Major Trauma Audit Report focussed on older adults 2017-2021

This report from the Major Trauma Audit (MTA) is focused on older adults, defined as those aged 65 years and over, with major trauma injuries. It will explore an in-depth analysis of 11,145 episodes of care between 2017 and 2021.  The MTA is a clinically led audit established by the National Office of Clinical Audit (NOCA) in 2013. It focuses on the care of the more severely injured trauma patients in Ireland’s healthcare system. In 2016, the MTA became the first national clinical audit endorsed by the National Clinical Effectiveness Committee (NCEC) and mandated by the Minister for Health. The methodological approach for the MTA was provided by the Trauma Audit and Research Network (TARN), which was based in the University of Manchester, United Kingdom until March 2024. Due to a cyberattack on the University of Manchester in July 2023, the TARN audit ceased data entry for 10 months and has now been migrated onto the National Health Service (NHS) England’s Outcomes and Registries Programme with the new title of National Major Trauma Registry (NMTR). Data entry will recommence from during 2024.  Twenty-six eligible hospitals have been participating in the MTA, and data have been collected on more than 35,000 patients. While the system was offline due to the cyberattack, data collection continued at hospital level on paper, and this data will be uploaded to the system during 2024. As there were no new data forthcoming, the MTA Governance Committee decided a focused report on older adults (aged 65 years and over) during 2017–2021 would be important. This was also in keeping with the aims and objectives of the audit: “To promote the use of the data for reflective clinical practice”.  The focus of this report is timely due to the publication of the Trauma System Implementation Programme Clinical Guidance Document: Management of Major Trauma in Older Adults (HSE, 2024) from the National Office for Trauma Services, Health Service Executive. The guidance describes 12 core evidence-based principles which all healthcare workers should implement when managing major trauma in older adults. Throughout the data chapters in this report, some of the relevant core principles are highlighted alongside the MTA data. It is important to reflect on how our system is performing against these core principles.  Older adults are the fastest-growing cohort of major trauma patients. In addition to having major trauma injuries, many older adults included in this report have additional comorbidities that make managing a major trauma more challenging. As the reconfiguration of the trauma system is under way in Ireland following the publication of A Trauma System for Ireland: Report of the Trauma Steering Group (Department of Health, 2018), details about subgroups of the major trauma population are essential for service planning. It is vital that services are age attuned for older adult patients to ensure they receive the right care and rehabilitation for their injuries. The loss of function and independence for older people is at jeopardy if the health service does not get this right.  Data from previous MTA reports (NOCA, 2022; NOCA, 2023b) have shown that older adults with major trauma are less likely to be recognised as having major injuries and therefore less likely to be pre-alerted, received by a trauma team or have an early assessment and management by a senior clinician than those aged 0–64 years. Outcomes for older adults with major trauma are also poorer than for their younger counterparts.  This report includes data from the 26 participating hospitals. Unless otherwise specified, the term ‘older adult’ will be defined throughout this report as those aged 65 years and over, and the younger major trauma cohort as those aged 0–64 years.  As has been stated in previous reports, the leading cause of major trauma is from low falls. Findings from this report will extend the understanding of the range of injuries associated with such incidents in an older adult population.  Opportunities for injury prevention and safety awareness have been highlighted in previous reports. A multifaceted, multi-agency approach to falls prevention is required at the population level in a similar way to the Road Safety Authority campaign to improve road safety. It is hoped that the data from this and previous reports will continue to inform the need for better safety measures in our homes, which are the most common setting of incidents causing injury. Some materials are already available on the NOCA website, including a home safety infographic, and a home safety checklist.  Each hospital is encouraged to use MTA reports for continuous quality improvement. Without the constant leadership provided by the hospital clinical leads for the MTA and the dedication and hard work of the audit coordinators, this audit would not be possible. The NOCA Executive Team and the MTA Governance Committee wish to thank the clinical leads, audit coordinators and staff in the participating hospitals for their continued commitment to and engagement with this audit. </p

Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release

<div><p>Human genetic studies show that the voltage gated sodium channel 1.7 (Na_v1.7) is a key molecular determinant of pain sensation. However, defining the Na_v1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Na_v1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Na_v1.7’s role in nociceptor physiology. We report that Na_v1.7 is the predominant functional TTX-sensitive Na_v in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Na_v1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Na_v1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.</p></div

Potency of PF-05089771 across hNa_v1.7 splice variants.

<p>Potency of PF-05089771 across hNa_v1.7 splice variants.</p

PF-05198007 reduces the capsaicin flare response in WT, but not Na_v1.7^Nav1.8Cre mice.

<p>A, B.Time-course plots showing the effects of PF-05198007 on skin blood flow measured before and after topical capsaicin application for WT (A) and Nav1.7^Nav1.8Cre (B) mice (for each genotype, n = 8 per group). C, D. Corresponding summary bar graphs showing flare response measured as area under the curve for WT (C) and Nav1.7^Nav1.8Cre (D) mice before and after PF-05198007 treatment. 1 mg/kg and 10 mg/kg PF-05198007 significantly reduced capsaicin-induced flare in WT mice (C, both 1 mg/kg and 10 mg/kg, p < 0.01, ANOVA) but had no effect in Na_v1.7^Nav1.8Cre mice (D, both 1 mg/kg and 10 mg/kg, p > 0.05, ANOVA).</p

Evidence for functional Na_v1.7 in human DRG neurons.

<p>A. Representative TTX-S current traces (recorded in the presence of 1 μM A-803467 and following graded voltage steps from -110 mV to 10 mV. B. Voltage dependence of activation (red, n = 4 for each voltage) generated from the protocol described in A and steady state fast inactivation (blue) generated by conditioning 500 msec prepulses to voltages between -110 mV and +10 mV followed by a test pulse to 0 mV from a holding potential of -110 mV (n = 4 for each voltage). Both datasets are fitted with Boltzmann functions. C. Representative timecourse relationship for peak TTX-S current following the application of 100 nM PF-05089771 and 500 nM TTX. D. Concentration-response relationship for PF-05089771 block of TTX-S current (IC₅₀, slope: 8.4 nM, 1.1; n = 3–6 per concentration) E. Example voltage traces from a current clamp recording. Single action potentials were evoked by a 20 ms suprathreshold current step at 0.1 Hz. The scale bar refers to the voltage traces whereas the start-to-start interval is 10 s. F. Summary pie charts showing that the application of 30 and 100 nM PF-05089771 resulted in action potential block in 3/7 and 5/8 DRG neurons respectively.</p

Na_v1.7 is the major TTX-sensitive Na_v channel in small diameter mDRG neurons.

<p>A. RNASeq analysis of Na_v channel mRNA from pooled small diameter mouse DRG neurons. B. Structure of PF-05198007 (4-(2-(3-amino-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide C. Patch clamp data showing concentration-response relationship for PF-05198007 assessed against recombinantly expressed mouse Na_v1.7, Na_v1.6 and Na_v1.1 (IC₅₀, Slope: 5.2 nM, 1.1; 149 nM, 1.5; 174 nM, 0.7 respectively; n = 3–4 per concentration). D. Representative patch clamp current traces of peak sodium current from small diameter mouse DRG neurons in the presence of A-803467 and following concurrent application of PF-05198007 and TTX. E. Representative peak TTX-S current <i>vs</i> time plot before and after 30 nM PF-05198007 and 500 nM TTX. G. Scatter plot of cell capacitance <i>vs</i> Na_v1.7/TTX-S ratio (n = 35). Note that in every cell tested, Na_v1.7 provided the predominant TTX-S sodium conductance.</p

PF-05089771 is a potent, state-dependent and selective inhibitor of Na_v1.7.

<p>A. Structure of PF-05089771 (4-(2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy)-5-chloro-2-fluoro-N-(thiazol-4-yl)benzenesulfonamide) B. Representative PatchXpress current recordings illustrating the near-complete block following 300 nM PF-05089771 application to half-inactivated WT hNa_v1.7 channels (97% ± 3%, n = 10) which was partially reversed following a 5 min washout duration. In contrast there was minimal block following application of 300 nM PF-05089771 to resting WT hNa_v1.7 channels (5% ± 3%, n = 4). Inset: PatchXpress voltage protocols for half-inactivation (upper) and resting state (lower). For a full description of the voltage protocols see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152405#sec002" target="_blank">Methods</a>. C. Block of half-inactivated WT hNa_v1.7 channels (n = 6–22 per concentration) was nearly 1000-fold more potent than resting channels (n = 4–11 per concentration) (11 nM <i>vs</i> 10 μM). D. Potency of PF-05089771 was similar across hNa_v1.7 splice variants. IC₅₀ values and Hill slopes are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152405#pone.0152405.t001" target="_blank">Table 1</a>. Data points represent n = 2–9 observations per concentration. E. PF-05089771 activity is impacted by mutation of a novel interaction site and not by local anaesthetic or toxin binding sites. Data points represent n = 3–6 observations per concentration except for hNa_v1.7 where n = 6–22 observations per concentration. F. Potency of PF-05089771 was assessed on orthologous channels cloned from common preclinical species. IC₅₀ values and Hill slopes are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152405#pone.0152405.t002" target="_blank">Table 2</a>. Data points represent n = 2–28 observations per concentration. G. PF-05089771 is a selective Na_v1.7 subtype-selective inhibitor. Selectivity was assessed across a collection of heterologously expressed human Na_vs on PatchXpress at the unique half inactivation voltage for each channel. Hill slopes and IC₅₀ values are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152405#pone.0152405.t003" target="_blank">Table 3</a>. Data points represent n = 3–12 observations per concentration except for hNa_v1.7 where n = 6–22 observations per concentration. Selectivity over the TTX-R Na_v1.5 and Na_v1.8 channels was greater than 1000-fold.</p

PF-05198007 increases action potential rheobase in small diameter mDRG neurons.

<p>A. Overlayed representative voltage traces in response to graded current step injections before (blue) and after PF-05198007 application (red). Current step stimulations are shown below. B. Example timecourse of change in rheobase following PF-05198007 application and washout. C. Summary bar graph, n = 8 neurons, ** p < 0.01, ANOVA. Data are shown ±SEM.</p

Potency of PF-05089771 assessed at orthologous channels from selected species.

<p>Potency of PF-05089771 assessed at orthologous channels from selected species.</p

PF-05198007 acts peripherally and centrally to influence neurotransmitter release.

<p>A. Upper: representative evoked EPSCs during control (blue) and after 30 mins PF-05198007 application (red). Lower: representative synaptically evoked action potential trace (blue) recorded in SG neurons of the dorsal horn following dorsal root stimulation. PF-05198007 (20 mins) abolished synaptically evoked action potentials (red). B. Example time course of EPSC block following PF-05198007 application to the whole preparation. C. Action potentials induced <i>via</i> current injection steps in SG neurons were not abolished by PF-05198007 (30 nM). Representative voltage traces are shown following current injection steps of -20, 0 and 50 pA before (blue traces) and after (red traces) PF-05198007 application. Line chart shows change in firing frequency (Hz) during control and after application of PF-05198007 for all neurons tested (n = 5, p > 0.05, paired t-test). D. Example time course of EPSC block following PF-05198007 application to the dorsal root alone. E. Representative EPSC traces and summary bar graph showing that the application of PF-05198007 (30 nM) to the dorsal root alone inhibited C-fibre mediated EPSCs and resulted in a significant conduction delay (n = 7, * p < 0.05; ANOVA on Ranks). F. PF-05198007 (30 nM; n = 15: 100 nM; n = 19) reduced veratridine evoked CGRP release in spinal cord synaptosomes. Reduction was compared with mexilitine (100 μM; n = 19), Ca²⁺ free conditions (n = 8) and TTX (500 nM; n = 6) (Data are shown ±SEM; * p < 0.05; ANOVA on Ranks).</p