High Thoracic Spinal Cord Injury Research Articles

Robotic Postural Training With Epidural Stimulation for the Recovery of Upright Postural Control in Individuals With Motor Complete Spinal Cord Injury: A Pilot Study.

Activity-based training and lumbosacral spinal cord epidural stimulation (scES) have the potential to restore standing and walking with self-balance assistance after motor complete spinal cord injury (SCI). However, improvements in upright postural control have not previously been addressed in this population. Here, we implemented a novel robotic postural training with scES, performed with free hands, to restore upright postural control in individuals with chronic, cervical (n = 5) or high-thoracic (n = 1) motor complete SCI, who had previously undergone stand training with scES using a walker or a standing frame for self-balance assistance. Robotic postural training re-enabled and/or largely improved the participants' ability to control steady standing, self-initiated trunk movements and upper limb reaching movements while standing with free hands, receiving only external assistance for pelvic control. These improvements were associated with neuromuscular activation pattern adaptations above and below the lesion. These findings suggest that the human spinal cord below the level of injury can generate meaningful postural responses when its excitability is modulated by scES, and can learn to improve these responses. Upright postural control improvements can enhance functional motor recovery promoted by scES after severe SCI.

Poster (Knowledge Generation) ID 1969160

Background This ongoing cross-sectional study aims to examine the potential association between moderate-to-severe sleep apnea and severe cardiovascular dysfunction after spinal cord injury (SCI). Methods This cross-sectional study included participants who were newly diagnosed with sleep apnea using a home-based/hospital unattended sleep screening test that quantifies the apnea-hypopnea index (AHI). Episodes of AD were defined as a sudden increase in systolic blood pressure (BP) of at least 20 mmHg. We exclude episodes of AD during sleep that were caused by triggers other than apnea or hypopnea. Participants This study included English-speaking adults with subacute or chronic (≥1 month after SCI onset), cervical or high-thoracic (T6 or more cranial), complete or incomplete SCI, who reported clinical symptoms and/or signs suggestive of sleep apnea. Results This study included 45 individuals (14 females and 31 males; age range: 20 to 84 years, mean age: 57.0 years) with motor complete (n=22) or incomplete SCI at cervical (n=38) or high thoracic levels. Time since SCI varied from 1.5 months to 52 years. Their mean apnea-hypopnea index (AHI) was 16.0 events/hour (AHI range: 0.8 to 51.7 events/hour). Higher AHI was significantly correlated with more frequent silent episodes of AD (Rsqr=0.220, p=0.001) during sleep. The AHI was not associated with systolic BP (p=0.903), diastolic BP (p=0.639), mean arterial pressure (p=0.714), and heart rate (p=0.669) during sleep. Conclusions The results of this cross-sectional study suggest that more severe sleep apnea is associated with frequent silent episodes of AD during sleep among individuals living with cervical or high-thoracic SCI.

Proinflammatory and Immunomodulatory Gene and Protein Expression Patterns in Spinal Cord and Spleen Following Acute and Chronic High Thoracic Injury.

In addition to paralysis and loss of sensation, high-level spinal cord injury (SCI) causes sympathetic dysfunction that can lead to autonomic dysreflexia (AD) and chronic immune suppression involving splenic leukopenia. Evidence has shown that treatment with either gabapentin or blockade of TNFα mitigates maladaptive plasticity and the underlying hemodynamic dysfunction, spleen atrophy, and immune dysfunction associated with AD. Because significant improvements long term was noted following treatments only during acute stages of recovery, we sought to systematically examine changes in proinflammatory and immunomodulatory cytokines to ascertain the reason. Adult female Wistar rats underwent complete T4 spinal transection before euthanasia at systematic intervals from 3 days to 8 weeks after injury. Using qRT-PCR and meso scale discovery (MSD) assays, the gene and protein expression of TNFα and IFNγ in the spleen, upper thoracic (T4-9) and lumbosacral (L5-S6) spinal cords were analyzed. We found that spleen atrophy occurs in a biphasic manner compared to naïve controls, with significant decreases in the spleen mass noted at 3 days and 8 weeks after injury. Splenic TNFα mRNA and protein levels did not change significantly over time, while IFNγ gene expression dipped acutely with trends for increased protein levels at more chronic time points. TNFα protein increased significantly only in thoracic spinal cord segments from 3 to 14 days post-injury. IFNγ mRNA and protein levels remained unelevated in injured spinal cords over time, with trends for increased protein levels at 2 and 8 weeks in the lumbosacral segments. Novel temporal-spatial cytokine expression profiles reveal that TNFα protein levels are increased solely in upper thoracic segments after high thoracic SCI, while IFNγ remains unaltered. Splenic leukopenia and latent systemic immunosuppression are not associated with altered TNFα or IFNγ expression in the spleen or spinal cord.

Caring for and Extracting Data from Rats with High-Thoracic Spinal Cord Injuries

Individuals who suffer from spinal cord injuries are very susceptible to autonomic dysreflexia, which unfortunately can lead to death in many cases. By studying this injury, a better understanding of the topic can be achieved, along with potential direction for assistive technologies. The purpose of this study was to ensure that rats with High-Thoracic Spinal Cord Injury were being properly cared for throughout the experimental acclimation process, with proper housing, surgical procedures, diet, and post-operative care. In the lab, these objectives were met, and then blood pressure and electrocardiography recordings were taken before and after the animal was paralyzed. This data was then analyzed with baseline and startle recordings to see the changes that these animals go through after a high-thoracic spinal cord injury. The technology developed from this data could help prevent autonomic dysreflexia and help those who suffer from spinal cord injuries have an easier and more tolerable lifestyle.

Cardio-centric hemodynamic management with and without adjuvant ethyl nitrite improves mean arterial pressure in rodents with chronic high-thoracic traumatic spinal cord injury

Objective: Traumatic spinal cord injury (SCI) causes an initial injury followed by a protracted phase of spinal cord tissue hypoxia. This tissue hypoxia contributes to secondary injury, leading to worse motor and cardio-autonomic outcomes in the chronic setting. No neuroprotective agents to mitigate secondary injury have been identified as efficacious in clinical trials. However, we have demonstrated that taking a cardio-centric approach to hemodynamic management following SCI by augmenting cardiac output and mean arterial pressure (MAP) with the b1-adrenoceptor agonist dobutamine (DOB), and further coupling DOB infusion with the inhalation of ethyl nitrite (ENO), an S-nitrosylating agent, is associated with improved spinal cord oxygenation in the acute phase post-SCI. Aim: To determine the influence of a cardio-centric approach to hemodynamic management with adjuvant ENO inhalation following SCI on long term outcomes. We hypothesized that treatment with DOB and ENO in the acute phase following SCI would mitigate secondary injury and improve cardiovascular outcomes in the chronic setting. Methods. A total of 34 male Wistar rats underwent a T3 contusion injury (300 kdyn) and were assigned into 4 treatment groups: control (n=6), ENO (n=6), DOB (n=12), and combined DOB and ENO (n=10). At 11-weeks post-SCI, a locomotor assessment was conducted using the Basso, Beattie and Bresnahan (BBB) locomotor rating scale. At 12-weeks post-SCI, rodents were anesthetized with intravenous urethane (2.44±0.50 g/kg) and instrumented with a solid-state pressure transducer in the carotid artery to measure MAP. Results. We observed a higher MAP in both DOB (113.6 ± 11.4 mmHg; p = 0.030) and ENO+DOB (116.7 ± 14.6 mmHg; p=0.013) treated groups when compared with controls (94.65 ± 11.62 mmHg). The MAP of ENO treated animals (91.6 ± 7.3 mmHg; P= 0.97) was not different from controls. No differences in BBB scores were found between DOB (15.17 ± 4.49), ENO+DOB (13.95 ± 3.86), ENO (12.5 ± 2.5) and control (11.8 ± 2.7)(P=0.29). Collectively, these data suggest that DOB treatment, alone or in combination with ENO, improves systemic hemodynamics in the chronic high-thoracic SCI setting US Department of Defense, ICORD Seed Grant, Craig H. Neilsen Foundation This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Experimental high-thoracic spinal cord injury reduces splanchnic sympathetic nerve activity and is associated with persistent hypotension

Objective: High-thoracic spinal cord injury (SCI) is associated with blood pressure (BP) dysregulation that consists of persistent hypotension, orthostatic intolerance and autonomic dysreflexia. Whilst several mechanisms have been suggested to underlie blood pressure dysregulation post-SCI, the most common inference made is that the sub-lesional sympathetic circuitry is hypoactive due to a loss of medullary input to the sympathetic preganglionic neurons. Yet, a remarkable paucity of data exists from electrophysiological studies that have assessed sympathetic nerve activity (SNA) in the setting of SCI. Aim: Assess the changes in SNA and resting BP in rats with and without high-thoracic SCI. Methods: 24 male Wistar rats (10wks old) were randomized and counterbalanced to receive a severe contusion SCI at the T3 spinal level (n=12) or remain as naïve controls (CON). Two weeks post-SCI, rats underwent our neurovascular terminal preparation. Animals were ventilated, anesthetized with inhalant isoflurane, and underwent catheterization of the left-femoral artery (BP), as well as the right femoral artery and vein for arterial blood gas sampling and i.v. fluid/drugs, respectively. Rats were then transitioned to urethane anesthesia (~2.1g.kg-1 i.v). Next, the splanchnic nerve was isolated from a retroperitoneal approach, cut, and the proximal end was recorded using a suction electrode for the measurement of splanchnic sympathetic nerve activity (sSNA). Following 30 minutes of hemodynamic stabilization, SNA and cardiovascular hemodynamics were sampled for 10 minutes, from which a 1 min recording was selected for analyses. Animals were subsequently administered a hexamethonium bolus (30 mg.kg-1) to block ganglionic transmission and the euthanized with chloral hydrate. Results: SCI animals exhibited lower systolic, diastolic and mean arterial BP (all p<0.007), but heart rate was not different between groups. SCI animals also exhibited lower total sSNA (1.9 ± 0.7 vs. 3.2 ± 1.9 mv.s-1, p=0.038) as well reduced burst height (2.2 ± 1.5 vs. 3.7 ± 0.8 v.s-1, p=0.033), but the number of sSNA spikes.s-1 was higher in SCI vs. CON (182 ± 65 vs. 155 ± 33, p=0.043). Blood gases were stable and similar between groups. Conclusions: Our findings show that persistent hypotension in SCI animals is associated with lower total sub-lesional sSNA. While SCI resulted in more spontaneous sSNA spikes, these spikes fail to coordinate into equally-sized sSNA bursts. International Spinal Research Trust and Natural Sciences and Engineering Research Council of Canada (NSERC). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Untreated Moderate-to-Severe Sleep-Related Breathing Disorders Are Associated with Increased Frequency of Episodes of Autonomic Dysreflexia during Sleep in Individuals with Subacute or Chronic Spinal Cord Injury: A Prospective Cross-Sectional Study. (P1-13.002)

<h3>Objective:</h3> This ongoing cross-sectional study is focused on the potential association between moderate-to-severe sleep-related breathing disorders (SRBDs) and more severe cardiovascular dysfunction following spinal cord injury (SCI). <h3>Background:</h3> Sleep-related breathing disorders (SRBDs) are common and under-recognized among individuals living with spinal cord injury (SCI). SRBDs can affect the sympathetic response, but the impact of untreated SRBDs on cardiovascular autonomic function after SCI remains incompletely understood. <h3>Design/Methods:</h3> This cross-sectional study included adults with subacute/chronic (≥1 month after SCI onset), cervical or high-thoracic (T6 or above) SCI. The diagnosis of SRBD was established using a home-based/hospital unattended sleep screening test that quantifies the apnea-hypopnea index (AHI). Moderate-to-severe SRBD was defined as an AHI ≥ 15 events per hour. Episodes of autonomic dysreflexia (AD) were defined as a sudden increase in systolic blood pressure (BP) ≥ 20 mmHg. <h3>Results:</h3> This study included 45 individuals (14 females, 31 males with ages from 20 to 84 years; mean age: 57.0 years) with motor complete (n=22) or incomplete (n=24) SCI at cervical (n=38), or high thoracic levels. Time from SCI onset varied from 1.5 months to 52 years (mean time: 49.4 months). Mean AHI was 16.0 events per hour (AHI range: 0.8–51.7). The AHI was not associated with systolic BP (mean+/−SEM: 122.0+/−2.2 mmHg; p=0.903), diastolic BP (72.6+/−3.0 mmHg; p=0.639), mean arterial pressure (90.1+/−2.4 mmHg; p=0.714), and heart rate (70.6+/−1.4 bpm; p=0.669) during sleep. However, the AHI was significantly, positively correlated with the number of silent episodes of AD (mean +/− SEM: 3.6+/−0.4; Rsqr=0.220, p=0.001) during sleep, after excluding other causes of AD. <h3>Conclusions:</h3> The results of this cross-sectional study suggest that more severe SBRBs are associated with frequent silent episodes of AD during sleep among individuals with SCI. Future research is needed to assess the effects of continuous positive airway pressure (CPAP) therapy on cardiovascular dysfunction following SCI. <b>Disclosure:</b> The institution of Dr. Furlan has received research support from Wings for Life Spinal Cord Research Foundation. The institution of Dr. Furlan has received research support from Craig H Neilsen Foundation. The institution of Dr. Furlan has received research support from Ontario Neurotrauma Foundation. The institution of Dr. Furlan has received research support from Cervical Spine Research Society. The institution of Dr. Furlan has received research support from J P Bickell Foundation. The institution of Dr. Furlan has received research support from Praxis Spinal Cord Institute. The institution of Dr. Furlan has received research support from Cervical Spine Research Society. Dr. Loh has stock in Dara3D. Dr. Boulos has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Jazz Pharmaceuticals. Dr. Boulos has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Paladin Labs. Dr. Boulos has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Dr. Boulos has received research support from Interaxon. The institution of Dr. Boulos has received research support from The Mahaffy Family Research Fund. The institution of Dr. Boulos has received research support from Canadian Institutes of Health Research. The institution of Dr. Boulos has received research support from Slamen-Fast New Initiatives in Neurology Award. The institution of Dr. Boulos has received research support from Green Mountain . Dr. Boulos has received personal compensation in the range of $5,000-$9,999 for serving as a speaker with Jazz Pharmaceuticals.

Feasibility Study of Bariatric Surgery in a Rat Model of Spinal Cord Injury to Achieve Beneficial Body Weight Outcome.

Approximately two thirds of spinal cord injury (SCI) persons become overweight or obese. Obesity increases the risk of developing type 2 diabetes and limits self-help techniques. Weight-loss surgery (WLS), including vertical sleeve gastrectomy (VSG), is regarded as highly effective in the long-term treatment of obesity and remission of associated type 2 diabetes. Given the increased risk of obesity post-SCI, WLS offers an attractive intervention strategy. Alterations in the physiology of energy homeostasis after SCI necessitate that SCI persons should not be regarded as similar to able-bodied persons. Because of current knowledge gaps, it is unknown whether an obese phenotype with SCI will respond to WLS similarly to the neurally intact obese phenotype. Therefore, this study tested the hypothesis that the VSG procedure is well tolerated and effective in an animal model of high-thoracic (T3) SCI. In Wistar male rats, subsequent to a 2-week recovery period after T3-SCI, but not control laminectomy surgery, daily consumption of a high-fat diet (HFD; 60% kcal from fat) was elevated over 4 weeks preceding VSG. After a 2-week recovery period post-VSG, HFD consumption in T3-SCI rats over a 4-week monitoring period returned to levels comparable to control. Body weight was significantly reduced in T3-SCI rats and remained reduced whereas control rats regained body weight. Further, no adverse complications directly attributable to the VSG procedure were identified. Thus, this rodent model is a viable tool for addressing fundamental questions regarding the mechanisms leading to obesity post-SCI and the development of translational strategies.

Acute Intermittent Hypoxia Improves Orthostatic Tolerance in Chronic but not Acute Spinal Cord Injured Rats

Spinal cord injury (SCI) causes hypotension and orthostatic intolerance due to disrupted sympathetic input to the heart and vasculature following injury1. A neuro‐therapeutic strategy shown to increase somatic motor function below the injury is acute intermittent hypoxia (AIH). While AIH is known to improve control over respiratory and non‐respiratory motor systems with incomplete cervical SCI2,3, cardio‐autonomic responses to AIH after SCI are unknown. In able‐bodied individuals, AIH increases blood pressure (BP), improves orthostatic tolerance (OT), and heightens sympathetic activity4. In incomplete SCI, intact neural pathways regulating sympathetic nerve activity suggest the potential for AIH to increase sub‐lesional sympathetic activity, thus improving cardiovascular function. Previous work has demonstrated that the response to AIH is greatest in rats at least 4 weeks post‐injury due to reestablishment of serotonergic pathways2, therefore the purpose of this project is to investigate whether AIH improves OT in rats following acute (2 weeks) and/or chronic (4 weeks) high‐thoracic SCI. We believe AIH will improve OT more in chronically versus acutely injured rats.12 Wistar rats underwent T3 300 kdyn SCI. At 14 (n=6) or 28 (n=6) days post‐SCI rats were tracheotomized, ventilated and arterial catheterization was performed to assess BP. Rats were subjected to lower body negative pressure (LBNP; recorded with manometer) to decrease mean arterial pressure (MAP) by 5 and 10 mmHg for 1 min. Rats were exposed to isocapnic AIH (10 x 1‐min FIO2=0.10 separated by 2 min of FIO2=1.00; targeting a PaCO2 of 40 mmHg). LBNP was repeated 90 minutes post‐AIH, the expected peak response. Blood gases were measured pre‐ and post‐AIH. A mixed‐design ANOVA was performed to examine effects of time post‐SCI (group) and AIH (treatment) on change in box pressure required to decrease MAP by ‐5 and ‐10 mmHg.There was a significant group*treatment interaction for the ‐5 mmHg (p=0.011) and ‐10 mmHg LBNP stage (p=0.017). Post hoc comparisons demonstrate that in chronic SCI the box pressure required to drop MAP by ‐5 and ‐10mmHg was increased by 41±16% (p=0.009) and 46±22% (p=0.079) versus pre‐AIH, respectively, implying improved OT (Fig 1).We demonstrate that AIH has the capacity to improve OT in a rodent model of SCI in a chronic, but not acute setting.

Preserved Cardio‐Inotropic Baroreflex Function Following Optimized Hemodynamic Management in High‐Thoracic Spinal Cord Injury

. Chronic high-level spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, notably impairments to cardiac contractile function and baroreflex control of blood pressure. Recently, our group has demonstrated that hemodynamic management targeting the heart (i.e. dobutamine, DOB), rather than standard vasopressor treatment (i.e. norepinephrine, NE) improves cord oxygenation and mitigates hemorrhage in a porcine model of acute T2 SCI. Yet, the potential long-term cardiovascular benefits of acute cardio-centric hemodynamic management remain elusive.Assess the chronic changes in hemodynamics and baroreflex function associated with acute DOB administration in animals with T2 SCI.17 Yucatan mini-pigs received a T2 weight-drop contusion SCI, with either DOB (2.5 ug/kg/min, n=6), NE (4.25 ug/kg/min, n=6) or no treatment (CON, n=5) starting at 30 mins until 6 hrs post-SCI. Animals were subsequently recovered and housed for 12 weeks post-SCI. During terminal experiments, animals were instrumented with left ventricular (LV), pulmonary artery and femoral artery catheters to assess LV function, cardiac output (Q) and blood pressure, respectively. Linear regression analyses were used to estimate cardiovagal baroreflex (V-BRx) gain from the relationship of pulse interval vs. systolic blood pressure, and "cardio-inotropic" baroreflex (I-BRx) gain from the relationship of LV contractile function (rate of pressure rise for a given end-diastolic volume) vs. diastolic blood pressure during modified Oxford tests.Data are presented as means±SD. At 12 weeks post-SCI, DOB animals had preserved cardiac output (∆Q=+531±471ml/min) and mean arterial pressure (MAP=81±9mmHg), whereas both Q and MAP were lower in CON animals (∆Q=-385±720ml/min, p=0.44; MAP=65±3mmHg, p<0.0037). In contrast, NE-treated animals had uncharacteristic hypertension as indicated by elevations to MAP (NE=88±11 vs. CON=65±3mmHg, p=0.0029), arterial elastance (NE=3.7±0.4 vs. CON=2.7±0.1mmHg/ml, p=0.016) and total peripheral resistance (NE=50.3±4.3 vs. CON:35.7±10.3mmHg/ml/min, p=0.074). I-BRx function also appeared to be improved in DOB (slope=-0.56±0.33ml/s) vs. CON (slope=-0.04±0.05ml/s, p=0.044), while V-BRx gain did not differ between groups.Cardio-centric management appears to optimize cardiovascular hemodynamics more effectively than vasopressor therapy in chronic high-thoracic SCI. Reduced secondary spinal cord damage with DOB therapy may preserve descending sympathetic pathways to the heart, ultimately improving baroreflex control of blood pressure.

Systems Thinking

Systems Thinking

Experimental high thoracic spinal cord injury impairs the cardiac and cerebrovascular response to orthostatic challenge in rats.

Spinal cord injury (SCI) impairs the cardiovascular responses to postural challenge, leading to the development of orthostatic hypotension (OH). Here, we apply lower body negative pressure (LBNP) to rodents with high-level SCI to demonstrate the usefulness of LBNP as a model for experimental OH studies, and to explore the effect of simulated OH on cardiovascular and cerebrovascular function following SCI. Male Wistar rats (n = 34) were subjected to a sham or T3-SCI surgery and survived into the chronic period postinjury (i.e., 8 wk). Cardiac function was tracked via ultrasound pre- to post-SCI to demonstrate the clinical utility of our model. At study termination, we conducted left-ventricular (LV) catheterization and insonated the middle cerebral artery to investigate the hemodynamic, cardiac, and cerebrovascular response to a mild dose of LBNP that is sufficient to mimic clinically defined OH in rats with T3-SCI but not sham animals. In response to mimicked OH, there was a greater decline in stroke volume, cardiac output, maximal LV pressure, and blood pressure in SCI compared with sham (P < 0.034), whereas heart rate was increased in sham but decreased in SCI (P < 0.029). SCI animals also had an exaggerated reduction in peak, minimum and mean middle cerebral artery flow, for a given change in blood pressure, in response to LBNP (P < 0.033), implying impaired dynamic cerebral autoregulation. Using a preclinical SCI model of OH, we demonstrate that complete high thoracic SCI impairs the cardiac response to OH and disrupts dynamic cerebral autoregulation.NEW & NOTEWORTHY This is the first use of LBNP to interrogate the cardiac and cerebrovascular responses to simulated OH in a preclinical study of SCI. Here, we demonstrate the utility of our simulated OH model and use it to demonstrate that SCI impairs the cardiac response to simulated OH and disrupts dynamic cerebrovascular autoregulation.

MANAGEMENT OF RECURRENT BRADYCARDIA WITH THEOPHYLLINE IN THE SETTING OF SPINAL CORD INJURY

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Cardiovascular complications are common in patients with cervical or high thoracic spinal cord injury (SCI) including autonomic dysreflexia and cardiac arrhythmias. Cardiac instability is a result of disruption of the descending sympathetic pathways and lack of compensation to parasympathetic responses via the vagus nerve for supraspinal control of the heart. We present a rare case of a 49-year-old male with recurrent episodes of bradycardia and subsequent complete heart block post SCI responding to theophylline. CASE PRESENTATION: 49-year-old male with a history significant for T5 fracture and spinal cord injury resulting in paraplegia was found to have brief episodes of bradycardia two months post accident during prolonged ventilator weaning. He was initially treated with and titrated off chronotropic agents (dopamine and isoproterenol). A month later, he began having recurrent episodes of transient complete heart block with the absence of ventricular activity for up to 30 seconds. After the period of heart block, he would progress to sinus bradycardia for about 30 seconds before transitioning to normal sinus rhythm. After specialty consultation, the patient was started on theophylline 100 mg three times daily with complete resolution of his symptoms for nine days. Then, during manual disimpaction, he had re-emergence of his transient complete heart block and had a brief cardiac arrest with pulseless electrical activity, which led to the implantation of a leadless pacemaker. DISCUSSION: This patient is unique in that cardiac dysrhythmias and cardiac arrest are more common in the acute phase of SCIs (2-6 weeks post injury), whereas this patient was 3 months post injury. Chronotropic and inotropic infusions are the primary treatment strategy for bradyarrhythmias. Dopamine and isoproterenol were trialed in the patient but stopped due to transient improvement in the symptoms. Minimizing vagal stimulation is important for the prevention of bradycardia associated with SCIs. Theophylline has been found to have anti-bradyarrhythmia effects and may be used for prevention of recurrent bradycardia. The mechanism is thought to be through antagonism of adenosine receptors, which is a crucial pathway in patients with high SCIs with unopposed vagal tone. In this case, initiation of oral theophylline prevented recurrent bradycardia and complete heart block for 9 days before a pacemaker was implanted. CONCLUSIONS: Routine use of theophylline to prevent cardiovascular complications in spinal cord injuries is not well known. Methylxanthine therapy may prevent recurrent bradyarrhythmias from occurring and avert or delay implantation of a pacemaker. REFERENCE #1: Furlan JC, Fehlings MG. Cardiovascular complications after acute spinal cord injury: pathophysiology, diagnosis, and management. Neurosurg Focus. 2008;25(5):E13. doi: 10.3171/FOC.2008.25.11.E13. REFERENCE #2: Alboni P, Rossi P, Ratto B, Pedroni P, Gatto E, Antonioli GE. Electrophysiologic effects of oral theophylline in sinus bradycardia. Am J Cardiol.1990; 65:1037-1039. REFERENCE #3: Whitman CB, Schroeder WS, Ploch PJ, Raghavendran K. Efficacy of aminophylline for treatment of recurrent symptomatic bradycardia after spinal cord injury. Pharmacotherapy. 2008 Jan;28(1):131-5. doi: 10.1592/phco.28.1.131. DISCLOSURES: No relevant relationships by Kirsten McGrew, source=Web Response No relevant relationships by Lindsay Saum, source=Web Response No relevant relationships by Adam Smalley, source=Web Response

Timing of tracheostomy in acute traumatic spinal cord injury: A systematic review and meta-analysis.

Patients with acute traumatic cervical or high thoracic level spinal cord injury (SCI) typically require mechanical ventilation (MV) during their acute admission. Placement of a tracheostomy is preferred when prolonged weaning from MV is anticipated. However, the optimal timing of tracheostomy placement in patients with acute traumatic SCI remains uncertain. We systematically reviewed the literature to determine the effects of early versus late tracheostomy or prolonged intubation in patients with acute traumatic SCI on important clinical outcomes. Six databases were searched from their inception to January 2020. Conference abstracts from relevant proceedings and the gray literature were searched to identify additional studies. Data were obtained by two independent reviewers to ensure accuracy and completeness. The quality of observational studies was evaluated using the Newcastle Ottawa Scale. Seventeen studies (2,804 patients) met selection criteria, 14 of which were published after 2009. Meta-analysis showed that early tracheostomy was not associated with decreased short-term mortality (risk ratio [RR], 0.84; 95% confidence interval [CI], 0.39-1.79; p = 0.65; n = 2,072), but was associated with a reduction in MV duration (mean difference [MD], 13.1 days; 95% CI, -6.70 to -21.11; p = 0.0002; n = 855), intensive care unit length of stay (MD, -10.20 days; 95% CI, -4.66 to -15.74; p = 0.0003; n = 855), and hospital length of stay (MD, -7.39 days; 95% CI, -3.74 to -11.03; p < 0.0001; n = 423). Early tracheostomy was also associated with a decreased incidence of ventilator-associated pneumonia and tracheostomy-related complications (RR, 0.86; 95% CI, 0.75-0.98; p = 0.02; n = 2,043 and RR, 0.64; 95% CI, 0.48-0.84; p = 0.001; n = 812 respectively). The majority of studies ranked as good methodologic quality on the Newcastle Ottawa Scale. Early tracheostomy in patients with acute traumatic SCI may reduce duration of mechanical entilation, length of intensive care unit stay, and length of hospital stay. Current studies highlight the lack of high-level evidence to guide the optimal timing of tracheostomy in acute traumatic SCI. Future research should seek to understand whether early tracheostomy improves patient comfort, decreases duration of sedation, and improves long-term outcomes. Systematic Review, level III.

Spinal Cord Injury Increases Pro-inflammatory Cytokine Expression in Kidney at Acute and Sub-chronic Stages

—Accumulating evidence supports that spinal cord injury (SCI) produces robust inflammatory plasticity. We previously showed that the pro-inflammatory cytokine tumor necrosis factor (TNF)α is increased in the spinal cord after SCI. SCI also induces a systemic inflammatory response that can impact peripheral organ functions. The kidney plays an important role in maintaining cardiovascular health. However, SCI-induced inflammatory response in the kidney and the subsequent effect on renal function have not been well characterized. This study investigated the impact of high and low thoracic (T) SCI on C-fos, TNFα, interleukin (IL)-1β, and IL-6 expression in the kidney at acute and sub-chronic timepoints. Adult C57BL/6 mice received a moderate contusion SCI or sham procedures at T4 or T10. Uninjured mice served as naïve controls. mRNA levels of the proinflammatory cytokines IL-1β, IL-6, TNFα, and C-fos, and TNFα and C-fos protein expression were assessed in the kidney and spinal cord 1 day and 14 days post-injury. The mRNA levels of all targets were robustly increased in the kidney and spinal cord, 1 day after both injuries. Whereas IL-6 and TNFα remained elevated in the spinal cord at 14 days after SCI, C-fos, IL-6, and TNFα levels were sustained in the kidney only after T10 SCI. TNFα protein was significantly upregulated in the kidney 1 day after both T4 and T10 SCI. Overall, these results clearly demonstrate that SCI induces robust systemic inflammation that extends to the kidney. Hence, the presence of renal inflammation can substantially impact renal pathophysiology and function after SCI.

Quantitative analysis of dysautonomia in patients with autonomic dysreflexia.

Autonomic dysreflexia (AD) is a life-threatening condition for individuals with cervical or high-thoracic spinal cord injury (SCI). The profile of autonomic dysfunction in AD using validated clinical autonomic tests has not been described so far, although it could be useful to identify SCI patients at greater risk of developing AD non-invasively. With this objective, 37 SCI patients (27% female) were recruited, and hemodynamic and cardiac parameters were continuously monitored to determine the presence of AD, defined as an increase of systolic blood pressure of 20mmHg or higher after bladder filling with saline. Then, standard autonomic function testing was performed, including Deep Breathing, Valsalva Manoeuvre and Tilt Table Test. Finally, baroreflex sensitivity (BRS), and spectral analysis of heart rate and blood pressure variability were measured at rest. Catecholamines and vasopressin levels were also measured at supine and upright positions. The severity of SCI was assessed through clinical and radiological examinations. AD was observed in 73.3% of SCI patients, being 63.6% of them asymptomatic during the dysreflexive episode. AD patients displayed a drop in sympathetic outflow, as determined by decreased noradrenalin plasma levels, reduced sympathovagal balance and increased BRS. In line with decreased sympathetic activity, the incidence of neurogenic orthostatic hypotension was higher in AD patients. Our results provide novel evidence regarding the autonomic dysfunction in SCI patients with AD compared to non-AD patients, posing non-invasively measured autonomic parameters as a powerful clinical tool to predict AD in SCI patients.

Cardio-centric hemodynamic management improves spinal cord oxygenation and mitigates hemorrhage in acute spinal cord injury

Chronic high-thoracic and cervical spinal cord injury (SCI) results in a complex phenotype of cardiovascular consequences, including impaired left ventricular (LV) contractility. Here, we aim to determine whether such dysfunction manifests immediately post-injury, and if so, whether correcting impaired contractility can improve spinal cord oxygenation (SCO2), blood flow (SCBF) and metabolism. Using a porcine model of T2 SCI, we assess LV end-systolic elastance (contractility) via invasive pressure-volume catheterization, monitor intraparenchymal SCO2 and SCBF with fiberoptic oxygen sensors and laser-Doppler flowmetry, respectively, and quantify spinal cord metabolites with microdialysis. We demonstrate that high-thoracic SCI acutely impairs cardiac contractility and substantially reduces SCO2 and SCBF within the first hours post-injury. Utilizing the same model, we next show that augmenting LV contractility with the β-agonist dobutamine increases SCO2 and SCBF more effectively than vasopressor therapy, whilst also mitigating increased anaerobic metabolism and hemorrhage in the injured cord. Finally, in pigs with T2 SCI survived for 12 weeks post-injury, we confirm that acute hemodynamic management with dobutamine appears to preserve cardiac function and improve hemodynamic outcomes in the chronic setting. Our data support that cardio-centric hemodynamic management represents an advantageous alternative to the current clinical standard of vasopressor therapy for acute traumatic SCI.

Vascular-Cognitive Impairment following High-Thoracic Spinal Cord Injury Is Associated with Structural and Functional Maladaptations in Cerebrovasculature.

Individuals living with chronic spinal cord injury (SCI) often exhibit impairments in cognitive function, which impede their rehabilitation and transition into the community. Although a number of clinical studies have demonstrated the impact of impaired cardiovascular control on cognitive impairment, the mechanistic understanding of this deleterious relationship is still lacking. The present study investigates whether chronic disruption of cardiovascular control following experimental SCI results in cerebrovascular decline and vascular cognitive impairment. Fourteen weeks following a high thoracic SCI (at the third thoracic segment), rats were subjected to a battery of in vivo and in vitro physiological assessments, cognitive-behavioral tests, and immunohistochemical approaches to investigate changes in cerebrovascular structure and function in the middle cerebral artery (MCA). We show that in the MCA of rats with SCI, there is a 55% (SCI vs. control: 13.4 ± 1.9% vs. 29.63 ± 2.8%, respectively) reduction in the maximal vasodilator response to carbachol, which is associated with reduced expression of endothelial marker cluster of differentiation 31 (CD31) and transient receptor potential cation channel 4 (TRPV 4) channels. Compared with controls, MCAs in rats with SCI were found to have 50% (SCI vs. control: 1.5 ± 0.2 vs. 1 ± 0.1 a.u., respectively) more collagen 1 in the media of vascular wall and 37% (SCI vs. control: 30.5 ± 2.9% vs. 42.0 ± 4.0%, respectively) less distensibility at physiological intraluminal pressure. Further, the cerebral blood flow (CBF) in the hippocampus was reduced by 32% in the SCI group (SCI vs. control: 44.3 ± 4.5 mL/100 g/min vs. 65.0 ± 7.2 mL/100 g/min, respectively) in association with impairment of short-term memory based on a novel object recognition test. There were no changes in the sympathetic innervation of the vasculature and passive structure in the SCI group. Chronic experimental SCI is associated with structural alterations and endothelial dysfunction in cerebral arteries that likely contribute to significantly reduced CBF and vascular cognitive impairment.

Diminished enteric neuromuscular transmission in the distal colon following experimental spinal cord injury

Neurogenic bowel following spinal cord injury (SCI) leads to decreased colonic motility, remodeling of the neuromuscular compartment and results in chronic evacuation difficulties. The distal colon of the rat serves a dual role for fluid absorption and storage that is homologous to the descending colon of humans. Dysmotility of the descending colon is one component of neurogenic bowel. We investigated the integrity of the enteric neuromuscular transmission responsible for the generation of excitatory and inhibitory junction potentials (EJPs and IJPs, respectively) in the distal colon of rats. We previously demonstrated a chronic reduction in colonic enteric neurons from rats with acute and chronic high-thoracic (T3) SCI and hypothesized that neurogenic bowel following T3-SCI results from diminished enteric neuromuscular transmission.Immunohistochemical labeling for myenteric neuronal nitric oxide synthase (nNOS) and choline acetyltransferase (ChAT) neurons demonstrated a significant loss of presumptive nitric oxide (NO) and acetylcholine (ACh) immunoreactive neurons in both 3-day and 3-week injured animals. Colonic neuromuscular transmission in response to transmural electrical stimulation of the colon was significantly reduced 3-days and 3-weeks following SCI in male rats. Specifically, cholinergic-mediated excitatory junction potentials (EJPs) and nitrergic-mediated slow inhibitory junction potentials (IJPs) were significantly reduced while ATP-mediated fast IJPs remained unaffected.We conclude that a reduction in excitatory and inhibitory enteric neuromuscular transmission contributes to neurogenic bowel observed following SCI, and that these loss-of-function changes involve enteric-mediated cholinergic and nitrergic pathways.

Blood pressure response to detrusor pressure elevation in patients with a reflex urinary bladder after a cervical or high thoracic spinal cord injury

In 12 patients with a reflex urinary bladder after a cervical or high thoracic spinal cord injury, blood pressure was measured every 30 s during cystometry. Four consecutive cystometries were performed by means of suprapubical catheters and 50 ml/min filling rate. The aim was to improve the methodological basis for cystometrical studies of paroxysmal hypertension and its treatment. In each cystometry there was an elevation of the systolic (20-60 mmHg) and the diastolic (15-55 mmHg) blood pressure. The maximum blood pressure always occurred during the emptying phase and always in close relation to the peak of the detrusor pressure. The amplitude of the blood pressure response varied intraindividually, but did not change in any particular direction during the series of cystometries. Thus, a cystometrical method which stimulates the detrusor in a physiological way is sufficient to give the typical uninhibited blood pressure reaction in most patients with a reflex bladder and a spinal reflex vasomotor function after a high level spinal cord injury. The blood pressure reaction obtained with this method is probably representative for the daily reaction during physiological reflex emptying of the bladder. To describe the maximum blood pressure reaction, it has to be measured during a well defined emptying phase and close to the occurrence of the maximum detrusor pressure. Since repetition of cystometry did not change the blood pressure response, this cystometrical method is useful for evaluation of pharmacological intervention.