Pre-Trauma Center Management of Intracranial Pressure in Severe Pediatric Traumatic Brain Injury.

OBJECTIVES: Pre-trauma center care is a critical component in severe pediatric traumatic brain injury (TBI). For geographically large trauma catchment areas, optimizing increased intracranial pressure (ICP) management may potentially improve outcomes. This retrospective study examined ICP management in nontrauma centers and during interfacility transport to the trauma center. METHODS: Charts from a pediatric level I trauma center were reviewed for admissions between 2008 and 2013. Patients with a Glasgow Coma Scale score of 8 or less, head Abbreviated Injury Scale score of 3 or higher, and requiring intubation at a nontrauma center were included. Exclusion criteria included head injury secondary to drowning, stroke, obstetrical complications, asphyxia, and afflicted head trauma (younger than 5 years). Trauma center charts contained coalesced data from first responders, nontrauma centers, and transport. RESULTS: Twenty-five patients (74%) had increased ICP upon admission at trauma center, 48% experienced ICPs greater than 20 cm H2O within 12 hours of admission, 12% required an urgent craniotomy, and 16% had herniation syndromes on neuroimaging. Pre-trauma center ICP management included osmotherapy and head-of-bed elevation. Sixty-four percent of patients with increased ICP at trauma center admission received pre-trauma center ICP management. CONCLUSIONS: Early increased ICP is a common presentation of severe pediatric TBI during pre-trauma center management. However, what constitutes optimal care remains unknown. Given the difficulties of diagnosing early increased ICP in this setting, prophylactic raising ICP-lowering strategies may be considered.

USP14 inhibitor attenuates cerebral ischemia/reperfusion-induced neuronal injury in mice.

Stroke is associated with over-production of misfolded and aggregating proteins. However, it remains largely unclear whether enhanced removal of protein aggregates following ischemic stroke is neuroprotective. Deubiquitinating enzymes (DUBs) are a large group of proteases that regulate protein degradation. The ubiquitin-specific protease 14 (USP14) is a DUB that is associated with the proteasome and negatively regulates proteasome activity. In this study, we examined the effect of 1-[1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl]-2-pyrrolidin-1-ylethanone (IU1), a specific small molecule inhibitor of USP14, on mouse focal cerebral ischemic stroke-induced neuronal injury in mice. We found that IU1 treatment attenuated ischemic stroke-caused neuronal injury, which was reflected by increased survival rate, reduced infarct volume, as well as decreased neuronal loss in the IU1-treated mice compared to the control-treated mice. Additionally, IU1 treatment is associated with reduced protein aggregates and enhanced proteasome functionality. These data not only highlight the significance of protein homeostasis in cerebral ischemia/reperfusion-induced neuronal injury but also extend the therapeutic role of DUB inhibitors.

S.T.A.R.T.T. plus: addition of prehospital personnel to a national multidisciplinary crisis resource management trauma team training course.

SUMMARY: The Simulated Trauma and Resuscitation Team Training (S.T.A.R.T.T.) course is a unique multidisciplinary trauma team training course deliberately designed to address the common crisis resource management (CRM) skills of trauma team members. Moreover, the curriculum has been updated to also target the specific learning needs of individual participating professionals: physicians, nurses and respiratory therapists. This commentary outlines further modifications to the course curriculum in order to address the needs of a relatively undertargeted group: prehospital personnel (i.e., emergency medical services). Maintenance of high participant satisfaction, regardless of profession, suggests that the S.T.A.R.T.T. course can be readily modified to incorporate prehospital personnel without losing its utility or popularity.

Disposition of a single oral dose of a cannabidiol medication in healthy cats.

The historical use of the marijuana plant for medicinal purposes is long. One of the historical uses has been for the treatment of epilepsy. Recently, the Food and Drug Administration has approved a highly purified cannabidiol medication for the add on therapy in people with certain forms of epilepsy. With the increase interest of the use of cannabidiol in the veterinary community, the aim of this study was to describe the disposition of a single dose of a cannabidiol medication in healthy cats in both the fed and fasted state. Pharmacokinetic analysis reveals that relative bioavailability of cannabidiol shows a near eleven-fold increase when administered in the fed state compared to the fasted state. Additionally, concentrations achieved at a dose of 5 mg/kg, may be sufficient to explore the therapeutic potential in cats with epilepsy.

A descriptive analysis of the Canadian prehospital and transport transfusion (CAN-PATT) network.

Objective: Out-of-hospital blood transfusion (OHBT) is becoming increasingly common across the prehospital environment, yet there is significant variability in OHBT practices. The Canadian Prehospital and Transport Transfusion (CAN-PATT) network was established to collaborate, standardize, and evaluate the effectiveness of out-of-hospital blood transfusion (OHBT) across Canada. The objectives of this study are to describe the setting and organizational characteristics of CAN-PATT member organizations and to provide a cross-sectional examination of the current OHBT practices of CAN-PATT organizations. Methods: This was a cross-sectional examination of all six critical care transport organizations that are involved in CAN-PATT network. Surveys were sent to identified leads from each organization. The survey focused on three main areas of interest: 1) critical care transport organizational service and coverage, 2) provider, and crew configurations, and 3) OHBT transfusion practices. Results: All six surveys were completed and returned. There are a total of 30 critical care transport bases (19 rotor-wing, 20 fixed-wing and 6 land) across Canada and 11 bases have a blood-on-board program. Crew configurations very between organizations as either dual paramedic or paramedic/nurse teams. Median transport times range from 30 to 46 minutes for rotor-wing assets and 64 to 90 minutes for fixed-wing assets. Half of the CAN-PATT organizations started their out-of-hospital blood transfusion programs within the last three years. Most organizations carry at least two units of O-negative, K-negative red blood cells and some organizations also carry group A thawed plasma, fibrinogen concentrate and/or prothrombin complex concentrate. All organizations advocate for early administration of tranexamic acid for injured patients suspected of bleeding. All organizations return un-transfused blood components to their local transfusion medicine laboratory within a predefined timeframe to reduce wastage. Conclusions: Variations in OHBT practices were identified and we have suggested considerations for standardization of transfusion practices and patient care as it relates to OHBT. This standardization will also enable a robust means of data collection to study and optimize outcomes of patients receiving OHBT. A fulsome description of the participating organizations within CAN-PATT should enhance interpretation of future OHBT studies that will be conducted by this network.

Memory conformity and the perceived accuracy of self versus other.

Here, we demonstrate that the decision to conform to another person's memory involves a strategic trade-off that balances the accuracy of one's own memory against that of another person. We showed participants three household scenes, one for 30 s, one for 60 s, and one for 120 s. Half were told that they would encode each scene for half as long as their virtual partner, and half were told that they would encode each scene for twice as long as their virtual partner. On a subsequent two-alternative-forced choice (2AFC) memory test, the simulated answer of the partner (accurate, errant, or no response) was shown before participants responded. Conformity to the partner's responses was significantly enhanced for the 30-s versus the 60- and 120-s scenes. This pattern, however, was present only in the group who believed that they had encoded each scene for half as long as their partner, even though the short-duration scene had the lowest baseline 2AFC accuracy in both groups and was also subjectively rated as the least memorable by both groups. Our reliance on other people's memory is therefore dynamically and strategically adjusted according to knowledge of the conditions under which we and other people have acquired different memories.

Venoconstrictor responses to activation of bradykinin-sensitive pericardial afferents involve the region of the hypothalamic paraventricular nucleus.

Veins are important in the control of venous return, cardiac output, and cardiovascular homeostasis. However, the effector systems modulating venous function remain to be fully elucidated. We demonstrated that activation of bradykinin-sensitive pericardial afferents elicited systemic venoconstriction. The hypothalamic paraventricular nucleus (PVN) is an important site modulating autonomic outflow to the venous compartment. We tested the hypothesis that the PVN region is involved in the venoconstrictor response to pericardial injection of bradykinin. Rats were anesthetized with urethane/alpha chloralose and instrumented for recording arterial pressure, vena caval pressure, and mean circulatory filling pressure (MCFP), an index of venous tone. The rats were fitted with a pericardial catheter and PVN injector guide tubes. Mean arterial pressure (MAP), heart rate (HR), and MCFP responses to pericardial injection of bradykinin (1, 10 µg/kg) were recorded before and after PVN injection of omega conotoxin GVIA (200 ng/200 nl). Pericardial injection of saline produced no systematic effects on MAP, HR, or MCFP. In contrast, pericardial injection of bradykinin was associated with short latency increases in MAP (16 ± 4 to 18 ± 2 mm Hg) and MCFP 0.35 ± 0.19 to 1.01 ± 0.27 mm Hg. Heart rate responses to pericardial BK were highly variable, but HR was significantly increased (15 ± 9 bpm) at the higher BK dose. Conotoxin injection in the PVN region did not affect baseline values for these variables. However, injection of conotoxin into the area of the PVN largely attenuated the pressor (-1 ± 3 to 6 ± 3 mm Hg), MCFP (-0.19 ± 0.07 to 0.20 ± 0.18 mm Hg), and HR (4 ± 14 bpm) responses to pericardial bradykinin injection. We conclude that the PVN region is involved in the venoconstrictor responses to pericardial bradykinin injection.

Does the public think it is reasonable to wait for more evidence before funding innovative health technologies? The case of PET scanning in Ontario.

OBJECTIVES: Many innovative health technologies do not have a sufficient evidence-base to allow for adequate assessment of their benefits. Funders in several countries have been exploring arrangements that allow for temporary or partial coverage of these technologies, but only as part of a further evaluation. The public's support of arrangements that restrict access to innovative technology until sufficient evidence is available is crucial if these arrangements are going to remain viable. The project's other objective is to examine the lay public's views on a case in which patients' publicly funded access to an innovative health technology is being delayed until there is sufficient evidence to justify a coverage decision. The case considered is the Ontario (Canada) government's decision to restrict access to positron emission tomography (PET) scans until further evidence becomes available. METHODS: The case was deliberated on by twenty-six members of the Toronto Health Policy Citizens' Council, with a follow-up survey administered to individual council members. RESULTS: The majority of council members agreed that the approach taken by the government was reasonable and in the best interests of its citizens. The council did express concerns regarding certain aspects of the case, including about the length of time it is taking to obtain further evidence. CONCLUSIONS: Public support for arrangements that limit access to new technologies will likely vary depending on the details of the specific arrangement being proposed. Deliberative public dialogue can be effectively used to identify cases the general public is most likely to support.

Pharmacokinetics of a commercially available product and a compounded formulation of extended-release levetiracetam after oral administration of a single dose in cats.

OBJECTIVE: To compare pharmacokinetics of levetiracetam in serum and CSF of cats after oral administration of extended-release (ER) levetiracetam. ANIMALS: 9 healthy cats. PROCEDURES: Cats received 1 dose of a commercially available ER levetiracetam product (500 mg, PO). Thirteen blood and 10 CSF samples were collected over a 24-hour period for pharmacokinetic analysis. After 1 week, cats received 1 dose of a compounded ER levetiracetam formulation (500 mg, PO), and samples were obtained at the same times for analysis. RESULTS: CSF concentrations of levetiracetam closely paralleled serum concentrations. There were significant differences between the commercially available product and the compounded formulation for mean ± SD serum maximum concentration (Cmax; 126 ± 33 µg/mL and 169 ± 51 µg/mL, respectively), Cmax corrected for dose (0.83 ± 0.10 µg/mL/mg and 1.10 ± 0.28 µg/mL/mg, respectively), and time to Cmax (5.1 ± 1.6 hours and 3.1 ± 1.5 hours, respectively). Half-life for the commercially available product and compounded formulation of ER levetiracetam was 4.3 ± 2.0 hours and 5.0 ± 1.6 hours, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: The commercially available product and compounded formulation of ER levetiracetam both maintained concentrations in healthy cats 12 hours after oral administration that have been found to be therapeutic in humans (ie, 5 µg/mL). Results of this study supported dosing intervals of 12 hours, and potentially 24 hours, for oral administration of ER levetiracetam to cats. Monitoring of serum concentrations of levetiracetam can be used as an accurate representation of levetiracetam concentrations in CSF of cats.

Blood on board: The development of a prehospital blood transfusion program in a Canadian helicopter emergency medical service.

OBJECTIVE: Prehospital blood transfusion has been adopted by many civilian helicopter emergency medical services agencies, and early outcomes are positive. The Shock Trauma Air Rescue Society operates six bases in Western Canada and started a blood on board process in 2013 in Regina that has expanded to all bases. Two units of O negative packed red blood cells are carried on every mission. We describe the processes and standard work ensuring safe storage, administration, and stewardship of this important resource. METHODS: The packed red blood cells are stored in an inexpensive, reusable temperature controlled cooler at 1°C-6°C. Close collaboration with local transfusion services and adherence to Canadian transfusion standards contributes to safety and sustainability. RESULTS: From October 1, 2013 to October 10, 2017, the Shock Trauma Air Rescue Society administered blood to 431 patients. Of this total, 62.9% received blood carried on our aircraft. A total of 463 blood box units were administered, and the majority of patients (69.0%) received both units. Blood used in Calgary, Alberta was 100% traceable, and only 1.2% of total units dispensed was wasted. The vast majority of unused units were returned to circulation. CONCLUSION: We describe the process to set up and monitor a prehospital blood transfusion program. Our standard work and stewardship processes minimize wastage of blood while keeping it readily available for our critically ill and injured patients.

Castration reduces blood pressure and autonomic venous tone in male spontaneously hypertensive rats.

OBJECTIVE: The development of arterial hypertension is sexually dimorphic. Venous tone is elevated in the spontaneously hypertensive rat model of hypertension. This study tested the hypothesis that endogenous androgens exacerbate venous tone in the developmental stages of spontaneous hypertension. METHODS: Male spontaneously hypertensive rats (SHRs) were subjected to sham operation, castration or castration + testosterone treatment. Ten-week-old SHR rats were instrumented for the measurement of arterial and venous pressure. A balloon catheter was advanced into the right atrium. Mean circulatory filling pressure (MCFP), an index of venous tone, was calculated. Mean arterial pressure (MAP) and MCFP were recorded from conscious rats. Postsynaptic adrenergic responsiveness was assessed by constructing cumulative dose-response curves to norepinephrine (NE). Baseline values and responsiveness to NE were obtained before and after autonomic blockade. RESULTS: MAP and MCFP were significantly reduced in castrated (MAP, 130 +/- 4 mmHg; MCFP, 5.5 +/- 0.2 mmHg) versus sham-operated SHRs (MAP, 149 +/- 5 mmHg; MCFP, 6.7 +/- 0.3 mmHg) or castrated + testosterone-treated SHRs (MAP, 145 +/- 6 mmHg; MCFP, 7.1 +/- 0.4 mmHg). Ganglion blockade abolished these differences in MAP and MCFP. Infusion of NE caused dose-dependent increases in MAP and MCFP. The MAP responses in castrated SHRs were displaced to the right of those for sham and castrated + testosterone-treated SHRs. This was not evident in the venous circulation, where there were no marked differences in the NE dose-MCFP response curves. CONCLUSION: Accordingly we conclude that endogenous male sex steroids contribute to the elevated arterial and venous pressures observed in the SHR.

Effect of kennel noise on hearing in dogs.

OBJECTIVE: To evaluate the degree of noise to which kenneled dogs were exposed in 2 typical kennels and to determine whether a measurable change in hearing might have developed as a result of exposure to this noise. ANIMALS: 14 dogs temporarily housed in 2 kennel environments. PROCEDURES: Noise levels were measured for a 6-month period in one environment (veterinary technical college kennel) and for 3 months in another (animal shelter). Auditory brainstem response testing was performed on dogs in the veterinary kennel 48 hours and 3 and 6 months after arrival. Temporal changes in the lowest detectable response levels for wave V were analyzed. RESULTS: Acoustic analysis of the kennel environments revealed equivalent sound level values ranging between 100 and 108 dB sound pressure level for the 2 kennels. At the end of 6 months, all 14 dogs that underwent hearing tests had a measured change in hearing. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the noise assessments indicated levels that are damaging to the human auditory system. Such levels could be considered dangerous for kenneled dogs as well, particularly given the demonstrated hearing loss in dogs housed in the veterinary kennel for a prolonged period. Noise abatement strategies should be a standard part of kennel design and operation when such kennels are intended for long-term housing of dogs.

Understanding the cardiovascular actions of soy isoflavones: potential novel targets for antihypertensive drug development.

Interest in and use of "natural" remedies has grown exponentially in recent years. Compounds that have attracted considerable attention are the isoflavones, particular those found in soy. This review will provide a critical evaluation of our current understanding of the effects, mechanisms of action, and potential clinical applications of soy isoflavones in hypertension. Current data indicate that soy isoflavones, such as genistein and daidzein and equol, relax vascular smooth muscle both in vitro and in vivo via a combination of mechanisms including potentiation of endothelial-dependent and endothelial-independent vasodilator systems and inhibition of constrictor mechanisms. These effects involve both classical genomic as well non genomic actions. Isoflavone actions are mediated in part via interactions with estrogen receptors where soy isoflavones induce unique receptor conformations and exert tissue dependent effects similar to the selective estrogen receptor modulators. Signaling pathways such as ERK1/2, PI3-Kinase/Akt and cAMP contribute to isoflavone isoflavone activation of eNOS in the vasculature as well. Isoflavones also target the kidney to increase renal blood flow and sodium excretion. Finally, soy isoflavones interact with humoral systems such as the renin angiotensin. Data from animal studies show consistently that the aggregate effect of these actions is attenuation of hypertension. In contrast, studies in humans remain controversial. Recent data also suggest that analogues of isoflavones may possess unique vascular actions. Thus significant opportunity remains for study of the effects and mechanisms of action of soy isoflavones on hypertension in both animals and humans.

A strategy to improve priority setting in health care institutions.

Priority setting (also known as resource allocation or rationing) occurs at every level of every health system and is one of the most significant health care policy questions of the 21st century. Because it is so prevalent and context specific, improving priority setting in a health system entails improving it in the institutions that constitute the system. But, how should this be done? Normative approaches are necessary because they help identify key values that clarify policy choices, but insufficient because different approaches lead to different conclusions and there is no consensus about which ones are correct, and they are too abstract to be directly used in actual decision making. Empirical approaches are necessary because they help to identify what is being done and what can be done, but are insufficient because they cannot identify what should be done. Moreover, to be really helpful, an improvement strategy must utilize rigorous research methods that are able to analyze and capture experience so that past problems are corrected and lessons can be shared with others. Therefore, a constructive, practical and accessible improvement strategy must be research-based and combine both normative and empirical methods. In this paper we propose a research-based improvement strategy that involves combining three linked methods: case study research to describe priority setting; interdisciplinary research to evaluate the description using an ethical framework; and action research to improve priority setting. This describe-evaluate-improve strategy is a generalizable method that can be used in different health care institutions to improve priority setting in that context.