skills in experimental design. Improvement in standards and greater attention paid to reporting will lead to improvement in reproducibility, replicability, and research quality. It is incumbent upon the research community to improve reporting practices; accurate and transparent reporting is integral to producing rigorous and ethical science.

Best-practice clinical decision-making for patient blood management (PBM) and transfusion in cardiac surgery requires high-quality, timely information. However, evidence will be misleading if published information lags too far behind evolving practice, or if trial results are biased, incomplete, or unreported. The result is that providers are deprived of accurate data, and patients will not receive best possible care. Publicly accessible trial registries provide information for structured audits of reporting compliance, and appraisal of evidence attrition and distortion. Trials related to blood management and transfusion in cardiac surgery and those registered in ClinicalTrials.gov were evaluated for relevance, reliability, transparency, timeliness, and prevalence of unreported trial results. Evidence was considered to have “disappeared” if no results were posted to the registry and no related PUBMED publications were available by July 2019. Data were summarized by descriptive statistics. A total of 181 registered trials were surveyed; 52% were prospectively registered. Most commonly reported primary outcomes were laboratory surrogate measures (34%). Patient- and practice-relevant outcomes—mortality/major morbidity (7%), transfusion (27%), and major bleeding (28%)—were less common. Only seven studies posted results to the registry within the mandated 12 months from study completion; median time to posting was 17 (interquartile range [IQR] 13, 37) months. Trial results for 58% were unreported 3–9 years after trial completion. A staggering amount of clinical trial evidence for PBM in cardiac surgery is missing from publicly accessible records and the literature. Investigators must be incentivized to promptly and completely report all results. Penalties for noncompliance are already in place and should be enforced. Simplified information linkage, centralized and routine audit cycles, and prioritization of robust “living” reviews may be more positive motivators. Implementation will require a sea change in the prevailing culture of research reporting, plus coordinated efforts of clinicians, applied statisticians, information technology specialists, and research librarians.

Reporting standards for animal research in Shock have not improved since Shock Society endorsed the ARRIVE guidelines in 2012. Particularly troubling is the omission of key information describing methodological quality and animal welfare. Both investigators and journal reviewers are strongly encouraged to actively consult the checklist to improve manuscript quality, and ensure that Shock upholds the highest standards of research quality and the humane treatment of animals.

BACKGROUND:Viscoelastic thromboelastography tests such as TEG™ are now routine for assessing the coagulation status of cardiac surgery patients. We compared TEG™ with a new technology, sonic estimation of elasticity via resonance (SEER) sonorheometry, to compare measures of coagulation dynamics of w

Reproducible science requires transparent reporting. The ARRIVE guidelines were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved.Here we introduce ARRIVE 2019. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise the items and split the guidelines into two sets, the ARRIVE Essential 10, which constitute the minimum requirement, and the Recommended Set, which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers to verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document that serves 1) to explain the rationale behind each item in the guidelines, 2) to clarify key concepts and 3) to provide illustrative examples. We aim through these changes to help ensure that researchers, reviewers and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.

Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting are vital to this process; it allows readers to assess the reliability of the findings, and repeat or build upon the work of other researchers. The NC3Rs developed the ARRIVE guidelines in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments.Despite widespread endorsement by the scientific community, the impact of the ARRIVE guidelines on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This Explanation and Elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2019, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature.

Poor quality data in preclinical trials can result from inconsistent and unstandardized experimental processes. Unpredictable pre-intervention variability generates unreliable data, biases outcomes and results in needless waste of animals and resources. We applied Define-Measure-Analyse-Improve-Control (DMAIC) quality improvement processes to pilot development of a swine model of trauma, haemorrhagic shock and coagulopathy. The goal was to reduce variability through protocol standardization and error reduction. Six male Sinclair swine were sequentially anesthetized, intubated, mechanically ventilated and instrumented, then subjected to multiple-hit injury, followed by fluid resuscitation monitoring and coagulation testing. Experimental tasks were defined and mapped. Performance measures were task performance times, subject stabilization time and number of task execution errors. Process improvement was assessed by reduced times and errors, and subject stability at target physiological values. Previously-overlooked performance errors and deficiencies were identified. ‘Mistake-proofing’ actions included personnel retraining, revisions of standard operating procedures and use of checklists. The quality improvement pilot trial produced a stable model with reduced protocol deviations. Data quality can be improved and animal waste minimized, if experimental planning incorporates strategies to ensure protocol adherence and reduced operator performance variation and errors. Properly designed pilot trials can be essential components of refinement and reduction strategies in animal-based research.

Background Hextend (HEX) is standard of care resuscitation fluid for combat-related traumatic hemorrhage. Because HEX has limited oxygen-carrying capacity, combination therapy with oxygen therapeutics could improve oxygen delivery after hemodynamic shock. We hypothesized that addition of perfluorocarbon (PFC) to HEX would improve hemodynamics and oxygen delivery marker response in a rabbit model of hemorrhagic shock. Methods Anesthetized New Zealand rabbits (n = 23) were randomly allocated to resuscitation with fresh whole blood (FWB), HEX, or HEX plus PFC (HEX + PFC) after 60 min of hemorrhagic hypotension. Mean arterial pressure (MAP) was sampled every 2–3 min for 120 min postinfusion; MAP profiles were modeled by a one-compartment pharmacokinetic model to determine peak MAP (Pmax), time to peak MAP (tmax), and postinfusion MAP persistence. Arterial blood was sampled every 15 min to examine pH, blood gases PO2 and pCO2, metabolites lactate and glucose, methemoglobin (metHb), and electrolytes. Results Compared with FWB and HEX, HEX + PFC administration resulted in delayed peak MAP and less persistent (P

The success of Tactical Combat Casualty Care (TCCC) in reducing potentially preventable combat deaths may rely on both specific interventions (such as tourniquets) and the systematized application of immediate care. Essential elements of a combat care system include clear specification of immediate care priorities, standardized methodology, and inclusion and training of all nonmedical personnel in early response. Although TCCC is fairly recent, the construct is similar to that first suggested during the mid-nineteenth century by John Turner Caddy (1822-1902), a British Royal Navy staff surgeon. Although naval warfare engagements at the time were relatively infrequent, casualties could be numerous and severe and often overwhelmed the small medical staff on board. Caddy recognized that nonmedical personnel properly trained in the fundamentals of combat injury management would result in lives saved and greatly improved morale. The novelty was in his attempt to make procedures simple enough to be performed by nonmedical personnel under stress. However, Caddy's guidelines were completely overlooked for nearly two centuries. The principles of best practice for managing combat trauma injuries learned in previous wars have often been lost between conflicts. Understanding the historical roots of combat first responder care may enable us to better understand and overcome barriers to recognition and retention of essential knowledge.

Coagulopathy and inflammation induced by hemorrhagic shock and traumatic injury are associated with increased mortality and morbidity. Vitamin C (VitC) is an antioxidant with potential protective effects on the proinflammatory and procoagulant pathways. We hypothesized that high-dose VitC administered as a supplement to fluid resuscitation would attenuate inflammation, coagulation dysfunction, and end-organ tissue damage in a swine model of multiple injuries and hemorrhage.Male Sinclair swine (n = 24; mean body weight, 27 kg) were anesthetized, intubated, mechanically ventilated, and instrumented for physiologic monitoring. Following stabilization, swine were subjected to shock/traumatic injury (hypothermia, liver ischemia and reperfusion, comminuted femur fracture, hemorrhagic hypotension), resuscitated with 500 mL of hydroxyethyl starch, and randomized to receive either intravenous normal saline (NS), low-dose VitC (50 mg/kg; LO), or high-dose VitC (200 mg/kg; HI). Hemodynamics, blood chemistry, hematology, and coagulation function (ROTEM) were monitored to 4 hours postresuscitation. Histological and molecular analyses were obtained for liver, kidney, and lung.Compared with VitC animals, NS swine showed significant histological end-organ damage, elevated acute lung injury scores, and increased mRNA expression of tissue proinflammatory mediators (IL-1β, IL-8, TNFα), plasminogen activation inhibitor-1 and tissue factor. There were no statistically significant differences between treatment groups on mean arterial pressure or univariate measures of coagulation function; however, NS showed impaired multivariate clotting function at 4 hours.Although correction of coagulation dysfunction was modest, intravenous high-dose VitC may mitigate the proinflammatory/procoagulant response that contributes to multiple organ failure following acute severe multiple injuries.Prospective randomized controlled blinded trial study, Preclinical (animal-based).

In 2010, the NC3Rs published the Animal Research:Reporting of In Vivo Experiments (ARRIVE) guidelinesto improve the reporting of animal research. Despiteconsiderable levels of support from the scientific community,the impact on the quality of reporting in animal researchpublications has been limited. This position paper highlightsthe strategy of an expert working group established torevise the guidelines and facilitate their uptake. The group’sinitial work will focus on three main areas: prioritisationof the ARRIVE items into a tiered system, development ofan explanation and elaboration document, and revision ofspecific items.

Vasoplegia is a clinical syndrome marked by severe arteriolar vasodilatation, hypotension, and low systemic vascular resistance refractory to multiple vasopressor treatment. We report our experience with hydroxocobalamin (B12) infusion as a potential rescue adjunct for refractory vasoplegia during cardiopulmonary bypass (CPB). We performed a retrospective chart review of 33 patients undergoing cardiac surgery between 1 January 2013 and 31 December 2015, who were given intravenous B12 for refractory hypotension during, or immediately following, CPB. We assessed mean arterial pressure (MAP) responses using semi-parametric group-based models (trajectory analysis). Vasopressor use was evaluated by norepinephrine-equivalent rates calculated five minutes prior, and up to 60 min following, B12 administration. Patients were mostly male (82%), had a mean (SD) age of 53 (13) yr, and median (IQR) EuroSCORE mortality index of 9 [4-40]. Four patterns of MAP responses to B12 were identified. In Group 1 (“poor responders”) nine of 33 patients (27%) had the highest median [IQR] mortality risk (EuroSCORE 40 [4-52]), lowest mean pre-B12 MAP (50 mmHg), and minimal hemodynamic response in spite of continued vasopressor support. In contrast, Group 2 “responders” (8/33, 24%) showed a brisk MAP response (> 15 mmHg) to B12, sustained for > 60 min post-infusion, with 50% vasopressor reduction. Groups 3 and 4 had the lowest median mortality risk (EuroSCORE 8) and highest pre-B12 MAP (72 mmHg). Although Group 3 patients (“sustainers”; 9/33, 27%) showed a sustained MAP improvement, those in Group 4 (“rebounders”; 7/33, 21%) were characterized by hypertensive overshoot followed by a decrease in MAP. These data indicate considerable heterogeneity in patient response to B12, potentially dependent on both patient preoperative condition and non-standardized time of administration. B12 may provide a useful alternative therapy for refractory hypotension and vasoplegia, but controlled clinical trials to assess efficacy are needed.

Trauma is responsible for a large proportion of the world's burden of disease, and is by far the biggest killer of young adults. Hemorrhage is the leading cause of preventable death and its effects are directly correlated with the incidence multi-organ failure in survivors. Trauma research is challenging due to patient heterogeneity, limited randomized controlled trials, and in vitro studies that fail to mimic the systemic injury response. Preclinical research remains essential for mechanistic and therapeutic discovery. Yet modeling the multifaceted nature of traumatic injury poses important experimental and welfare challenges associated with the onset of injury and prehospital and intra-operative care, the limited inter-species validation of coagulation profiles, the use of anesthesia/analgesia, and its impact on the systemic response to trauma; and the challenge of sustaining intensive care in recovery models. Proper model selection depends on the purpose of a given model and the criteria by which the experimental readouts will be clinically relevant. Such complexity warrants further refinement of experimental methodology and outcome measures to improve its clinical efficacy, while ensuring animal well-being. We review the experimental methodologies currently used for modeling traumatic hemorrhagic shock and addressing their impact on clinical translation. The aim of the review is to improve transparency and form a consensus when reporting methodology in trauma modeling.

Clinicians have limited experience with assessment and treatment of overdose from newer anticonvulsant medications. The aim of this investigation was to evaluate clinical effects of newer anticonvulsant overdose, determine if a relationship exists between dose and clinical effect, and if a particular agent appears more toxic in overdose. This was a retrospective study using electronic poison center data, evaluating clinical outcomes from newer anticonvulsant overdose. The Toxicall™ database from January 1, 2002 to December 31, 2011 was queried using key words: "gabapentin," "lamotrigine," "levetiracetam," "tiagabine," "topiramate," "zonisamide," "pregabalin," and "oxcarbazine." Polypharmacy overdose and children less than 15 years of age were excluded. Charts were reviewed by two abstractors for pharmaceutical, self-reported dose, clinical effect score, and clinical signs, symptoms, and vital signs recorded in the chart. Ordinal logistic regression was used to evaluate the relationship between drug type, dose, age, and sex to clinical effect score. Out of 501 cases identified, 347 met the final inclusion criteria. There were 116 gabapentin, 67 lamotrigine, 15 levetiracetam, 15 tiagabine, 56 topiramate, 23 pregabalin, and 55 oxcarbazepine cases. Overdose of newer anticonvulsants frequently results in altered mental status. Seizures may be more common with tiagabine, lamotrigine, and oxcarbazepine. There was one death reported from intentional overdose of topiramate. An information index was created to rank drug toxicity based on reported signs and symptoms for each overdose. There was no significant effect of dose on severity of outcome (β = 0.12, p = 0.23). However, the risk of a more severe outcome score was significantly increased with tiagabine relative to other drugs (β = 2.8, p = 0.001). Lamotrigine ranked highest in terms of toxicity (HT = 1.66) and number of interventions performed (HI = 1.17), and levetiracetam the lowest (HT = 0.98; HI = 0.88). We could not identify a dose-effect in these data which likely reflects the limitations of self-reported doses. Despite limitations of these data, the risk of more severe outcome scores appear to be higher with tiagabine overdose while lamotrigine overdose appears to result in more reported signs, symptoms, and interventions.

Background Logistics complicate fluid resuscitation of traumatic shock on the battlefield. Traumatic shock can result in oxygen debt (O 2 D) accumulation that is fatal. However, the ability of fluid strategies to repay O 2 D are not commonly reported. This pilot study examined various resuscitation fluids, including a combination of PEGylated bovine hemoglobin and hypertonic saline (AfterShock™) on their ability to repay O 2 D in traumatic shock. Methods 41 anesthetized swine underwent hemorrhage to an O 2 D of 80mL/kg. Animals received one of the following: 500mL whole blood, 500mL AfterShock™, 500mL hypertonic (7.2%) saline, 250mL hypertonic (7.2%) saline, 500mL Hetastarch (6%), or 500mL lactated Ringer's. Oxygen transport variables (O 2 D, oxygen consumption, oxygen delivery, central venous hemoglobin oxygen saturation, oxygen extraction ratios), lactate clearance, and survival were monitored for 3h after treatment. Data were analyzed using mixed-model ANOVA and comparisons were made to the performance of whole blood. Results Only animals receiving AfterShock™, 500mL hypertonic saline, and 500mL Hetastarch survived to 180min. While not statistically significant AfterShock™ demonstrated trends in improving the repayment of O 2 D and in improving oxygen transport variables despite having lower levels of global oxygen delivery compared to whole blood, Hetastarch and 500mL hypertonic saline groups. Conclusion Use of 500mL AfterShock™, 500mL of 7.2% saline or 500mL of Hetastarch resulted in improved short-term survival. While not statistically significant, AfterShock™ demonstrated trends in improving O 2 D. These findings may have implications for designing resuscitation fluids for combat casualty care.

Exploratory pilot studies are crucial to best practice in research but are frequently conducted without a systematic method for maximizing the amount and quality of information obtained. We describe the use of response surface regression models and simultaneous optimization methods to develop a rat model of hemorrhagic shock in the context of chronic hypertension, a clinically relevant comorbidity. Response surface regression model was applied to determine optimal levels of two inputs--dietary NaCl concentration (0.49%, 4%, and 8%) and time on the diet (4, 6, 8 weeks)--to achieve clinically realistic and stable target measures of systolic blood pressure while simultaneously maximizing critical oxygen delivery (a measure of vulnerability to hemorrhagic shock) and body mass M. Simultaneous optimization of the three response variables was performed though a dimensionality reduction strategy involving calculation of a single aggregate measure, the "desirability" function. Optimal conditions for inducing systolic blood pressure of 208 mmHg, critical oxygen delivery of 4.03 mL/min, and M of 290 g were determined to be 4% [NaCl] for 5 weeks. Rats on the 8% diet did not survive past 7 weeks. Response surface regression model and simultaneous optimization method techniques are commonly used in process engineering but have found little application to date in animal pilot studies. These methods will ensure both the scientific and ethical integrity of experimental trials involving animals and provide powerful tools for the development of novel models of clinically interacting comorbidities with shock.

Identification of occult shock is a major clinical problem compounded by inadequate criteria for assessing the efficacy of fluid resuscitation. We suggest that these problems may be resolved in part by understanding both the physiological mechanisms underlying oxygen debt accumulation and, more importantly, the debt repayment schedule during resuscitation. We present a simplified tutorial that incorporates the concept of the oxygen supply-delivery relationship with that of oxygen debt and show how this is relevant to the understanding of shock and resuscitation. Use of oxygen debt metrics as end points for shock have been controversial; however, much of the controversy may have been due to incomplete understanding of basic physiology of shock and semantic confusion between the various metrics proposed as end points. Here, we provide working definitions for the frequently misunderstood concepts of oxygen deficit and oxygen debt and discuss the relatively novel concept of oxygen debt repayment schedule. We introduce predictions made on the basis of data derived from animal models of hemorrhagic shock. Our calculations suggest that the amount of debt repaid in the first 2 h of resuscitation, rather than the restoration of volume per se, influences the likelihood of organ damage. Because of difficulties inherent in measuring oxygen debt in the prehospital and emergency settings, various metabolic end points such as lactate and base deficit have been proposed as surrogates. We demonstrate the heuristic value of this model in providing a predictive framework for both the optimum therapeutic time window and optimum fluid loadings before critical transitions to an irreversible shock state can occur. The model also provides an unambiguous and objective standard for quantifying the behavior of various postulated shock "markers".

After severe hemorrhage, low-volume resuscitation with hypertonic fluids is increasingly preferred to more aggressive resuscitation strategies. Oxygen delivery to the tissues may be improved by augmentation with hemoglobin [Hb]-based oxygen-carrying compounds (HBOCs); however, previous studies have reported negative outcomes presumably related to extravasation of tetrameric Hb. The purpose of this study was to evaluate a novel large molecular weight polymer of cross-linked bovine Hb (OxyVita; OXYVITA Inc, New Windsor, NY) in a cocktail of hypertonic saline and Hextend (HX; HBOC-C) as an alternative to standard small-volume resuscitation using Hextend (HX) only. Outcomes were survival to 3 h and duration of MAP support more than 60 mmHg without additional fluid support. Conscious male Long-Evans rats were hemorrhaged to 60% total blood volume over 40 min. There were 4 groups: HBOC-C administered in a pressure-titrated infusion, HX titration, HBOC-C administered as a bolus, and HX bolus. Cardiovascular parameters, arterial gases, acid-base status, metabolites, electrolytes, Hb level, and oxygen saturation were measured at baseline, during each 20% hemorrhage increment, and 1, 2, and 3 h after the initiation of hemorrhage. Small-volume resuscitation with HBOC-C significantly improved survival to 3 h and improved MAP support times regardless of method of administration. However, physiological status at the end of hemorrhage significantly influenced survival regardless of resuscitation treatment. These results suggest that HBOC-augmented hypertonic cocktails are of promise in improving survival and providing target MAP support during small-volume resuscitation. Experimental evaluation of any resuscitation therapy should account for the degree of preexisting physiological compromise before therapy is initiated.

Pharmaceutically induced metabolic down-regulation may be a useful therapeutic adjunct when tissue oxygen supply is restricted. We hypothesized that protein synthesis inhibition in a non-hibernating species should lower oxygen demand, resulting in aerobic metabolic rate depression at the whole animal level. We compared metabolic responses and measures of systemic oxygenation of conscious catheterized rats given either protein synthesis inhibition (PSI) agents or carrier controls (normal saline and DMSO). Core temperature was measured by implanted transmitters, and VO2 was determined in an open flow-through metabolic chamber at 25 degrees C. Mean arterial pressure MAP and heart rate HR were determined from arterial pressure transducer tracings; arterial blood gases and lactate were sampled every 15 min. PSI rats exhibited an immediate transient decline in VO2, followed by a secondary decline to new resting levels; VO2 for the first hour was significantly lower than that for rats receiving DMSO vehicle. Unlike controls, PSI rats showed an overall 3.5 degrees C decline in core temperature, coupled with increased arterial lactate. There were no differences in MAP and HR of PSI rats compared to controls. Although hypothermic response to toxic agents typical of rodents cannot be ruled out completely, the mild hypothermia and reduced VO2 exhibited by PSI rats may be partially attributed to the action of protein synthesis agents.

Resonance Raman spectroscopy offers a mechanism for the noninvasive measurement of in vivo and in situ hemoglobin oxygen saturation (HbO(2)Sat) in living tissue. Clinically informative signals can be provided by resonance enhancement with deep violet excitation. It is notable that fluorescence does not significantly degrade the quality of the signals. During the controlled hemorrhage and resuscitation of rats, signal intensity ratios of oxy- vs. deoxyhemoglobin from sublingual mucosa correlated with co-oximetry values of blood withdrawn from a central venous catheter. The spectroscopic application described here has potential as a noninvasive method for the diagnosis of clinical shock and guidance of its therapy.

Current management of acute inhalational carbon monoxide (CO) toxicity includes hyperbaric or normobaric O2 therapy. However, efficacy has not been established. The purpose of this study was to establish therapeutic proof of concept for a novel injectable antidote consisting of the combination of hydroxocobalamin and ascorbic acid into a reduced form (B12r) as demonstrated by clinically significant increase (500 ppm) in CO2 production, reduced carboxyhemoglobin (COHgb) half-life (COHgb t1/2), and increased cerebral O2 delivery and attenuation of CO-induced microglial damage in a preclinical rodent model of CO toxicity.B12r-mediated conversion of CO to CO2 and COHgb t1/2 in human blood were measured by gas analysis and Raman resonance spectroscopy. Rats were exposed to either air or CO and then injected with saline or B12r. Cognitive assessment was tested in a Morris water maze. Brain oxygenation was measured with Licox. Brain histology was assessed by fluorescent antibody markers and cell counts.B12r resulted in significant CO2 production (1,170 ppm), compared with controls. COHgb t1/2 was reduced from 33 minutes (normal saline) to 17.5 (p0.001). In rat models, severe CO-induced brain hypoxia (PbtO2, 18 mm Hg) was followed by significant reduction in τ25 to 12 minutes for B12r rats versus 40 minutes for normal saline-treated rats (p0.0001). There was major attenuation of CO-induced microglial damage, although cognitive performance differences were minimal.Our preclinical data suggest that the novel synergism of hydroxocobalamin with ascorbic acid has the potential to extract CO through conversion to CO2, independently of high-flow or high-pressure O2. This resulted in a clinically significant off-gassing of CO2 at levels five to eight times greater than those of controls, a clinically significant reduction in COHgb half-life, and evidence of increased brain oxygenation and amelioration of myoglial damage in rat models. Reduced hydroxocobalamin has major potential as an injectable antidote for CO toxicity.

Severe traumatic injury and haemorrhagic shock are frequently associated with disruptions of coagulation function (such as trauma-induced coagulopathy TIC) and activation of inflammatory cascades. These pathologies may be exacerbated by current standard of care resuscitation protocols. Observational studies suggest early administration of plasma to severely-injured haemorrhaging patients may correct TIC, minimise inflammation, and improve survival. The proposed randomised clinical trial will evaluate the clinical effectiveness of pre-hospital plasma administration compared with standard- of-care crystalloid resuscitation in severely-injured patients with major traumatic haemorrhage. This is a prospective, randomized, open-label, non-blinded trial to determine the effect of pre-hospital administration of thawed plasma (TP) on mortality, morbidity, transfusion requirements, coagulation, and inflammatory response in severely-injured bleeding trauma patients. Two hundred and ten eligible adult trauma patients will be randomised to receive either two units of plasma, to be administered in-field, vs standard of care normal saline (NS). Main analyses will compare subjects allocated to TP to those allocated to NS, on an intention-to-treat basis. Primary outcome measure is all-cause 30-day mortality. Secondary outcome measures include coagulation and lipidomic/pro-inflammatory marker responses, volume of resuscitation fluids (crystalloid, colloid) and blood products administered, and major hospital outcomes (e.g. incidence of MSOF, length of ICU stay, length of hospital stay). This study is part of a US Department of Defense (DoD)-funded multi-institutional investigation, conducted independently of, but in parallel with, the University of Pittsburgh and University of Denver. Demonstration of significant reductions in mortality and coagulopathic/inflammatory-related morbidities as a result of pre-hospital plasma administration would be of considerable clinical importance for the management of haemorrhagic shock in both civilian and military populations. ClinicalTrials.gov: NCT02303964 on 28 November 2014

IntroductionThe newer cyanide antidote, hydroxocobalamin, due to its pigmentation, has been found to cause interferences in some laboratory assays. Co-oximetry may also be affected by hydroxocobalamin, leading to false elevations in hemoglobin concentration, methemoglobin, carboxyhemoglobin, and false decreases in oxyhemoglobin. The Masimo Radical-7 is a medical device that performs noninvasive oximetry and estimates hemoglobin (Hb) concentration and percent carboxyhemoglobin (COHb), methemoglobin (MetHb), and oxyhemoglobin saturation (O2Hb).Study ObjectivesThe study sought to determine the effect of hydroxocobalamin on noninvasive measurement of hemoglobin indices using the Masimo Radical-7 monitor.MethodsSeven asymptomatic volunteers who were unexposed to cyanide had baseline heart rate (HR), blood pressure (BP), and oximeter measurements recorded followed by an infusion of five grams of hydroxocobalamin over 15 minutes. The above parameters were subsequently recorded at: 5, 10, 15, 30 and 60 minutes post infusion. Data were analyzed by calculating the area under the curve (AUC) for each variable and comparing the results to expected values by pairedttests. Expected AUC values were calculated by extrapolating baseline values across the entire time period.ResultsThe mean differences from baseline values with 95% confidence intervals andttests of mean difference were: SBP: 11 mm Hg (95% CI, 0-22;P= .051); HR: -9 (95% CI, -15 to -3;P= .01); Hb: -0.1 (95% CI, -0.7 to 0.4;P= .57); O2Hb: 0 g/dL (95% CI, -1 to 1;P= .41); COHb: -1 (95% CI, -3 to 1;P= .25); MetHb: -0.2 (95% CI, -0.3 to 0;P= .03).DiscussionAfter infusion of hydroxocobalamin there was a significant elevation of systolic blood pressure and decrease in heart rate. There were no significant differences in Hb, O2Hb, and COHb. Although percent methemoglobin concentrations were statistically lower, the authors feel this difference is of trivial clinical significance.ConclusionThe administration of hydroxocobalamin does not significantly impact noninvasive oximetry.CashinB,MatlockA,KangC,ReynoldsP,WillsB.Effect of hydroxocobalamin on surface oximetry in nonexposed humans.Prehosp Disaster Med.2013;28(4):1-3.

Most duckling mortality occurs during the week following hatching and is often associated with cold, windy, wet weather and scattering of the brood. We estimated the thermoregulatory demands imposed by cold, windy weather on isolated 1-d-old mallard (Anas platyrhynchos) ducklings resting in cover. We measured O2 consumption and evaporative water loss at air temperatures from 5 degrees to 25 degrees C and wind speeds of 0.1, 0.2, 0.5, and 1.0 m/s. Metabolic heat production increased as wind increased or temperature decreased but was less sensitive to wind than that of either adult passerines or small mammals. Evaporative heat loss ranged from 5% to 17% of heat production. Evaporative heat loss and the ratio of evaporative heat loss to metabolic heat production was significantly lower in rest phase. These data were used to define a standard operative temperature (Tes) scale for night or heavy overcast conditions. An increase of wind speed from 0.1 to 1 m/s decreased Tes by 3 degrees -5 degrees C.

Current management strategies for hemorrhaging trauma patients recommend fluid resuscitation with relatively small or restricted fluid volumes. Because most recommended fluids are essentially plasma expanders with limited oxygen carrying capacity, hemoglobin [Hb]-based oxygen-carrying compounds (HBOCs) have been suggested as an adjunct to improve oxygen delivery to the tissues. We review evidence from clinical to animal trials as to the efficacy of three competing low volume fluid resuscitation strategies (LVFR), and the potential in this context for HBOCs as oxygen therapeutic adjuncts. Unfortunately data are too limited in quantity and quality to allow any reliable conclusions as to the efficacy and safety of HBOC-augmented LVFR. There is an imperative need for higher quality and adequately-powered animal trials and clinical randomized controlled trials to clarify the efficacy and safety of both LVFR and adjunct HBOCs for traumatic hemorrhage.

Knowledge of central venous pressure (CVP) is considered valuable in the assessment and treatment of various states of critical illness and injury. We tested a noninvasive means of determining CVP (NICVP) by monitoring upper arm blood flow changes in response to externally applied circumferential pressure to the upper arm veins. Thirty-six patients who were undergoing CVP monitoring as part of their care had NICVP determined and compared with CVP. Volume changes were measured in the upper arm using tetra-polar impedance plethysmography underneath a blood pressure cuff. The cuff was inflated over 5 s to a pressure greater than CVP but less than diastolic arterial pressure. After 45 to 60 s, the cuff was rapidly deflated. Noninvasive CVP was determined as the cuff pressure noted at the maximum derivative of the volume increase under the cuff during deflation. Noninvasive CVP was then compared with invasively measured CVP taken during the same period by Bland-Altman analysis. A total of 108 trials (three per subject) were performed on 36 patients. Mean bias was j0.26 mmHg (95% confidence interval (CI): j0.67, 0.15). Limits of agreement were j2.7 and 2.2 mmHg with the 95% CI for the lower limit of agreement (j3.4, j2.0 mmHg) and for the upper limit of agreement (1.5, 2.9 mmHg). Correlation between CVP and NICVP was 0.95 (95% CI: 0.93 to 0.97; P G 0.0001). Noninvasive CVP as determined in this study may be a clinically useful substitute for traditional CVP measurement and may offer a tool for early diagnosis and treatment of acute states in which knowledge of CVP would be helpful. KEYWORDS—Monitoring, catheter, critical illness, injury, volume assessment

Time profiles of arterial lactate concentrations have been proposed as markers for both the degree of physiological derangement during shock and effectiveness of clinical resuscitation, but have not been evaluated for use in short-term experimental protocols. We developed two quantitative mixed models of sequential arterial lactate concentrations to evaluate competing low-volume (

Objective: To evaluate resonance Raman spectroscopy for the detection of changes in sublingual mucosal hemoglobin oxygen saturation (Smo 2 ) in response to hemorrhage and resuscitation, and to compare Smo 2 with other indicators of tissue oxygenation including central venous oxygen saturation (Scvo 2 ), lactate, base excess, and shed blood volume. Design: Prospective single group pilot study. Setting: University laboratory. Subjects: Five Sprague-Dawley rats. Interventions: Animals were anesthetized and instrumented for measurement of arterial and central venous blood gases. Raman spectroscopy was performed using a krypton ion laser providing excitation at 406.7 nm (5 mW). A 1-mm 2 region of the sublingual tongue surface was chosen for investigation. Animals were subjected to stepwise hemorrhage until approximately 50% of the blood volume was removed. At each hemorrhage and resuscitation interval, Raman spectroscopy was performed and corresponding arterial and central venous blood gas and lactate measurements were made. Smo 2 was calculated as the ratio of the oxygenated heme spectral peak height to the sum of the oxy- and deoxyhemoglobin spectral peak heights. Raman spectroscopy-derived Smo 2 measurements were compared with Scvo 2 as well as with other indicators of oxygenation. Measurements and Main Results: The mean difference between Smo 2 and Scvo 2 for all paired measurements was 5.8 ± 11.7 absolute saturation points. Smo 2 was significantly (p < .0001) correlated with Scvo 2 (r =.80), lactate (r = -.78), base excess (r =.80), and shed blood volume (r = -.75). Smo 2 and Scvo 2 showed similar levels of precision for predicting elevated lactate and base deficit. Conclusions: These studies demonstrate the ability of Raman spectroscopy to noninvasively track microvascular hemoglobin oxygenation in tissue and favorably correlate with other important indicators of tissue oxygenation such as Scvo 2 , lactate, base deficit, and shed blood volume. The technique shows promise as a method to noninvasively monitor tissue oxygenation.

Heated taxidermic mounts are used to measure standard operative temperature, Tes ( C), a thermal index describing several aspects of the environment experienced by a particular animal (Gagge 1940; Bakken 1976, 1992; Bakken et al. 1981). Replicated mounts respond differently because of variation in construction (Larochelle 1998), natural insulation (Bakken et al. 1981), and pelt weathering (Wiersma and Piersma 1994). Calibration can minimize replication problems inherent in data from uncalibrated mounts (Bakken et al. 1981; Bakken 1992) but has not always been used (Walsberg and Wolf 1996). Mounts are calibrated by measuring both the heater power, P (W), of mounts and the net heat production, (W), M E of live animals in the same enclosure under the same conditions (Bakken et al. 1981). Mounts cannot generally make separate estimates of metabolic heat production, M, and evaporative heat loss, E. Calibration could be repeated for each replicate mount, but a less laborious procedure is to standardize individual mounts against a calibrated reference mount. Mounts can be standardized for air temperature and wind in a simple wind tunnel, as both fibrous insulation samples and mounts show a simple, monotonic response to these factors (Campbell et al. 1980; Bakken 1991). For solar radiation, side-by-side out