Search

Azilsartan Kamedoxomil is an AT1-subtype angiotensin II receptor blocker (ARB). During the laboratory synthesis of Azilsartan Kamedoxomil, four related substances of Azilsartan Kamedoxomil were observed and identified. These were 2-Ethoxy-3-[[4-[2- [4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]-5-oxo-1,2,4-oxadiazol-3-yl]phenyl]phenyl] methyl] benzimidazole-4-carboxylic acid (azilsartan N-medoxomil, 9), (5-methyl-2-oxo- 1,3-dioxol-4-yl)methyl 2-ethoxy-3-[[4-[2-[4-[(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl]-5- oxo-1,2,4-oxadiazol-3-yl]phenyl]phenyl] methyl] benzimidazole-4-carboxylate (azilsartan dimedoxomil, 10), (5-methyl-2-oxo-1,3-dioxo-4-yl)methyl 1-[2’-(4,5-dihydro-5-oxo-4H- 1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-methoxy-1H-benzimidazole-7-carboxylate (methoxy analogue of azilsartan medoxomil, 11), Methyl 1-((2’-amidobiphenyl-4-yl) methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (amide methyl ester, 12). The present work describes the origin, synthesis and characterization of these related substances.

This paper provides a description of an alternative, novel and commercially viable process which has been developed for the preparation of Azilsartan, a pro-drug of Azilsartan medoxomil, an angiotensin II receptor blocker. The present work also provides a primary account of the synthesis and characterization of the novel intermediates (6, 7 & 10) of Azilsartan, with their spectral data.

Eletriptan hydrobromide (1) is a selective serotonin (5-HT1) agonist, used for the acute treatment of the headache phase of migraine attacks. During the manufacture of eletriptan hydrobromide the formation of various impurities were observed and identified by LC–MS. To control the formation of these impurities during the preparation of active pharmaceutical ingredients, the structure of the impurities must be known. Major impurities of the eletriptan hydrobromide synthesis were prepared and characterized by using various spectroscopic techniques, i.e., mass spectroscopy, FTIR , 1H NMR, 13C NMR/DEPT, and further confirmed by co-injection in HPLC. The present study will be of great help in the synthesis of highly pure eletriptan hydrobromide related compounds.

Purpose: Chronic pain is common among people with spinal cord injury (PwSCI) and impacts mental health (MH). Mindfulness may buffer the association of pain with MH, but few studies have examined this among PwSCI. This study examines the extent to which mindfulness moderates the association of pain intensity with MH among PwSCI., Method: PwSCI ( N = 64) and chronic pain provided demographic and disability information, ratings of pain intensity (0-10 Numeric Rating Scale), pain interference, depression (eight-item Patient Health Questionnaire [PHQ-8]), anxiety (Generalized Anxiety Disorder-7 [GAD-7]), positive affect/wellbeing (SCI-QOL Positive Affect and Well-Being Short Form [PAWB-SF]), stress (Perceived Stress Scale-4 [PSS-4]), and mindfulness (15-item Five Facet Mindfulness Questionnaire [FFMQ-15]) at the time of their enrollment in a randomized controlled trial of a mindfulness intervention. The present, cross-sectional study used baseline data. Pain intensity, pain interference, mindfulness (FFMQ-15), the Pain Intensity × FFMQ-15 interaction, and relevant covariates were regressed on the four outcome measures (PHQ-8, GAD-7, PAWB-SF, and PSS-4)., Results: There was a significant Pain Intensity × FFMQ-15 interaction effect on PHQ-8 ( p = .008) and GAD-7 ( p = .021), such that mindfulness buffered the positive relation of pain intensity with depression and anxiety. Additionally, there was a significant Pain Intensity × FFMQ-15 interaction effect on PAWB-SF ( p = .032), but contrary to the hypothesis, mindfulness intensified a positive relation between pain intensity and positive affect/well-being., Conclusion: Dispositional mindfulness may buffer the association of pain intensity with depression and anxiety. Examining interventions to enhance mindfulness among PwSCI is warranted. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Purpose: Our goal was to evaluate if self-administered bladder neuromodulation with transcutaneous tibial nerve stimulation could safely replace overactive bladder medications in people with spinal cord injury., Materials and Methods: We performed a 3-month, randomized, investigator-blinded, tibial nerve stimulation vs sham-control trial in adults with spinal cord injury and neurogenic bladder performing intermittent catheterization and taking overactive bladder medications. The primary outcome was a reduction in bladder medications while maintaining stable bladder symptoms and quality of life based on pre/post Neurogenic Bladder Symptom Score and the Incontinence Quality of Life questionnaire, respectively. Secondary outcomes included changes in pre/post cystometrogram, 2-day voiding diaries, and an anticholinergic medication side effect survey., Results: Fifty people consented to the study, with 42 completing the trial. No dropouts were due to stimulation issues. All baseline demographics and surveys were comparable at baseline. Cystometrogram parameters were also comparable at baseline, except the stimulation group had a higher proportion of loss of bladder compliance compared to the control group. At the end of the trial, a significantly greater percentage of the tibial nerve stimulation group was able to reduce medications (95% vs 68%), by a 26.2% difference in medication reduction (95% CI 1.17%-51.2%). Function and quality of life surveys and cystometrograms at the end of the trial were alike between groups. Transcutaneous tibial nerve stimulation satisfaction surveys and adherence to protocol were high., Conclusions: In people with chronic spinal cord injury performing intermittent catheterization, transcutaneous tibial nerve stimulation can be an option to reduce or replace overactive bladder medications., Clinical Trial Registration No.: NCT03458871.

Introduction: Spasticity is one of the most common secondary complications following a spinal cord injury (SCI), which can significantly debilitate a patient irrespective of the severity of the injury. Intrathecal baclofen therapy can effectively reduce global spasticity in bilateral lower extremities at lower doses and allows precise dose titration to manage spasticity optimally. In complex patients with spasticity and multiple medical comorbidities, multidisciplinary teamwork is required to assess ITB safety and deliver timely intervention to prevent secondary complications of spasticity and improve quality of life., Case Presentation: A 61-year-old African American male with multiple comorbidities, including end-stage renal disease (ESRD) requiring dialysis sustained non-traumatic SCI due to epidural abscess resulting in paraplegia and severe debilitating spasticity. Spasticity gradually worsened and interfered with his ability to achieve independence with functional activities appropriate for his neurological level of injury. A multidisciplinary team approach in this complex case resulted in a successful ITB trial and subsequent ITB implantation, resulting in reduced spasticity and improved quality of life. To our knowledge, this is the first case report of the administration of intrathecal baclofen pump therapy in a person with SCI and end-stage renal disease (ESRD) dependent on hemodialysis., Discussion: ITB therapy can be safely delivered in a person with SCI and multiple medical comorbidities, including ESRD, dependent on hemodialysis to manage spasticity. However, a careful evaluation and discussion among the multidisciplinary team managing the patient's morbidities and patient is required to assess the risks and benefits of ITB therapy to allow the patient to make an informed decision., (© 2024. The Author(s), under exclusive licence to International Spinal Cord Society.)

Background: Guidelines fail to recommend objective measures to assist with treatment of neurogenic bowel dysfunction (NBD) in spinal cord injury (SCI)., Objectives: The main objective was to review the literature to identify the objective measures used in all NBD populations and to present their results and any correlations performed to validated subjective measures., Methods: A systematic review of the literature was performed in accordance with PRISMA (2020) guidelines, including all records from January 2012 to May 2023 with MeSH terms like "neurogenic bowel" indexed in the following databases: PubMed, EMBASE, CINAHL, Cochrane Central Trials Register, and ClinicalTrials.gov. Abstracts were excluded if they did not include objective measures or if they only mentioned the esophagus, stomach, and/or small bowel. Records were screened independently by at least two collaborators, and differences were resolved by unanimous agreement., Results: There were 1290 records identified pertaining to NBD. After duplicates were removed, the remaining records were screened for a total of 49 records. Forty-one records (82%) included subjective measures. Two-thirds of the articles involved the population with SCI/disease ( n = 552) and one-third were non-SCI NBD ( n = 476). Objective measures were categorized as (1) transit time, (2) anorectal physiology testing, and (3) miscellaneous. Of the 38 articles presenting results, only 16 (42%) performed correlations of objective measures to subjective measures., Conclusion: There is an abundance of literature supporting the use of objective outcome measures for NBD in SCI. Strong correlations of subjective measures to objective outcome measures were generally lacking, supporting the need to use both measures to help with NBD management., (© 2024 American Spinal Injury Association.)

Objective: To systematically review vagus nerve stimulation (VNS) studies to present data on the safety and efficacy on motor recovery following stroke, traumatic brain injury (TBI), and spinal cord injury (SCI)., Methods: Data sources: PubMed, EMBASE, SCOPUS, and Cochrane., Study Selection: Clinical trials of VNS in animal models and humans with TBI and SCI were included to evaluate the effects of pairing VNS with rehabilitation therapy on motor recovery., Data Extraction: Two reviewers independently assessed articles according to the evaluation criteria and extracted relevant data electronically., Data Synthesis: Twenty-nine studies were included; 11 were animal models of stroke, TBI, and SCI, and eight involved humans with stroke. While there was heterogeneity in methods of delivering VNS with respect to rehabilitation therapy in animal studies and human non-invasive studies, a similar methodology was used in all human-invasive VNS studies. In animal studies, pairing VNS with rehabilitation therapy consistently improved motor outcomes compared to controls. Except for one study, all human invasive and non-invasive studies with controls demonstrated a trend toward improvement in motor outcomes compared to sham controls post-intervention. However, compared to non-invasive, invasive VNS, studies reported severe adverse events such as vocal cord palsy, dysphagia, surgical site infection, and hoarseness of voice, which were found to be related to surgery., Conclusion: Our review suggests that VNS (non-invasive or invasive) paired with rehabilitation can improve motor outcomes after stroke in humans. Hence, VNS human studies are needed in people with TBI and SCI. There are risks related to device implantation to deliver invasive VNS compared to non-invasive VNS. Future human comparison studies are required to study and quantify the efficacy vs. risks of paired VNS delivered via different methods with rehabilitation, which would allow patients to make an informed decision., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=330653., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Korupolu, Miller, Park and Yozbatiran.)

Study Design: Systematic review and meta-analysis., Objective: Surgical decompression is a cornerstone in the management of patients with traumatic spinal cord injury (SCI); however, the influence of the timing of surgery on neurological recovery after acute SCI remains controversial. This systematic review aims to summarize current evidence on the effectiveness, safety, and cost-effectiveness of early (≤24 hours) or late (>24 hours) surgery in patients with acute traumatic SCI for all levels of the spine. Furthermore, this systematic review aims to evaluate the evidence with respect to the impact of ultra-early surgery (earlier than 24 hours from injury) on these outcomes., Methods: A systematic search of the literature was performed using the MEDLINE database (PubMed), Cochrane database, and EMBASE. Two reviewers independently screened the citations from the search to determine whether an article satisfied predefined inclusion and exclusion criteria. For all key questions, we focused on primary studies with the least potential for bias and those that controlled for baseline neurological status and specified time from injury to surgery. Risk of bias of each article was assessed using standardized tools based on study design. Finally, the overall strength of evidence for the primary outcomes was assessed using the GRADE approach. Data were synthesized both qualitatively and quantitively using meta-analyses., Results: Twenty-one studies met inclusion and exclusion criteria and formed the evidence base for this review update. Seventeen studies compared outcomes between patients treated with early (≤24 hours from injury) compared to late (>24 hours) surgical decompression. An additional 4 studies evaluated even earlier time frames: <4, <5, <8 or <12 hours. Based on moderate evidence, patients were 2 times more likely to recover by ≥ 2 grades on the ASIA Impairment Score (AIS) at 6 months (RR: 2.76, 95% CI 1.60 to 4.98) and 12 months (RR: 1.95, 95% CI 1.26 to 3.18) if they were decompressed within 24 hours compared to after 24 hours. Furthermore, moderate evidence suggested that patients receiving early decompression had an additional 4.50 (95% CI 1.70 to 7.29) point improvement on the ASIA motor score. With respect to administrative outcomes, there was low evidence that early decompression may decrease acute hospital length of stay. In terms of safety, there was moderate evidence that suggested the rate of major complications does not differ between patients undergoing early compared to late surgery. Furthermore, there was no difference in rates of mortality, surgical device-related complications, sepsis/systemic infection or neurological deterioration based on timing of surgery. Firm conclusions were not possible with respect to the impact of ultra-early surgery on neurological, functional or safety outcomes given the poor-quality studies, imprecision and the overlap in the time frames examined., Conclusions: This review provides an evidence base to support the update on clinical practice guidelines related to the timing of surgical decompression in acute SCI. Overall, the strength of evidence was moderate that early surgery (≤24 hours from injury) compared to late (>24 hours) results in clinically meaningful improvements in neurological recovery. Further studies are required to delineate the role of ultra-early surgery in patients with acute SCI., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest concerning the research, authorship, and/or publication of this article.

Study Design: Systematic review update., Objectives: Interventions that aim to optimize spinal cord perfusion are thought to play an important role in minimizing secondary ischemic damage and improving outcomes in patients with acute traumatic spinal cord injuries (SCIs). However, exactly how to optimize spinal cord perfusion and enhance neurologic recovery remains controversial. We performed an update of a recent systematic review (Evaniew et al, J. Neurotrauma 2020) to evaluate the effects of Mean Arterial Pressure (MAP) support or Spinal Cord Perfusion Pressure (SCPP) support on neurological recovery and rates of adverse events among patients with acute traumatic SCI., Methods: We searched PubMed/MEDLINE, EMBASE and ClinicalTrials.gov for new published reports. Two reviewers independently screened articles, extracted data, and evaluated risk of bias. We implemented the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach to rate confidence in the quality of the evidence., Results: From 569 potentially relevant new citations since 2019, we identified 9 new studies for inclusion, which were combined with 19 studies from a prior review to give a total of 28 studies. According to low or very low quality evidence, the effect of MAP support on neurological recovery is uncertain, and increased SCPP may be associated with improved neurological recovery. Both approaches may involve risks for specific adverse events, but the importance of these adverse events to patients remains unclear. Very low quality evidence failed to yield reliable guidance about particular monitoring techniques, perfusion ranges, pharmacological agents, or durations of treatment., Conclusions: This update provides an evidence base to support the development of a new clinical practice guideline for the hemodynamic management of patients with acute traumatic SCI. While avoidance of hypotension and maintenance of spinal cord perfusion are important principles in the management of an acute SCI, the literature does not provide high quality evidence in support of a particular protocol. Further prospective, controlled research studies with objective validated outcome assessments are required to examine interventions to optimize spinal cord perfusion in this setting., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Study Design: Clinical practice guideline development following the GRADE process., Objectives: Hemodynamic management is one of the only available treatment options that likely improves neurologic outcomes in patients with acute traumatic spinal cord injury (SCI). Augmenting mean arterial pressure (MAP) aims to improve blood perfusion and oxygen delivery to the injured spinal cord in order to minimize secondary ischemic damage to neural tissue. The objective of this guideline was to update the 2013 AANS/CNS recommendations on the hemodynamic management of patients with acute traumatic SCI, acknowledging that much has been published in this area since its publication. Specifically, we sought to make recommendations on 1. The range of mean arterial pressure (MAP) to be maintained by identifying an upper and lower MAP limit; 2. The duration of such MAP augmentation; and 3. The choice of vasopressor. Additionally, we sought to make a recommendation on spinal cord perfusion pressure (SCPP) targets., Methods: A multidisciplinary guideline development group (GDG) was formed that included health care professionals from a wide range of clinical specialities, patient advocates, and individuals living with SCI. The GDG reviewed the 2013 AANS/CNS guidelines and voted on whether each recommendation should be endorsed or updated. A systematic review of the literature, following PRISMA standards and registered in PROSPERO, was conducted to inform the guideline development process and address the following key questions: (i) what are the effects of goal-directed interventions to optimize spinal cord perfusion on extent of neurological recovery and rates of adverse events at any time point of follow-up? and (ii) what are the effects of particular monitoring techniques, perfusion ranges, pharmacological agents, and durations of treatment on extent of neurological recovery and rates of adverse events at any time point of follow-up? The GDG combined the information from this systematic review with their clinical expertise in order to develop recommendations on a MAP target range (specifically an upper and lower limit to target), the optimal duration for MAP augmentation, and the use of vasopressors or inotropes. Using methods outlined by the GRADE working group, recommendations were formulated that considered the balance of benefits and harms, financial impact, acceptability, feasibility and patient preferences., Results: The GDG suggested that MAP should be augmented to at least 75-80 mmHg as the "lower limit," but not actively augmented beyond an "upper limit" of 90-95 mmHg in order to optimize spinal cord perfusion in acute traumatic SCI. The quality of the evidence around the "target MAP" was very low, and thus the strength of this recommendation is weak. For duration of hemodynamic management, the GDG "suggested" that MAP be augmented for a duration of 3-7 days. Again, the quality of the evidence around the duration of MAP support was very low, and thus the strength of this recommendation is also weak. The GDG felt that a recommendation on the choice of vasopressor or the use of SCPP targets was not warranted, given the dearth of available evidence., Conclusion: We provide new recommendations for blood pressure management after acute SCI that acknowledge the limitations of the current evidence on the relationship between MAP and neurologic recovery. It was felt that the low quality of existing evidence and uncertainty around the relationship between MAP and neurologic recovery justified a greater range of MAP to target, and for a broader range of days post-injury than recommended in previous guidelines. While important knowledge gaps still remain regarding hemodynamic management, these recommendations represent current perspectives on the role of MAP augmentation for acute SCI., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

To explore the use of 5-minute heart rate variability (HRV) during inpatient rehabilitation in the acute phase of traumatic spinal cord injury (SCI)., Longitudinal observational study., Acute inpatient rehabilitation (AIR)., 10 patients with acute traumatic SCI., 5-minute HRV supine recordings twice daily on three different days per patient., HRV values were evaluated (1) within a single day (Early versus Late); (2) across the inpatient admission (initial, mid, and discharge); (3) by SCI phenotypes and by clinical outcomes (ex. pressure injuries (PI))., Patients had an average age of 38 years, 80% male, and 40% with tetraplegia. There were no HRV differences between Early and Late recordings, across the inpatient admission, demographics, or SCI phenotype. However, improvement in neurologic exam was accompanied by increased parasympathetic tone (mean RR increased by 172 ms SD 61, P = .005). Patients with PI demonstrated lower sympathetic (SNS) activity (decreased LF by 472 ms 2 SD 240, P = .049) and lower PNS activity (decreased RMSSD by 1.2 ms SD 0.5, P = .02), compared to no PI. Comparisons to uninjured reference values and chronic SCI suggest a changing autonomic nervous system (ANS) from uninjured to acute to chronic as measured by HRV., Conclusions: This preliminary evidence suggests HRV in acute SCI is stable across time and day during inpatient rehabilitation and may be correlated to clinical sequalae of ANS dysfunction and neurologic recovery. Comparisons to published work suggest that HRV may measure the progression in the ANS from acute to chronic phase after SCI.

Study Design: Descriptive study., Objectives: The study's main objective was to describe the common targets of phenol neurolysis and review the safety and efficacy of the dose used for this spasticity management procedure in people with spinal cord injury (SCI)., Setting: An acute rehabilitation hospital., Methods: Data from people with SCI who underwent phenol neurolysis procedures for spasticity management between April 2017 and August 2018 were included in this study. We collected demographics and phenol neurolysis procedure-related information., Results: A total of 66 people with SCI and spasticity underwent phenol neurolysis of 303 nerves over 102 encounters. During these encounters, 97% of procedures were performed using both electrical stimulation and ultrasound guidance. The median (IQR) total volume of 6% aqueous phenol used per encounter was 4.0 (2.0-6.0) ml with a median (IQR) of 1.5 (1.0-2.3) ml per nerve. The most frequent target was the obturator nerve (33%), followed by the pectoral nerves (23%). Immediate post-phenol neurolysis improvement or reduction in spasticity was reported for 92% of all documented encounters. There was no documentation of any post-procedure-related adverse events in this cohort during this specified time frame., Conclusions: Our findings suggest that phenol neurolysis can be safely used to manage spasticity in people with SCI under combined electrical stimulation and ultrasound guidance. Further research is required to assess the procedure's safety, efficacy, and cost-effectiveness on patient-reported outcomes compared to other spasticity interventions., (© 2022. The Author(s), under exclusive licence to International Spinal Cord Society.)

Objectives: This systematic review aims to gain a comprehensive understanding of the feasibility, acceptability, and efficacy of mindfulness-based interventions (MBIs) on depression, anxiety, fatigue, and health-related quality of life among individuals with upper motor neuron disorders (UMNDs)., Data Sources: PubMed, PsycINFO, Excerpta Medica Database, and Cumulative Index to Nursing and Allied Health Literature were searched for relevant studies published between January 2001 and June 2021., Study Selection: Clinical trials published in English evaluating MBIs in adults with the 4 most common UMNDs (multiple sclerosis, brain injury including stroke, spinal cord injury, amyotrophic lateral sclerosis) were included., Data Extraction: Two reviewers independently performed the risk of bias assessment using standardized tools and extracted desired data electronically., Data Synthesis: A total of 44 studies were included: 26 randomized controlled trials, 10 nonrandomized controlled trials, and 8 pre-post intervention studies. The average ± SD duration of MBIs was 8±2 weeks. On average, 85%±14% of participants completed the MBI, and the retention rate at follow-up was 80%±16%. Only 14% of the studies delivered MBIs virtually, and feasibility metrics were similar to in-person studies. Among studies reporting acceptability data, most participants reported satisfaction with the MBI. Randomized controlled trials that evaluated the effects of MBI on depression, anxiety, fatigue, and quality of life revealed greater relative improvement in these outcomes among MBI participants compared with controls, with differences greater when compared with passive control than active control participants. None of the studies included in this review studied dose response., Conclusions: Based on current data, MBIs are feasible and offer a promising approach to address the biopsychosocial needs of individuals with UMNDs. MBIs are associated with a high acceptance rate among participants, with notable improvements in depression, anxiety, fatigue, and quality of life post intervention. Future studies are needed to evaluate alternate models of delivery of MBIs and the dose-response relationship., (Published by Elsevier Inc.)

Background: Loss of upper extremity function after tetraplegia results in significant disability. Emerging evidence from pilot studies suggests that functional electrical stimulation (FES) therapy may enhance recovery of upper extremity function after tetraplegia. The aim of this trial was to determine the effectiveness of FES therapy delivered by the Myndmove stimulator in people with tetraplegia., Methods: A multi-center , single-blind, parallel-group, two-arm, randomized controlled trial was conducted comparing FES to conventional therapy in adults (≥18 years) with C4-C7 traumatic incomplete tetraplegia between 4 and 96 months post-injury, and with a baseline spinal cord injury independence measure III -self-care (SCIM III-SC) score of ≤10. Participants were enrolled at four SCI-specialized neurorehabilitation centers in the U.S. and Canada. Participants were stratified by center and randomized in a 1:1 ratio to receive either 40 sessions of FES or conventional therapy targeting upper extremities over a 14-week period. Blinded assessors measured SCIM III, Toronto Rehabilitation Institute Hand Function Test, and Graded Redefined Assessment of Strength, Sensibility, and Prehension at baseline, after 20th session, after 40th session or 14 weeks after 1st session, and at 24 weeks after 1st session. The primary outcome measure was change in SCIM III-SC from baseline to end of the treatment. Based on the primary outcome measure, a sample size of 60 was calculated. Seventeen participants' progress in the study was interrupted due to the COVID-19 lockdown. The protocol was modified for these participants to allow them to complete the study., Results: Between June 2019 to August 2021, 51 participants were randomized to FES ( n  = 27) and conventional therapy ( n  = 24). Both groups gained a mean of 2 points in SCIM-SC scores at the end of treatment, which was a clinically meaningful change. However, there was no statistically significant difference between the groups on any outcomes., Conclusion: Forty sessions of FES therapy delivered by the MyndMove stimulator are as effective as conventional therapy in producing meaningful functional improvements that persist after therapy is completed. Limitations of this study include the impact of COVID-19 limiting the ability to recruit the target sample size and per-protocol execution of the study in one-third of the participants., Registration: This trial is registered at www.ClinicalTrials.gov, NCT03439319., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Anderson, Korupolu, Musselman, Pierce, Wilson, Yozbatiran, Desai, Popovic and Thabane.)

Objectives: To evaluate baseline characteristics, describe pulmonary outcomes, and identify weaning predictors for people with acute traumatic spinal cord injury (SCI) who are dependent on mechanical ventilation at admission to acute inpatient rehabilitation (AIR)., Methods: The retrospective study was conducted at an AIR facility in the United States. It included 91 adults with acute traumatic SCI from 2015 to 2019 who were dependent on mechanical ventilation., Results: People who successfully weaned (85%) had fewer days from time of SCI to AIR admission (22 vs. 30, p = .04), higher vital capacity at admission to AIR (12 vs. 3 mL/kg predicted body weight [PBW]; p < .001), and lower (caudal) neurological injury level ( p < .001) compared to those who failed weaning. The risk of pneumonia was higher in people who failed weaning compared to those who were weaned successfully (risk ratio, 5.5; 95% confidence interval [95% CI], 2.3-13). Receiver operating characteristics (ROC) curves suggest a vital capacity cutoff of 5.8 mL/kg PBW could predict weaning. The vital capacity of ≥ 5.8 mL/kg PBW is associated with 109 times higher odds (95% CI, 11-1041; p < .001) of weaning than vital capacity below that threshold., Conclusion: In this retrospective study, there was an increased risk of pneumonia in people with SCI who failed weaning at discharge from AIR. Vital capacity was a better predictor of weaning from mechanical ventilation compared to the neurological level of injury, with a cutoff of 5.8 mL/kg PBW predictive of weaning success. Further research is needed on this critical topic., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest., (© 2022 American Spinal Injury Association.)

Introduction: Spasticity is a common consequence of spinal cord injury (SCI), estimated to affect up to 93% of people living with SCI in the community. Problematic spasticity affects around 35% people with SCI spasticity. The early period after injury is believed to be the most opportune time for neural plasticity after SCI. We hypothesize that clinical interventions in the early period could reduce the incidence of spasticity. To address this, we evaluated the spasticity outcomes of clinical trials with interventions early after SCI., Methods: We performed a systematic review of the literature between January 2000 and May 2021 to identify control trials, in humans and animals, that were performed early after SCI that included measures of spasticity in accordance with PRISMA guidelines., Results: Our search yielded 1,463 records of which we reviewed 852 abstracts and included 8 human trial peer-reviewed publications and 9 animal studies. The 9 animal trials largely supported the hypothesis that early intervention can reduce spasticity, including evidence from electrophysiological, behavioral, and histologic measures. Of the 8 human trials, only one study measured spasticity as a primary outcome with a sample size sufficient to test the hypothesis. In this study, neuromodulation of the spinal cord using electric stimulation of the common peroneal nerve reduced spasticity in the lower extremities compared to controls., Conclusion: Given the prevalence of problematic spasticity, there is surprisingly little research being performed in the early period of SCI that includes spasticity measures, and even fewer studies that directly address spasticity. More research on the potential for early interventions to mitigate spasticity is needed., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Biotherapeutics are highly efficacious, but the pain and inconvenience of chronic injections lead to poor patient compliance and compromise effective disease management. Despite innumerable attempts, oral delivery of biotherapeutics remains unsuccessful due to their degradation in the gastrointestinal (GI) environment and poor intestinal absorption. We have developed an orally ingestible robotic pill (RP) for drug delivery, which protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine as a safe, pain-free injection since the intestines are insensate to sharp stimuli. The payload is delivered upon inflation of a balloon folded within the RP, which deflates immediately after drug delivery. Here we present results from two clinical studies demonstrating the safety, tolerability and performance of the RP in healthy humans. In the first study, three versions of the RP (A, B and C) were evaluated, which were identical in all respects except for the diameter of the balloon. The RP successfully delivered a biotherapeutic (octreotide) in 3 out of 12 subjects in group A, 10 out of 20 subjects in group B and 16 out of 20 subjects in group C, with a mean bioavailability of 65 ± 9% (based on successful drug deliveries in groups A and B). Thus,  reliability of drug delivery with the RP ranged from 25 to 80%, with success rate directly related to balloon size. In a separate study, the deployment of the RP was unaffected by fed or fasting conditions suggesting that the RP may be taken with or without food. These promising clinical data suggest that biotherapeutics currently administered parenterally may be safely and reliably delivered via this versatile, orally ingestible drug delivery platform., (© 2021. The Author(s).)

Context/objective: Pneumonia is the leading cause of death after acute spinal cord injury (SCI). High tidal volume ventilation (HVtV) is used in SCI rehabilitation centers to overcome hypoventilation while weaning patients from the ventilator. Our objective was to determine if HVtV in the acute post-injury period in SCI patients is associated with lower incidence of ventilator-associated pneumonia (VAP) when compared to patients receiving standard tidal volume ventilation., Design: Cohort study., Setting: Red Duke Trauma Institute, University of Texas Health Science Center at Houston, TX, USA., Participants: Adult Acute Cervical SCI Patients, 2011-2018., Interventions: HVtV., Outcome Measures: VAP, ventilator dependence at discharge, in-hospital mortality., Results: Of 181 patients, 85 (47%) developed VAP. HVtV was utilized in 22 (12%) patients. Demographics, apart from age, were similar between patients who received HVtV and standard ventilation; patients were younger in the HVtV group. VAP developed in 68% of patients receiving HVtV and in 44% receiving standard tidal volumes ( P  = 0.06). After adjustment, HVtV was associated with a 1.96 relative risk of VAP development (95% credible interval 1.55-2.17) on Bayesian analysis. These results correlate with a >99% posterior probability that HVtV is associated with increased VAP when compared to standard tidal volumes. HVtV was also associated with increased rates of ventilator dependence., Conclusions: While limited by sample size and selection bias, our data revealed an association between HVtV and increased VAP. Further investigation into optimal early ventilation settings is needed for SCI patients, who are at a high risk of VAP.

Study Design: Retrospective cohort study., Objectives: The primary objective of this study was to evaluate safety and efficacy of higher tidal volumes (HVt) compared to moderate Vt (MVt) in people with spinal cord injury (SCI) admitted to acute inpatient rehabilitation (AIR) facility on mechanical ventilation via tracheostomy., Setting: AIR facility in the United States., Methods: Eighty-four adults with SCI were divided into MVt group if maximum Vt received in AIR was <15 ml/kg predicted body weight (PBW) and HVt group if maximum Vt was >15 ml/kg PBW. Primary outcomes were incidence of pneumonia and composite pulmonary adverse events (pneumonia, weaning failure, or acute care transfers due to respiratory complications). Secondary outcomes were AIR preweaning days defined as time from AIR admission to beginning of weaning, weaning days defined as days from start to end of weaning, and AIR ventilator days calculated as days on ventilator from AIR admission to discharge., Results: MVt was utilized in 50 patients and HVt was utilized in 34 patients. The risk of pneumonia in HVt group was 4.3 times higher [95% confidence interval (CI): 1.5-12] compared to MVt group. Odds of pulmonary adverse events in HVt group was 5.4 times higher (CI: 1.8-17) compared to MVt group. There was no difference in preweaning days, weaning days, or AIR ventilator days between the two groups., Conclusions: Our data suggest that HVt is associated with increased risk of pneumonia and higher odds of pulmonary adverse events in tracheostomized patients with SCI which warrants further investigation.

Introduction: This protocol is describing a multicentre, single-blind randomised controlled trial. The objective is to compare the efficacy of MyndMove therapy versus conventional therapy (CT) in improving upper extremity function in individuals with C4-C7 traumatic, incomplete spinal cord injury (SCI). It is being conducted in two US and two Canadian SCI rehabilitation centres., Methods and Analysis: Sixty people aged 18 years or older with a C4-C7 incomplete (AIS B-D) SCI between 4 months and 8 years postinjury are randomised to receive 40 sessions of MyndMove neuromodulation therapy or CT within a 14-week period of time. Therapy sessions are 1 hour in duration with a dose of 3-5 sessions per week. Assessments occur prior to randomisation, after 20 sessions, after 40 sessions and 10 weeks after the last session. The primary outcome measure is the efficacy of MyndMove therapy versus CT in improving upper extremity function as measured by Spinal Cord Independence Measure III: Self-Care subscore after 40 sessions. Secondary outcomes include: (1) improvements in the SCIM mobility subscore; (2) upper limb functions measured by Graded Redefined Assessment of Strength, Sensibility and Prehension and (3) Toronto Rehab Institute Hand Function Test; (4) To assess safety as measured by serious and non-serious adverse events recorded for participants in both groups of the study population over the duration of the study; (5) to compare the change in quality of life as measured by the Spinal Cord Injury-Quality of Life; and (6) to evaluate the impact on healthcare resource utilisation., Ethics and Dissemination: All ethical approvals were obtained prior to enrolling any participants. Dissemination of the results of the study will be made at peer-reviewed academic meetings and through peer-reviewed medical journals TRIAL REGISTRATION NUMBER: NCT03439319., Competing Interests: Competing interests: MyndTec Inc is the contracting organisation of this study and through funding provided by US Army Medical Research and Materiel Command, researchers are reimbursed for doing this study. All investigators have an interest in completing the study., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

An outbreak of a novel coronavirus disease (COVID-19) that emerged in the Chinese city of Wuhan has rapidly become a global public health pandemic. As of March 2020, the Centers for Disease Control and Prevention (CDC) has described priority levels for testing patients with suspected COVID-19 and information on when to seek medical attention. However, there is a paucity of further guidance for people with spinal cord injury (SCI) who may not present with typical symptoms of COVID-19 due to altered physiology. This may pose challenges with surveillance, risk stratification, and initial management of this vulnerable population. In this point-counterpoint discussion, we outline important differences in presentation along with COVID-19 cases co-morbid with SCI.

Biotherapeutic agents must be administered parenterally to obtain therapeutic blood concentrations, lowering patient compliance and complicating care. An oral delivery platform (ODP) was developed to deliver drugs into the small intestinal wall. This proof-of-concept study was performed in 17 anesthetized, laparotomized swine. In 8 swine weighing 17.4 ± 1.2 kg (mean ± SEM), 20 IU of recombinant human insulin (RHI) were auto-injected into the jejunal wall by placing the ODP inside the jejunum via an enterotomy. In 9 control swine weighing 17.0 ± 0.4 kg, 20 IU of RHI were injected subcutaneously. In both groups, under a 60-80 mg/dL euglycemic glucose clamp, blood glucose was measured with a handheld glucometer and serum insulin was measured using ELISA, at 10-minute intervals between -20 and +420 minutes after RHI delivery. The peak serum concentration of RHI was 517 ± 109 pmol/L in the ODP and 342 ± 50 pmol/L in the subcutaneous group (ns). The areas under the insulin concentration curves (83 ± 18 and 81 ± 10 nmol/L·min) were also similar in both groups. The mean time to peak serum concentration of insulin was 139 ± 42 minutes in the ODP and 227 ± 24 minutes in the subcutaneous group (ns). In conclusion, (a) The bioactivity of RHI was preserved after its delivery into the jejunal wall, (b) the intrajejunal route delivered insulin as rapidly and physiologically as the subcutaneous route, and (c) these pharmacokinetic and pharmacodynamic characteristics of RHI after intrajejunal delivery suggest that drugs currently administered parenterally, such as basal insulin, could be successfully delivered into the proximal intestinal wall via the ingestible capsule., (© 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Background: Electrophysiological measures are being increasingly utilized due to their ability to provide objective measurements with minimal bias and to detect subtle changes with quantitative data on neural function. Heterogeneous reporting of trial outcomes limits effective interstudy comparison and optimization of treatment. Objective: The objective of this systematic review is to describe the reporting of electrophysiological outcome measures in spinal cord injury (SCI) clinical trials in order to inform a subsequent consensus study. Methods: A systematic search of PubMed and EMBASE databases was conducted according to PRISMA guidelines. Adult human SCI clinical trials published in English between January 1, 2008 and September 15, 2018 with at least one electrophysiological outcome measure were eligible. Findings were reviewed by all authors to create a synthesis narrative describing each outcome measure. Results: Sixty-four SCI clinical trials were included in this review. Identified electrophysiological outcomes included electromyography activity (44%), motor evoked potentials (33%), somatosensory evoked potentials (33%), H-reflex (20%), reflex electromyography activity (11%), nerve conduction studies (9%), silent period (3%), contact heat evoked potentials (2%), and sympathetic skin response (2%). Heterogeneity was present in regard to both methods of measurement and reporting of electrophysiological outcome measures. Conclusion: This review demonstrates need for the development of a standardized reporting set for electrophysiological outcome measures. Limitations of this review include exclusion of non-English publications, studies more than 10 years old, and an inability to assess methodological quality of primary studies due to a lack of guidelines on reporting of systematic reviews of outcome measures., Competing Interests: The authors declare no conflicts of interest., (© 2019 Thomas Land Publishers, Inc.)

Objectives: We investigated whether transcutaneous tibial nerve stimulation (TTNS) in acute spinal cord injury was safe and feasible, and could achieve neuromodulation and improve cystometrogram parameters during acute inpatient rehabilitation., Materials and Methods: Participants were consecutive acute traumatic spinal cord injury patients admitted for acute inpatient rehabilitation, randomized to a 2-week trial of TTNS v sham stimulation. Primary outcomes were safety and feasibility of TTNS and secondary outcomes were bladder measures based on pre- and post-TTNS cystometrogram by group and within groups, including bladder capacity, detrusor hyperreflexia, pressures, and detrusor-sphincter dyssynergia, as well as filling sensations and desire to void. The principle investigator and subjects were blinded to treatment allocation., Results: A total of 19 subjects consented to the study and completed the stimulation protocol. Morbidity was similar between groups and compliance was 100% to the TTNS protocol. Based on a lack of rehabilitation interruptions and comments from staff, TTNS was feasible. Post-cystometrogram parameters were significant for lower volumes until sensation in the control group and prolonged volumes until sensation in the TTNS group. The control group had significant changes of increased detrusor-sphincter dyssynergia and decreased bladder capacity. This was not significantly changed in the TTNS group., Conclusions: TTNS is a safe and feasible modality that can be performed during inpatient rehabilitation of acute traumatic spinal cord injury. Bladder capacity and episodes of detrusor-sphincter dyssynergia significantly worsened in the control group and did not significantly change in the TTNS group, suggesting that TTNS can alter the course of neurogenic bladder via neuromodulation., (© 2018 International Neuromodulation Society.)

Aim: Percutaneous tibial nerve stimulation is used to decrease incontinence in chronic neurogenic bladder. We report the findings from a subset of patients in a randomized control trial of transcutaneous tibial nerve stimulation (TTNS) for bladder neuromodulation in acute spinal cord injury (SCI) in whom heart rate variability (HRV) was recorded before and after cystometrogram (CMG). The aim was to correlate autonomic nervous system (ANS) changes associated with the CMG changes after the trial using HRV analyses. Methods: The study was a double-blinded sham-controlled 2-week trial with consecutive acute SCI patients admitted for inpatient rehabilitation, randomized to TTNS vs. control sham stimulation. Pre- and Post- trial CMG were performed with concurrent 5-min HRV recordings with empty bladder and during filling. Primary outcomes were changes with CMG between/within groups and associations to the HRV findings. Results: There were 10 subjects in the TTNS group and 6 in the control group. Pre-trial baseline subject characteristics, blood pressures (BPs), and CMG were similar between groups. In both groups, the pre-trial systolic BP increased during filling CMG. After the trial, the control group had significantly increased detrusor pressure and counts of detrusor-sphincter dyssynergia on CMG, not seen in the TTNS group. Also, the control group did not maintain rising BP post-trial, which was observed pre-trial and remained in the TTNS group post-trial. HRV was able to detect a difference in the ANS response to bladder filling between groups. Post-trial HRV was significant for markers of overall increased parasympathetic nervous system activity during filling in the controls, not seen in the TTNS group. Conclusion: Preliminary evidence suggests that TTNS in acute SCI is able to achieve bladder neuromodulation via modulation of ANS functions. Clinical Trial Registration: clinicaltrials.gov, NCT02573402.

Background: Non-invasive transcranial direct current stimulation has been shown to modulate cortical excitability in various studies. Similarly, recent preliminary studies suggest that transcutaneous spinal direct current stimulation (tsDCS) may engender a modulation effect on spinal and cortical neurons., Objective: The purpose of this study was to evaluate the dose-response effects of tsDCS in healthy subjects and thereby lay groundwork for expanding treatment options for patients with spinal cord injury (SCI)., Methods: Nine healthy subjects received each of the following 2 tsDCS conditions: Anodal and cathodal, in random order with at least 1 week washout period between each session. In order to test safety and dose response, various current intensities were used (2, 2.5 and 3 mA) for 20 minutes. The active electrode was placed vertically over T10-T11, and the reference electrode was placed over the left shoulder. To evaluate corticospinal excitability, motor evoked potentials over soleus muscle elicited by transcranial magnetic stimulation were measured. To assess spinal cord excitability, H- and M- wave over soleus muscle to calculate Hmax/ Mmax ratio were measured., Results: Linear regression showed a dose response with cathodal tsDCS on motor evoked potentials measured from the left leg as well as with anodal tsDCS on Hmax/ Mmax ratio measured from the left leg., Conclusions: These findings indicate tsDCS effects are dose-dependent. These effects should be investigated in a larger sample.

Introduction: This is a prospective clinical pilot case series. Improvement of arm and hand functions after spinal cord injury (SCI) is one of the major rehabilitation goals. Electrical stimulation of the primary motor cortex via transcranial direct current stimulation (tDCS) coupled with high-intensity repetitive motor training may have potential to facilitate improvement in motor function in chronic, incomplete cervical SCI. We investigated the relationship between motor recovery and changes in white matter integrity in response to treatment intervention. This study was conducted in The Institute for Rehabilitation and Research Memorial Hermann, Houston, USA., Case Presentation: Four right-handed adults with chronic, incomplete cervical SCI (age, 36-63 years, American Spinal Injury Association Impairment Scale grade C-D) were enrolled in 10 sessions of anodal tDCS at 2 mA versus sham tDCS followed by 1 h of robotic-assisted arm training. Changes in arm and hand function were measured with Jebsen-Taylor Hand Function Test and Motor Activity Log-Amount of Use. Diffusion tension imaging was used to measure changes in fractional anisotropy (FA) of corticospinal tracts (CSTs)., Discussion: After 10 sessions of treatment, we found greater improvement in hand function and hand usage in patients who received active tDCS treatment versus sham treatment. There was an overall positive change in FA values across all patients. We show changes in arm and hand function associated with changes in CST tractographic mapping to quantify the motor system components in chronic incomplete cervical SCI., Competing Interests: The authors declare no conflict of interest.

A 5-year old female presented with acute tetraparesis and areflexia. Initial imaging and cerebrospinal fluid analysis were suggestive of acute disseminated encephalomyelitis (ADEM). Minimal clinical response with intravenous steroids prompted further work up. Limited nerve conduction studies suggested possible acute motor-sensory axonal neuropathy, a rare variant of Guillain-Barré syndrome (GBS). Repeat imaging was compatible with polyradiculopathy indicating concomitance of ADEM and GBS. The patient suffered severe motor deficits and neuropathic pain. Slow but significant functional recovery was noted after intensive inpatient rehabilitation followed by continued rehabilitation via home health services.

Objective: To evaluate the potential annual net cost savings of implementing an ICU early rehabilitation program., Design: Using data from existing publications and actual experience with an early rehabilitation program in the Johns Hopkins Hospital Medical ICU, we developed a model of net financial savings/costs and presented results for ICUs with 200, 600, 900, and 2,000 annual admissions, accounting for both conservative- and best-case scenarios. Our example scenario provided a projected financial analysis of the Johns Hopkins Medical ICU early rehabilitation program, with 900 admissions per year, using actual reductions in length of stay achieved by this program., Setting: U.S.-based adult ICUs., Interventions: Financial modeling of the introduction of an ICU early rehabilitation program., Measurements and Main Results: Net cost savings generated in our example scenario, with 900 annual admissions and actual length of stay reductions of 22% and 19% for the ICU and floor, respectively, were $817,836. Sensitivity analyses, which used conservative- and best-case scenarios for length of stay reductions and varied the per-day ICU and floor costs, across ICUs with 200-2,000 annual admissions, yielded financial projections ranging from -$87,611 (net cost) to $3,763,149 (net savings). Of the 24 scenarios included in these sensitivity analyses, 20 (83%) demonstrated net savings, with a relatively small net cost occurring in the remaining four scenarios, mostly when simultaneously combining the most conservative assumptions., Conclusions: A financial model, based on actual experience and published data, projects that investment in an ICU early rehabilitation program can generate net financial savings for U.S. hospitals. Even under the most conservative assumptions, the projected net cost of implementing such a program is modest relative to the substantial improvements in patient outcomes demonstrated by ICU early rehabilitation programs.

Background: As the population ages and critical care advances, a growing number of survivors of critical illness will be at risk for intensive care unit (ICU)-acquired weakness. Bed rest, which is common in the ICU, causes adverse effects, including muscle weakness. Consequently, patients need ICU-based interventions focused on the muscular system. Although emerging evidence supports the benefits of early rehabilitation during mechanical ventilation, additional therapies may be beneficial. Neuromuscular electrical stimulation (NMES), which can provide some muscular activity even very early during critical illness, is a promising modality for patients in the ICU., Objective: The objectives of this article are to discuss the implications of bed rest for patients with critical illness, summarize recent studies of early rehabilitation and NMES in the ICU, and describe a protocol for a randomized, phase II pilot study of NMES in patients receiving mechanical ventilation., Design: The study was a randomized, sham-controlled, concealed, phase II pilot study with caregivers and outcome assessors blinded to the treatment allocation., Setting: The study setting will be a medical ICU., Participants: The study participants will be patients who are receiving mechanical ventilation for 1 day or more, who are expected to stay in the ICU for an additional 2 days or more, and who meet no exclusion criteria., Intervention: The intervention will be NMES (versus a sham [control] intervention) applied to the quadriceps, tibialis anterior, and gastrocnemius muscles for 60 minutes per day., Measurements: Lower-extremity muscle strength at hospital discharge will be the primary outcome measure., Limitations: Muscle strength is a surrogate measure, not a patient-centered outcome. The assessments will not include laboratory, genetic, or histological measures aimed at a mechanistic understanding of NMES. The optimal duration or dose of NMES is unclear., Conclusions: If NMES is beneficial, the results of the study will help advance research aimed at reducing the burden of muscular weakness and physical disability in survivors of critical illness.

Activins are pluripotent hormones/growth factors that belong to the TGF-β superfamily of growth and differentiation factors (GDFs). They play a role in cell growth, differentiation and apoptosis, endocrine function, metabolism, wound repair, immune responses, homeostasis, mesoderm induction, bone growth, and many other biological processes. Activins and the related bone morphogenic proteins (BMPs) transduce their signal through two classes of single transmembrane receptors. The receptors possess intracellular serine/threonine kinase domains. Signaling occurs when the constitutively active type II kinase domain phosphorylates the type I receptor, which upon activation, phosphorylates intracellular signaling molecules. To generate antagonistic ligands, we generated chimeric molecules that disrupt the receptor interactions and thereby the phosphorylation events. The chimeras were designed based on available structural data to maintain high-affinity binding to type II receptors. The predicted type I receptor interaction region was replaced by residues present in inactive homologs or in related ligands with different type I receptor affinities., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Transdermal iontophoresis is an active drug delivery method that has the potential to transform treatment of conditions such as acute pain that require a succession of on-demand metered-dose drug deliveries. However, current monophasic iontophoresis methods fail to meet these requirements due to their inability to halt the passive diffusion of active agents when therapy is not required. We have developed a biphasic iontophoretic system to overcome these limitations. The viability of this system was assessed in an in vitro porcine skin preparation using FeCl(2) (127 Daltons), a charged molecule which can undergo both active and passive transdermal diffusion. The transport properties of the system were modeled using a Fourier Transform-derived optimum estimate transfer function. Using this model, experimental results showed good correlation to predicted values for both cumulative dose (R(2)=0.912, n=10), and density dose (R(2)=0.802, n=10). Results also showed the ability to effectively deliver the compound during active periods while minimizing delivery during inactive periods. While preliminary, our results suggest biphasic iontophoresis is a viable means of delivering on-demand drug therapy while minimizing unwanted off-demand delivery.

Objective: There are barriers to providing early physical medicine and rehabilitation (PM&R) in the intensive care unit (ICU). We present a specific model for undertaking quality improvement (QI) projects and a case study focused on QI for early PM&R in the ICU., Methods: The QI project was undertaken using a 4-step model: (1) summarizing the evidence, (2) identifying barriers, (3) establishing performance measures, and (4) ensuring patients receive the intervention. To evaluate the application and outcomes of this model, we present data collected during a 4-month QI period versus an immediately preceding 3-month control period., Results: Deep sedation was a major barrier to early PM&R that was addressed in the QI project. Compared to the control period, there was a decrease in medical ICU (MICU) days with any benzodiazepine use (73% vs 96% of days, P = .03) and narcotic use (77% vs 96%, P = .05) and improved delirium status (MICU days without delirium, 53% vs 21%, P = .003). In addition, more QI patients had physical therapy consultations (93% vs 59%, P = .004) and greater number of rehabilitation treatments with higher functional mobility (treatments involving sitting or greater mobility, 78% vs 56%, P = .03). Hospital data for the QI period demonstrated a decrease in average length of stay in the MICU (4.9 vs 7.0 days, P = .02) and hospital (14.1 vs 17.2, P = .03) compared to the prior year., Conclusion: A structured QI model can be applied to implementation of early PM&R in the ICU resulting in markedly improved delirium status, delivery of PM&R, functional mobility, and length of stay.

Purpose: The aim of this study was to describe the frequency, physiologic effects, safety, and patient outcomes associated with traditional rehabilitation therapy in patients who require mechanical ventilation., Materials and Methods: Prospective observational report of consecutive patients ventilated 4 or more days and eligible for rehabilitation in a single medical intensive care unit (ICU) during a 13-week period was conducted., Results: Of the 32 patients who met the inclusion criteria, only 21 (66%) received physician orders for evaluation by rehabilitation services (physical and/or occupational therapy). Fifty rehabilitation treatments were provided to 19 patients on a median of 12% of medical ICU days per patient, with deep sedation and unavailability of rehabilitation staff representing major barriers to treatment. Physiologic changes during rehabilitation therapy were minimal. Joint contractures were frequent in the lower extremities and did not improve during hospitalization. In 53% and 79% of initial ICU assessments, muscle weakness was present in upper and lower extremities, respectively, with a decreased prevalence of 19% and 43% at hospital discharge, respectively. New impairments in physical function were common at hospital discharge., Conclusions: This pilot project illustrated important barriers to providing rehabilitation to mechanically ventilated patients in an ICU and impairments in strength, range of motion, and functional outcomes at hospital discharge., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objectives: To (1) reduce deep sedation and delirium to permit mobilization, (2) increase the frequency of rehabilitation consultations and treatments to improve patients' functional mobility, and (3) evaluate effects on length of stay., Design: Seven-month prospective before/after quality improvement project., Setting: Sixteen-bed medical intensive care unit (MICU) in academic hospital., Participants: 57 patients mechanically ventilated 4 days or longer., Intervention: A multidisciplinary team focused on reducing heavy sedation and increasing MICU staffing to include full-time physical and occupational therapists with new consultation guidelines., Main Outcome Measures: Sedation and delirium status, rehabilitation treatments, functional mobility., Results: Compared with before the quality improvement project, benzodiazepine use decreased markedly (proportion of MICU days that patients received benzodiazepines [50% vs 25%, P=.002]), with lower median daily sedative doses (47 vs 15 mg midazolam equivalents [P=.09] and 71 vs 24 mg morphine equivalents [P=.01]). Patients had improved sedation and delirium status (MICU days alert [30% vs 67%, P<.001] and not delirious [21% vs 53%, P=.003]). There were a greater median number of rehabilitation treatments per patient (1 vs 7, P<.001) with a higher level of functional mobility (treatments involving sitting or greater mobility, 56% vs 78%, P=.03). Hospital administrative data demonstrated that across all MICU patients, there was a decrease in intensive care unit and hospital length of stay by 2.1 (95% confidence interval: 0.4-3.8) and 3.1 (0.3-5.9) days, respectively, and a 20% increase in MICU admissions compared with the same period in the prior year., Conclusions: Using a quality improvement process, intensive care unit delirium, physical rehabilitation, and functional mobility were markedly improved and associated with decreased length of stay., (Copyright 2010 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

A 44-year-old morbidly obese (body mass index 69 kg/m(2)) woman presented to our medical intensive care unit (ICU) with septic shock and multiorgan failure requiring mechanical ventilation, a vasopressor infusion, and haemodialysis. Before this admission, the patient reported being able to ambulate approximately 3 m with a walker. Intensive physical therapy was started on ICU day 2, and the patient was successfully mobilised throughout her ICU stay despite the extreme challenges posed by her morbid obesity and critical illness. After only a 9 day stay, the patient was discharged directly home from the medical ICU, walking a total distance of 37 m in a single physical therapy session.