Occam's Razor and Prehospital Documentation: When the Simpler Solution Resulted in Better Documentation.

INTRODUCTION: The Tactical Combat Casualty Care (TCCC) card has undergone several changes since its first introduction in 1996. In 2013, updates to the card included more data points to increase prehospital documentation quality and enable performance improvement. This study reviews the proportions of data collected before and after the implementation of the new TCCC card. METHODS: This is a secondary analysis of a previously described dataset from the Department of Defense Trauma Registry (DODTR) focused on prehospital medical care. In this sub-analysis, we defined the pre-implementation period as 2009-2013 followed by a 1-year run-in with the post-implementation period as 2015-2019. Our primary outcome was documentation of a pulse rate and our secondary outcomes included documentation of other vital signs. We used multivariable logistic regression models to adjust for confounders. RESULTS: There were 18,182 encounters that met inclusion for this analysis-14,711 before and 3,471 after the update. Across all vital signs, there was a peak around 2012-2013 with a drop noted in 2015. Comparing the preimplementation and post-implementation groups, there were higher proportions with documentation of a pulse rate (62% versus 49%), respirations (51% versus 45%), systolic pressure (53% versus 46%), diastolic pressure (49% versus 41%), oxygen saturation (55% versus 46%), and pain score (27% versus 19%, all p is less than 0.001) in the pre-implementation group. When adjusting for injury severity score (ISS), casualty category, and year of injury, the odds ratio of documentation of a pulse after implementation was 0.01 (95% CI: 0.00-0.01). When adjusting for ISS and casualty category, the odds ratio was 0.64 (95% CI: 0.60-0.70). When adjusting for ISS only, the odds ratio was 0.58 (95% CI: 0.54-0.63). CONCLUSIONS: Implementation of the new TCCC card resulted in overall lower documentation proportions which persisted after adjusting for measurable confounders.

Scopolamine Toxicity in an Elderly Patient.

We present a case of a 66-year-old female who was to undergo a scheduled operation and placed on our institution's ERAS (Enhanced Recovery After Surgery) protocol. The intraoperative course was unremarkable. The patient developed delayed emergence in the Post-Anesthesia Care Unit. On physical exam, the patient was noted to have a transdermal scopolamine patch adjacent to an area of skin breakdown. She also displayed signs of central anti-cholinergic toxicity including mydriasis and tachycardia. Following removal of the scopolamine patch and administration of physostigmine, her mental status returned to baseline. This interesting case highlights the importance of considering patient specific factors such as age when implementing ERAS protocols perioperatively. It also demonstrates the risks associated with scopolamine and the importance of risk/benefit analysis prior to administration.

AGGRESSIVE ENACTMENTS: CONTAINING THE "NO" IN CLINICAL WORK WITH SURVIVORS OF ABUSE.

Identity development depends on the ability to say 'no.' Setting limits enables a relationship between two separate individuals to develop. Early trauma can leave the individual so vigilant to others' demands that internal prohibitions against intrusion remain silenced, which we conceptualize as a 'no' that could not be sufficiently articulated to keep the person safe. For those who have not been able to assert this fundamental limit, the consulting room provides a potential anchoring point to formulate and work through unconscious meanings. Being able to articulate and register the legitimacy of one's own no becomes an important challenge, as tensions regarding power and powerlessness, trust and distrust, are acted out within the consulting room. Case material illustrates how psychoanalytic ideas regarding transference, countertransference, and enactment help the clinician tolerate the intrusion of past into present, inviting the type of mentalization that moves towards repair rather than merely reenacting the trauma.

Mandated wrapping of airway cart instruments: Limited access without the intended safety benefits.

OBJECTIVES/HYPOTHESIS: Isolated case studies have shown improper sterilization or contamination of equipment from anesthesia carts can lead to transmission of disease and even death. Citing this literature, national accrediting agencies mandated all instruments in the otolaryngology airway carts at San Antonio Military Medical Center be packaged to prevent contamination. This study sought to determine the infection and safety implications of packaged airway cart instruments. STUDY DESIGN: Retrospective chart review. METHODS: A review of upper aerodigestive tract procedures, some of which penetrated mucosa, was performed by analyzing 100 patient records during the unpackaged period and 100 during the packaged period. A comparison of infections, deaths, and length of stay in the hospital was included in the analysis. Additionally, a timed simulation to setup a simple group of instruments for an emergency airway situation from both the unpackaged and packaged airway carts was performed using a total of 11 surgical technologists and nurses. RESULTS: Each group had a total of four airway infections and neither had any deaths. The average length of hospital stay was 0.36 days for the unpackaged period and 0.44 days from the packaged period. None of these variables reached statistical significance. The average time to find and set out the correct instruments for the two groups was 46.6 and 95.5 seconds for the unpackaged and packaged airway carts, respectively (P = .004). CONCLUSIONS: This study suggests individually packaging of instruments used for emergency airway cases may put lives at risk when time matters and fails to decrease the risk of infection. LEVEL OF EVIDENCE: 3 Laryngoscope, 129:715-719, 2019.

Regional Anesthesia in the Setting of Arm Replantation: A Case Report.

The perioperative implementation of continuous peripheral nerve blocks is poorly described within the literature for replantation surgeries beyond digital replantation. The management of replantation patients presents a challenging balance between pain control and limb perfusion. We report the successful use of a continuous interscalene catheter in a therapeutically anticoagulated patient after midshaft humerus arm replantation. The benefits of the continuous peripheral nerve block for the patient included improved pain control and potentially improved limb perfusion making it a valuable component of this patient's treatment.

Intraoperative Endotracheal Cuff Pressure Study: How Education and Availability of Manometers Help Guide Safer Pressures.

INTRODUCTION: Endotracheal intubation is a medical procedure that is often indicated in both the perioperative and critical care environments. Cuffed endotracheal tubes (ETT) allow for safer and more efficient delivery of positive pressure ventilation, as well as create a barrier to reduce the risk of micro-aspiration and anesthetic pollution in the operating room environment. Over-inflation of the endotracheal cuff can lead to serious and harmful sequelae. This study aimed to assess if departmental education paired with ready access to a manometer to assess cuff pressure would result in an improvement in the proportion of ETT cuff pressures in the goal range. MATERIALS AND METHODS: A quality improvement study was conducted at the San Antonio Military Medical Center (SAMMC; Department of Defense hospital in San Antonio, TX). The initiative was divided into three key periods: pre-implementation, implementation, and post-implementation. During the pre-implementation period, ETT cuff pressures were obtained to assess the baseline state of ETT cuff pressures for patients in the operating room; the proportion of in-range (20-30 cmH2O) pressures was calculated. During the implementation phase, operating rooms were equipped with manometers and anesthesia departmental education was performed regarding the use of the manometers. Three months later, post-implementation cuff pressures were measured in the OR, and the proportion of in-range pressures was again calculated. RESULTS: The pre-implementation data showed an average cuff pressure of 48.92 cmH2O and a median of 38.5 cmH2O. Of the 100 pre-implementation pressures, 20 were in the goal range. Post-implementation data had an average cuff pressure of 41.96 cmH2O and a median of 30 cmH2O. A chi-squared test of pressures in the safe range from the pre-implementation versus post-implementation values yielded a highly significant p-value of 0.0003. CONCLUSION: The data from this study clearly demonstrated a statistically significant improvement in the proportion of in-range cuff pressures following the quality improvement initiative. This study supports the use of department-wide education and the availability of manometers in each OR to yield safer cuff pressures for intubated patients. This study did not aim to determine an optimal ETT cuff pressure, but utilized data already available to determine a safe cuff pressure. Further research needs to be performed to assess whether routine monitoring of cuff pressure results in improved patient outcomes.

miR-208a as a biomarker of isoproterenol-induced cardiac injury in Sod2+/- and C57BL/6J wild-type mice.

This investigation examined microRNA-208a (miR-208a) as a potential biomarker of isoproterenol (ISO)-induced cardiac injury in superoxide dismutase-2 (Sod2(+/-) ) and the wild-type mice, and the potential sensitivity of Sod2(+/-) mice to ISO-induced toxicity. A single intraperitoneal injection of ISO was administered to age-matched wild-type and Sod2(+/-) mice at 0, 80, or 160 mg/kg. Plasma miR-208a, cardiac troponin I (cTnI), and ISO systemic exposure were measured at various time points postdose. Hearts were collected for histopathology examination and for tissue expression of miR-208a and myosin heavy chain 7. ISO administration caused increases in cTnI and miR-208a plasma levels that correlated with myocardial damage; however, the magnitude of increase differed according to the types of mice. At similar ISO systemic exposure, the magnitude of cTnI was greater in wild-type mice compared to Sod2(+/) (-) mice; however, the magnitude of miR-208a was greater in Sod2(+/-) mice than that of the wild-type mice. Myocardial degeneration occurred at ≥3 hr in the wild-type and ≥6 hr in Sod2(+/) (-) mice. At ≥24 hr after ISO administration, miR-208a appeared superior to cTnI in indicating myocardial injury in both wild-type and Sod2(+/-) mice. Sod2(+/-) mice were not more sensitive than wild-type mice to ISO-induced toxicity.

Myeloperoxidase-mediated bioactivation of 5-hydroxythiabendazole: a possible mechanism of thiabendazole toxicity.

Thiabendazole (TBZ), an antihelminthic and antifungal agent, is associated with a host of adverse effects including nephrotoxicity, hepatotoxicity, and teratogenicity. Bioactivation of the primary metabolite of TBZ, 5-hydroxythiabendazole, has been proposed to yield a reactive intermediate. Here we show that this reactive intermediate can be catalyzed by myeloperoxidase (MPO), a neutrophil-bourne peroxidase. Using a cell viability endpoint, we examined the toxicity of TBZ, 5OH-TBZ, and MPO-generated metabolites in cell-based models including primary rat proximal tubule epithelial cells, NRK-52E rat proximal tubule cells, and H9C2 rat myocardial cells. Timecourse experiments with MPO showed complete turnover of 5OH-TBZ within 15 min and a dramatic leftward shift in dose-response curves after 12h. After a 24h exposure in vitro, the LC(50) of this reactive intermediate was 23.3 ± 0.2 µM reduced from greater than 200 µM from 5OH-TBZ alone, an approximately 10-fold decrease. LC(50) values were equal in all cell types used. Comparison of lactate dehydrogenase leakage and caspase 3/7 activity revealed that cell death caused by the reactive intermediate is primarily associated with necrosis rather than apoptosis. This toxicity can be completely rescued via incubation with rutin, an inhibitor of MPO. These results suggest that MPO-mediated biotransformation of 5OH-TBZ yields a reactive intermediate which may play a role in TBZ-induced toxicity.

Peripheral white blood cell toxicity induced by broad spectrum cyclin-dependent kinase inhibitors.

Cyclin-dependent kinases (CDKs) have been pursued for more than a decade for the treatment of cancer. CDK inhibitors are expected to slow the rate of cell division and potentially increase the apoptotic fraction of rapidly dividing cells. Although CDK activity is often increased in tumors, normal dividing tissues are also susceptible to the cytostatic and cytotoxic effects of CDK inhibitor action. Therefore the typical toxicity profile associated with cytotoxic anti-cancer therapy, bone marrow suppression and gastrointestinal toxicity, is expected with CDK inhibitors. Bone marrow toxicity and the ensuing delayed peripheral leukocyte suppression often limit the therapeutic application of cytotoxic anticancer drugs. Here we characterize an unusual bone marrow-independent acute toxicity toward leukocytes from broad spectrum CDK inhibitors in monkeys and rodents. The potential combination of both acute and delayed immunosuppression would likely further restrict the application of these particular compounds. Since the cells targeted were non-proliferating, it was assumed that the toxicity was not driven by the intended pharmacological mechanism thereby facilitating the development of a testing strategy to identify compounds with a reduced potential for acute leukocyte toxicity. This testing strategy resulted in a CDK inhibitor void of bone marrow-independent leukocyte toxicity that is currently undergoing clinical testing.

Inhibiting matrix metalloproteinases with prinomastat produces abnormalities in fetal growth and development in rats.

BACKGROUND: Matrix metalloproteinases (MMPs) play key roles in remodeling of the extracellular matrix during embryogenesis and fetal development. The objective of this study was to determine the effects of prinomastat, a potent selective MMP inhibitor, on fetal growth and development. METHODS: Prinomastat (25, 100, 250 mg/kg/day, p.o.) was administered to pregnant female Sprague-Dawley rats on gestational days (GD) 6-17. A Cesarian section was carried out on GD 20 and the fetuses were evaluated for viability and skeletal and soft tissue abnormalities. RESULTS: Prinomastat treatment at the 250 mg/kg/day dose produced a decrease in body weight and food consumption in the dams. A dose-dependent increase in post-implantation loss was observed in the 100 and 250 mg/kg/day-dose groups, resulting in only 22% of the dams having viable litters for evaluation at the 250 mg/kg/day dose. Fetal skeletal tissue variations and malformations were present in all prinomastat treated groups and their frequency increased with dose. Variations and malformation in fetal soft tissue were also increased at the 100 and 250 mg/kg/day doses. Prinomastat also interfered with fetal growth of rat embryo cultures in vitro. CONCLUSIONS: These data confirm that MMP inhibition has a profound effect on fetal growth and development in vivo and in vitro.

Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes.

Mitochondrial dysfunction is a common mechanism of drug-induced toxicity. Early identification of new chemical entities (NCEs) that perturb mitochondrial function is of significant importance to avoid attrition in later stages of drug development. One of the most informative ways of assessing mitochondrial dysfunction is by measuring mitochondrial oxygen consumption. However, the conventional polarographic method of measuring oxygen consumption is not amenable to high sample throughput or automation. We present an alternative, low-bulk, high-throughput approach to the analysis of isolated-mitochondrial oxygen consumption using luminescent oxygen-sensitive probes. These probes are dispensable and are analyzed in standard microtitre plates on a fluorescence plate reader. Respiratory substrate and adenosine diphosphate (ADP) dependencies of mitochondrial oxygen consumption were assessed using the fluorescence-based method, and results compared favourably to conventional polarographic analysis. To assess assay performance, the method was then applied to the analysis of a panel of classical modulators of oxidative phosphorylation. The effect of uncoupler concentration was analyzed in detail to identify factors which would be important in applying this method to large scale NCE screening and mechanistic investigations. Results demonstrate that the 96-well format can accommodate up to approximately 200 compounds/day at a single concentration or alternatively IC(50) values can be generated for approximately 25 compounds. Throughput may be increased by moving to a 384-well plate format.

Assessment of hepatocytes and liver slices as in vitro test systems to predict in vivo gene expression.

The use of in vitro systems to predict in vivo responses to chemical agents provides the benefits of requiring fewer animals, reducing variability between samples, requiring less test material, and enabling higher throughput. In the present study rat tissue slices and primary hepatocytes were compared as in vitro systems to predict in vivo changes in gene expression in response to treatment with known liver toxicants or inducers. Five compounds (phenobarbital, carbon tetrachloride, Wy-14,634, alpha-napthylisothiocyanate, and tacrine) were chosen for their established and diverse mechanisms of hepatoxicity or microsomal induction. Expression profiles from male Sprague-Dawley rats or in vitro systems treated for 24 h were measured by DNA oligonucleotide microarrays containing 8700 probe sets. Qualitative comparison of expression revealed a >80% concordance between in vivo liver and both in vitro systems; however, the responsiveness of both in vitro systems to compound-induced changes in gene expression was far less than that of in vivo. Furthermore, both in vitro systems appeared similar in their ability to reproduce compound-induced changes in gene expression observed in vivo.

Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project.

The role that metabonomics has in the evaluation of xenobiotic toxicity studies is presented here together with a brief summary of published studies. To provide a comprehensive assessment of this approach, the Consortium for Metabonomic Toxicology (COMET) has been formed between six pharmaceutical companies and Imperial College of Science, Technology and Medicine (IC), London, UK. The objective of this group is to define methodologies and to apply metabonomic data generated using (1)H NMR spectroscopy of urine and blood serum for preclinical toxicological screening of candidate drugs. This is being achieved by generating databases of results for a wide range of model toxins which serve as the raw material for computer-based expert systems for toxicity prediction. The project progress on the generation of comprehensive metabonomic databases and multivariate statistical models for prediction of toxicity, initially for liver and kidney toxicity in the rat and mouse, is reported. Additionally, both the analytical and biological variation which might arise through the use of metabonomics has been evaluated. An evaluation of intersite NMR analytical reproducibility has revealed a high degree of robustness. Second, a detailed comparison has been made of the ability of the six companies to provide consistent urine and serum samples using a study of the toxicity of hydrazine at two doses in the male rat, this study showing a high degree of consistency between samples from the various companies in terms of spectral patterns and biochemical composition. Differences between samples from the various companies were small compared to the biochemical effects of the toxin. A metabonomic model has been constructed for urine from control rats, enabling identification of outlier samples and the metabolic reasons for the deviation. Building on this success, and with the completion of studies on approximately 80 model toxins, first expert systems for prediction of liver and kidney toxicity have been generated.