Temperature Control After Cardiac Arrest-A Rational Approach.

This Viewpoint discusses hypothermic temperature control for neuroprotection among survivors of out-of-hospital cardiac arrest and offers a rational approach to treating such patients as investigations continue.

A Modified Delphi Consensus Approach to Define Entrustable Professional Activities for Neurocritical Care Advanced Practice Providers.

OBJECTIVES: To define consensus entrustable professional activities (EPAs) for neurocritical care (NCC) advanced practice providers (APPs), establish validity evidence for the EPAs, and evaluate factors that inform entrustment expectations of NCC APP supervisors. DESIGN: A three-round modified Delphi consensus process followed by application of the EQual rubric and assessment of generalizability by clinicians not affiliated with academic medical centers. SETTING: Electronic surveys. SUBJECTS: NCC APPs ( n = 18) and physicians ( n = 12) in the United States with experience in education scholarship or APP program leadership. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The steering committee generated an initial list of 61 possible EPAs. The panel proposed 30 additional EPAs. A total of 47 unique nested EPAs were retained by consensus opinion. The steering committee defined six core EPAs addressing medical knowledge, procedural competencies, and communication proficiency which encompassed the nested EPAs. All core EPAs were retained and subsequently met the previously described cut score for quality and structure using the EQual rubric. Most clinicians who were not affiliated with academic medical centers rated each of the six core EPAs as very important or mandatory. Entrustment expectations did not vary by prespecified groups. CONCLUSIONS: Expert consensus was used to create EPAs for NCC APPs that reached a predefined quality standard and were important to most clinicians in different practice settings. We did not identify variables that significantly predicted entrustment expectations. These EPAs may aid in curricular design for an EPA-based assessment of new NCC APPs and may inform the development of EPAs for APPs in other critical care subspecialties.

DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage-gated sodium channel 1.7 (Nav1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Nav1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Nav1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP), and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch-clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II (a selective Nav1.7 channel blocker)-sensitive sodium currents. Bath-applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN, while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain also showed electrophysiological and immunofluorescence results indicating an increased expression of Nav1.7 associated with spontaneous activity. Nav1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Nav1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain.SIGNIFICANCE STATEMENT This work demonstrates that the expression and function of the voltage-gated sodium channel Nav1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of-function mutations in human Nav1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Nav1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact, indicating an important novel therapeutic avenue for neuropathic pain as a class.

Dorsal root ganglion neurons become hyperexcitable and increase expression of voltage-gated T-type calcium channels (Cav3.2) in paclitaxel-induced peripheral neuropathy.

Here, it is shown that paclitaxel-induced neuropathy is associated with the development of spontaneous activity (SA) and hyperexcitability in dorsal root ganglion (DRG) neurons that is paralleled by increased expression of low-voltage-activated calcium channels (T-type; Cav3.2). The percentage of DRG neurons showing SA and the overall mean rate of SA were significantly higher at day 7 in rats receiving paclitaxel treatment than in rats receiving vehicle. Cav3.2 expression was increased in L4-L6 DRG and spinal cord segments in paclitaxel-treated rats, localized to small calcitonin gene-related peptide and isolectin B4 expressing DRG neurons and to glial fibrillary acidic protein-positive spinal cord cells. Cav3.2 expression was also co-localized with toll-like receptor 4 (TLR4) in both the DRG and the dorsal horn. T-type current amplitudes and density were increased at day 7 after paclitaxel treatment. Perfusion of the TLR4 agonist lipopolysaccharide directly activated DRG neurons, whereas this was prevented by pretreatment with the specific T-type calcium channel inhibitor ML218 hydrochloride. Paclitaxel-induced behavioral hypersensitivity to mechanical stimuli in rats was prevented but not reversed by spinal administration of ML218 hydrochloride or intravenous injection of the TLR4 antagonist TAK242. Paclitaxel induced inward current and action potential discharges in cultured human DRG neurons, and this was blocked by ML218 hydrochloride pretreatment. Furthermore, ML218 hydrochloride decreased firing frequency in human DRG, where spontaneous action potentials were present. In summary, Cav3.2 in concert with TLR4 in DRG neurons appears to contribute to paclitaxel-induced neuropathy.

Amputee socks: Sock thickness changes with normal use.

BACKGROUND: Prosthetic socks are expected to decrease in thickness and have reduced volume accommodation with normal use. It is unknown, however, to what degree they reduce in thickness over time. OBJECTIVE: The goal of this study was to determine a correlation between the age of a prosthetic sock (defined as the out-of-package time) and the resulting change in thickness under standardized weight-bearing and non-weight-bearing conditions. STUDY DESIGN: Experimental, mechanical assessment. METHODS: Used prosthetic socks were donated by donors with transtibial amputation. Sock thickness was measured on a custom instrument under conditions representative of normal use. Stress-thickness response was compared to that of equivalent new socks to quantify the effects of use on sock performance. RESULTS: Sock thickness changed non-linearly over time. On average, socks were 75% ± 17% of their initial thickness after 1 month, while socks older than 1 month were 72% ± 18% of their initial thickness. The elasticity of socks did not change with age. CONCLUSION: The volume accommodation provided by used socks cannot be reliably predicted by ply or age. Direct measurement of total sock thickness may provide meaningful insight to quantify prosthetic users' socket fit and guide volume accommodation recommendations. CLINICAL RELEVANCE: The mean difference in thickness between 3-ply and 5-ply used socks was equal to the standard deviation of each ply group (0.3mm). Therefore, it is possible that a 3-ply sock worn for as a little as 1 month could have a greater thickness than a 5-ply sock worn for a month.

Preliminary evaluation of a novel bladder-liner for facilitating residual limb fluid volume recovery without doffing.

For people who wear a prosthetic limb, residual-limb fluid volume loss during the day may be problematic and detrimentally affect socket fit. The purpose of this research was to test the capability of a novel liner with adjustable bladders positioned within its wall to mitigate volume loss and facilitate limb fluid volume recovery and retention. Bioimpedance analysis was used to monitor fluid volume changes in the anterior and posterior residual limb of participants with transtibial amputation. Participants underwent six cycles of sitting for 90 s, standing for 90 s, and walking for 5 min with liquid within the bladder-liners. Between the third and fourth cycles, participants sat for 10 min with liquid left within the bladders (Liquid-In) or removed (Liquid-Out). Results showed that participants recovered more fluid volume during the 10 min of sitting with Liquid-Out than Liquid-In (p = 0.09 for anterior and p = 0.04 for posterior). However, those fluid volume recoveries were not well retained in the short term (after the fourth cycle) or the long term (after the sixth cycle). Physiologic differences between sessions, reflected in the rates of fluid volume change at the outset of the session, and excessive stiffness of the bladder-liners may have affected fluid volume retentions.

The Cancer Chemotherapeutic Paclitaxel Increases Human and Rodent Sensory Neuron Responses to TRPV1 by Activation of TLR4.

Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1(+) neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS-RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1(+) neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy. Significance statement: In this original work, it is shown for the first time that paclitaxel activates peripheral sensory and spinal neurons directly and sensitizes these cells to transient receptor potential vanilloid subtype 1 (TRPV1)-mediated capsaicin responses via Toll-like receptor 4 (TLR4) in multiple species. A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1-coexpressing HEK293 cells, and in both rat and mouse spinal cord slices. Moreover, this is the first study to show that this interaction plays an important role in the generation of behavioral hypersensitivity in paclitaxel-related neuropathy. The key translational implications are that TLR4 and TRPV1 antagonists may be useful in the prevention and treatment of chemotherapy-induced peripheral neuropathy in humans.

MAPK signaling downstream to TLR4 contributes to paclitaxel-induced peripheral neuropathy.

Toll-like receptor 4 (TLR4) has been implicated as a locus for initiation of paclitaxel related chemotherapy induced peripheral neuropathy (CIPN). This project explores the involvement of the immediate down-stream signal molecules in inducing paclitaxel CIPN. Mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NFκB) were measured in dorsal root ganglia (DRG) and the spinal cord over time using Western blot and immunohistochemistry in a rat model of paclitaxel CIPN. The effects of MAPK inhibitors in preventing and reversing behavioral signs of CIPN were also measured (group sizes 4-9). Extracellular signal related kinase (ERK1/2) and P38 but not c-Jun N terminal kinase (JNK) or PI3K-Akt signaling expression was increased in DRG. Phospho-ERK1/2 staining was co-localized to small CGRP-positive DRG neurons in cell profiles surrounding large DRG neurons consistent with satellite glial cells. The expression of phospho-P38 was co-localized to small IB4-positive and CGRP-positive DRG neurons. The TLR4 antagonist LPS derived from Rhodobacter sphaeroides (LPS-RS) inhibited paclitaxel-induced phosphorylation of ERK1/2 and P38. The MAPK inhibitors PD98059 (MEK1/2), U0126 (MEK1/2) and SB203580 (P38) prevented but did not reverse paclitaxel-induced behavioral hypersensitivity. Paclitaxel treatment resulted in phosphorylation of Inhibitor α of NFκB (IκBα) in DRG resulting in an apparent release of NFκB from the IκBα-NFκB complex as increased expression of nuclear NFκB was also observed. LPS-RS inhibited paclitaxel-induced translocation of NFκB in DRG. No change was observed in spinal NFκB. These results implicate TLR4 signaling via MAP kinases and NFκB in the induction and maintenance of paclitaxel-related CIPN.

How do walking, standing, and resting influence transtibial amputee residual limb fluid volume?

The purpose of this research was to determine how fluid volume changes in the residual limbs of people with transtibial amputation were affected by activity during test sessions with equal durations of resting, standing, and walking. Residual limb extracellular fluid volume was measured using biompedance analysis in 24 participants. Results showed that all subjects lost fluid volume during standing with equal weight-bearing, averaging a loss rate of -0.4%/min and a mean loss over the 25 min test session of 2.6% (standard deviation [SD] 1.1). Sixteen subjects gained limb fluid volume during walking (mean gain of 1.0% [SD 2.5]), and fifteen gained fluid volume during rest (mean gain of 1.0% [SD 2.2]). Walking explained only 39.3% of the total session fluid volume change. There was a strong correlation between walk and rest fluid volume changes (-0.81). Subjects with peripheral arterial disease experienced relatively high fluid volume gains during sitting but minimal changes or losses during sit-to-stand and stand-to-sit transitioning. Healthy female subjects experienced high fluid volume changes during transitioning from sit-to-stand and stand-to-sit. The differences in fluid volume response among subjects suggest that volume accommodation technologies should be matched to the activity-dependent fluid transport characteristics of the individual prosthesis user.

How does adding and removing liquid from socket bladders affect residual-limb fluid volume?

Adding and removing liquid from socket bladders is a means for people with limb loss to accommodate residual-limb volume change. We fit 19 people with transtibial amputation using their regular prosthetic socket with fluid bladders on the inside socket surface to undergo cycles of bladder liquid addition and removal. In each cycle, subjects sat, stood, and walked for 90 s with bladder liquid added, and then sat, stood, and walked for 90 s again with the bladder liquid removed. The amount of bladder liquid added was increased in each cycle. We used bioimpedance analysis to measure residual-limb fluid volume. Results showed that the preferred bladder liquid volume was 16.8 +/- 8.4 mL (mean +/- standard deviation), corresponding with 1.7% +/- 0.8% of the average socket volume between the bioimpedance voltage-sensing electrodes. Residual-limb fluid volume driven out of the residual limb when bladder liquid was added was typically not recovered upon subsequent bladder liquid removal. Of the 19 subjects, 15 experienced a gradual residual-limb fluid volume loss over the test session. Care should be taken when implementing adjustable socket technologies in people with limb loss. Reducing socket volume may accentuate residual-limb fluid volume loss.

How do sock ply changes affect residual-limb fluid volume in people with transtibial amputation?

The purpose of this research was to investigate the influence of sock addition and removal on residual-limb fluid volume in people using prosthetic limbs. We used bioimpedance analysis to measure residual-limb extracellular fluid volume on 28 transtibial amputee subjects during 30 min test sessions. Upon addition of a one-ply polyester sock, residual-limb fluid volume changes ranged from -4.0% to 0.8% (mean -0.9 +/- 1.3%) of the initial limb fluid volume. Changes for sock removal ranged from -1.2% to 2.8% (mean 0.5 +/- 0.8%). Subjects who reduced in fluid volume with both addition and removal of a sock and subjects with high positive ratios between the fluid-volume loss upon sock addition and gain upon sock removal (high add/remove [AR] ratios) tended to have arterial disease, were obese, and were smokers. Subjects with low positive AR ratios, subjects who increased in fluid volume both with sock addition and removal, and a single subject who increased in fluid volume with sock addition and decreased with sock removal tended to be nonsmokers and either individuals in good health without complications or individuals without arterial problems. Results are relevant for the anticipation of limb volume changes during prosthetic fitting and toward the design of adjustable-socket technologies.

Post-doffing residual limb fluid volume change in people with trans-tibial amputation.

BACKGROUND: Residual limb volume may change after doffing, affecting the limb shape measured and used as a starting point for socket design. OBJECTIVES: The purpose of this study was to compare residual limb fluid volume changes after doffing for different test configurations. STUDY DESIGN: The study was a repeated measures experimental design with three conditions (Sit, Liner, and Walk). METHODS: Residual limb fluid volume on 30 people with trans-tibial amputation was measured using bioimpedance analysis. Three tests were conducted--Sit: sit for 10 minutes, remove the prosthesis, socks and liner, sit for 10 minutes; Liner: sit for 10 minutes, remove the prosthesis and socks but not the liner, sit for 10 minutes; Walk: conduct sit, stand and walk activities for 30 minutes, remove the prosthesis, socks and liner, sit for 10 minutes. RESULTS: The percentage fluid volume increase after doffing was significantly higher for Walk (2.8%) than for Sit (1.8%) (p = 0.03). The time to achieve a maximum or stable fluid volume was shorter for Liner (4.3 min) than for Sit (6.6 min) (p = 0.03). CONCLUSIONS: Activity before doffing intensified the post-doffing limb fluid volume increase. Maintaining a liner after doffing caused limb fluid volume to stabilize faster than removing the liner. Clinical relevance To minimize residual limb volume increase before casting or imaging, practitioners should have patients sit with their prosthesis donned for 10 minutes. Leaving a liner on the residuum will not reduce the post-doffing volume increase, but it will help to more quickly achieve a consistent limb fluid volume.

Amputee socks: how does sock ply relate to sock thickness?

BACKGROUND: The term 'sock ply' may be a source of confusion in prosthetics practice because there may not be a consistent relationship between sock ply and sock thickness. OBJECTIVES: The purpose of this study was to characterize how sock ply related to sock thickness for different sock materials commonly used in limb prosthetics. We also evaluated how sock thickness changed under loading conditions experienced while wearing a lower limb prosthesis compared with unstressed conditions. STUDY DESIGN: Experimental. Mechanical assessment. METHODS: Seven sock materials of varying ply and sheaths were tested using a custom instrument. Sock thickness under eight different compressive stress conditions and two different biaxial in-plane tensile strain conditions were measured. RESULTS: For socks woven from a single material, thickness under walking stance phase conditions averaged 0.7, 1.2 and 1.5 mm for 1, 3 and 5-ply, respectively. For socks woven from several materials, the corresponding results were 0.4, 0.7 and 0.8 mm, respectively. Sock ply did not sum, e.g. a 3-ply sock was not three times the thickness of a 1-ply sock. CONCLUSIONS: Sock thickness and compressive stiffness are strongly dependent upon sock material, interface pressure, and in-plane biaxial strain.

Preliminary investigation of residual-limb fluid volume changes within one day.

The purpose of this research was to investigate rates of residual-limb fluid volume change within one day for people with transtibial limb loss. Rates of fluid volume change during 30 min test sessions of sitting, standing, and walking activities were measured twice a day, once in the morning and once in the afternoon, on 12 regular prosthesis users with the use of bioimpedance analysis. Between test sessions, all subjects consumed food and drink, and subject activity ranged from low to high. The rate of fluid volume change within sessions ranged from -8.5 to 5.9 %/h (median: -2.2%/h). The rate of fluid volume change between sessions ranged from -2.7 to 0.9 %/h (median: -1.0%/h). The between-session rate of fluid volume change correlated highly with afternoon within-session rates of change (r = 0.9) but was not well correlated with morning within-session rates of change (r = 0.8). Subjects with peripheral arterial complications showed greater fluid volume loss rates during test sessions than between sessions. Rate of fluid volume change may be affected by sitting, standing, and walking activities; presence of peripheral arterial complications; being female; time since amputation; and wearing the socket without doffing for extended periods.

Effects of elevated vacuum on in-socket residual limb fluid volume: case study results using bioimpedance analysis.

Bioimpedance analysis was used to measure the residual limb fluid volume of seven transtibial amputee subjects using elevated vacuum sockets and nonelevated vacuum sockets. Fluid volume changes were assessed during sessions with the subjects sitting, standing, and walking. In general, fluid volume losses during 3 or 5 min walks and losses over the course of the 30 min test session were less for elevated vacuum than for suction. Numerous variables, including the time of day that data were collected, soft tissue consistency, socket-to-limb size and shape differences, and subject health, may have affected the results and had an equivalent or greater effect on limb fluid volume compared with elevated vacuum. Researchers should well consider these variables in the study design of future investigations on the effects of elevated vacuum on residual limb volume.

Clinical utility of in-socket residual limb volume change measurement: case study results.

Bioimpedance analysis was used to measure conductive tissue extracellular fluid (ECF) volume changes in the residual limbs of four unilateral transtibial amputee subjects during standing and walking conditions. Results showed that all residual limbs experienced ECF volume decreases during 5 min standing intervals. During 5 min of walking immediately after a standing interval, the residual limbs of healthy subjects increased in ECF volume while those of diseased subjects, one with peripheral vascular disease and another with cardiovascular insufficiency and a high-salt intake, decreased. One subject demonstrated less absolute value ECF volume change during standing and walking at 12 months post-surgical revision compared with at six months. Presentation of bioimpedance data to patients improved compliance to practitioner recommendations and patient understanding. Results were useful towards clinical assessment, patient education, and decision-making about treatment.