Disordered cardiovascular control after spinal cord injury.

Damage to the spinal cord disrupts autonomic pathways, perturbing cardiovascular homeostasis. Cardiovascular dysfunction increases with higher levels of injury and greater severity. Disordered blood pressure control after spinal cord injury (SCI) has significant ramifications as cord-injured people have an increased risk of developing heart disease and stroke; cardiovascular dysfunction is currently a leading cause of death among those with SCI. Despite the clinical significance of abnormal cardiovascular control following SCI, this problem has been generally neglected by both the clinical and research community. Both autonomic dysreflexia and orthostatic hypotension are known to prevent and delay rehabilitation, and significantly impair the overall quality of life after SCI. Starting with neurogenic shock immediately after a higher SCI, ensuing cardiovascular dysfunctions include orthostatic hypotension, autonomic dysreflexia and cardiac arrhythmias. Disordered temperature regulation accompanies these autonomic dysfunctions. This chapter reviews the human and animal studies that have furthered our understanding of the pathophysiology and mechanisms of orthostatic hypotension, autonomic dysreflexia and cardiac arrhythmias. The cardiovascular dysfunction that occurs during sexual function and exercise is elaborated. New awareness of cardiovascular dysfunction after SCI has led to progress toward inclusion of this important autonomic problem in the overall assessment of the neurological condition of cord-injured people.

Pulsatile versus nonpulsatile flow during cardiopulmonary bypass: microcirculatory and systemic effects.

BACKGROUND: Controversy exists regarding the optimal perfusion modality during cardiopulmonary bypass (CPB). Here we compare the effects of pulsatile versus nonpulsatile perfusion on microvascular blood flow during and after CPB. METHODS: High-risk cardiac surgical patients were randomly assigned to have pulsatile (n=10) or nonpulsatile (n=10) flow during CPB. The sublingual microcirculation was assessed using orthogonal polarization spectral imaging. Hemodynamic and microvascular variables were obtained after anesthesia (baseline), during CPB, and post-CPB. RESULTS: Compared with baseline, a normal microcirculatory blood flow pattern was accomplished at all time points under pulsatile flow conditions. Peaking 24 hours postoperatively, a higher proportion of normally perfused microvessels occurred under pulsatile versus nonpulsatile flow (56.0%±3.9% vs 33.3%±4.1%; p<0.05). Concurrently, pulsatility resulted in a reduction in the prevalence of pathologic hyper-dynamically perfused vessels (6.0%±3.4% vs 19.6%±8.8%; p<0.05). Leukocyte adherence decreased relative to the nonpulsatile group both during and after CPB. Furthermore, peak lactate levels were reduced under pulsatile flow conditions postoperatively. CONCLUSIONS: Pulsatile perfusion is superior to nonpulsatile perfusion at preserving the microcirculation, which may reflect attenuation of the systemic inflammatory response during CPB. We suggest the implementation of pulsatile flow can better optimize microvascular perfusion, and may lead to improved patient outcomes in high-risk cardiac surgical procedures requiring prolonged CPB time.

Predicting the need for tracheostomy in patients with cervical spinal cord injury.

BACKGROUND: Approximately 75% of hospitalized patients with a cervical spinal cord injury (CSCI) will require intubation and mechanical ventilation (MV) because of compromised respiratory function. It is difficult to predict those CSCI patients who will require prolonged ventilation and therefore will most benefit from early tracheostomy. This study intended to show the benefits of tracheostomy, particularly early, and to identify predictors of prolonged MV after CSCI. METHODS: A retrospective review of patients aged 16 years and older with acute CSCI admitted to London Health Science Center from 1991 to 2010 was performed. Demographic data and clinical parameters were extracted from medical records and the trauma registry. Regression analysis was used to identify predictors of prolonged MV. RESULTS: There were 66 eligible patients of which 42 (62%) had a tracheostomy performed. Five patients (7.6%) remained ventilator dependent and seven (10.6%) died more than 7 days after injury secondary to sepsis. After adjusting for the number of ventilator days after injury, patients who had a tracheostomy had fewer pulmonary complications than those who did not have a tracheostomy (p = 0.001). Early tracheostomy resulted in fewer days on the ventilator and a shorter hospital stay. Clinical parameters that predicted MV to be required longer than 7 days were Injury Severity Score > 32, complete SCI, and a PAO2/FIO2 ratio < 300 3 days after MV was initiated. CONCLUSION: We recommend early tracheostomy if the Injury Severity Score is >32, the patient has a complete SCI, and the PAO2/FIO2 ratio is <300 3 days after MV was initiated. LEVEL OF EVIDENCE: Prognostic study, level III.

Remote inflammatory response in liver is dependent on the segmental level of spinal cord injury.

BACKGROUND: Traumatic spinal cord injury (SCI) triggers a systemic inflammatory response (SIR) that contributes to a high incidence of secondary organ complications, particularly after a cervical or high-level thoracic injury. Because liver plays a key role in initiating and propagating the SIR, the aim of this study was to assess the effects that SCI at differing segmental levels has on the intensity of the inflammatory response in the liver. METHODS: Using male Wistar rats, clip compression SCI was performed at the 4th thoracic (T4 SCI; high-level SCI) or the 12th thoracic (T12 SCI; low-level SCI) spinal cord segment. Sham-injured rats had a partial laminectomy, but no SCI. Leukocyte recruitment to the liver, hepatic blood flow, and hepatocellular injury/death were assessed using intravital microscopy and histology. Chemokine and cytokine concentrations were assessed in the liver. Outcomes were measured at 1.5 hours, 12 hours, and 24 hours after SCI. RESULTS: At 12 hours after injury, T4 SCI caused a threefold increase in hepatic leukocyte recruitment compared with T12 SCI (p < 0.05). T4 SCI induced 50% more hepatocyte injury than T12 SCI at 12 hours (p < 0.05). Hepatic blood flow decreased after SCI, but not after sham injury, and stayed decreased only after T4 SCI at 24 hours after injury. The T4 SCI-induced changes were accompanied by increases in the hepatic concentrations of interleukin-1ß, leptin, interleukin 10, and cytokine-induced neutrophil chemoattractant-1 at 1.5 hours. CONCLUSIONS: Our findings indicate that traumatic SCI triggers an acute SIR that contributes to hepatocellular injury. SCI-induced remote injury/dysfunction to the liver appears to be transient and is more robust after an upper thoracic SCI compared with a lower thoracic SCI.

An anatomic study of the interspinous space of the lumbosacral spine.

PURPOSE: The purpose of this study is to quantify the interspinous anatomy at the L4/5 and L5/S1 levels. METHODS: One hundred reconstructed computer tomography scans of the lumbosacral spine were reviewed by two separate surgeons. Data were collected from the midline sagittal reconstructed image at the L4-5 and L5-S1 levels. Measurements obtained included the disc angle, anterior and posterior disc height, and maximum interspinous space in both the anterior-posterior and cephalad-caudal directions. The disc height and disc angle were correlated with the interspinous height. RESULTS: The mean age of the patients reviewed was 47 years (range: 16-91; standard deviation: 20). According to our data population, the average length of the interspinous space was larger at the L4-5 level (13 mm) than the L5-S1 level (9 mm). The interspinous height was similar between the two levels. A poor correlation existed between the disc height or disc angle and the interspinous height. There was no correlation between measurements and age. CONCLUSIONS: The interspinous space available, as defined by computer tomography, at the L5/S1 level, is less able to accommodate current interspinous devices compared to the adjacent L4/5 level. The limiting factor is the length of the sacral part of the L5-S1 interspinous space.

A selective phosphodiesterase-4 inhibitor reduces leukocyte infiltration, oxidative processes, and tissue damage after spinal cord injury.

We tested the hypothesis that a selective phosphodiesterase type 4 inhibitor (PDE4-I; IC486051) would attenuate early inflammatory and oxidative processes following spinal cord injury (SCI) when delivered during the first 3 days after injury. Rats receiving a moderately severe thoracic-clip-compression SCI were treated with the PDE4-I (0.5, 1.0, and 3.0 mg/kg IV) in bolus doses from 2-60 h post-injury. Doses at 0.5 mg/kg and 1.0 mg/kg significantly decreased myeloperoxidase (MPO) enzymatic activity (neutrophils), expression of a neutrophil-associated protein and of ED-1 (macrophages), and estimates of lipid peroxidation in cord lesion homogenates at 24 h and 72 h post-injury by 25-40%. The 3.0 mg/kg dose had small or no effects on these measures. The PDE4-I treatment (0.5 or 1.0 mg/kg) reduced expression of the oxidative enzymes gp91(phox), inducible nitric oxide synthase, and cyclooxygenase-2, and diminished free radical generation by up to 40%. Treatment with 0.5 mg/kg PDE4-I improved motor function (as assessed by the Basso-Beattie-Bresnahan scale) significantly from 4-8 weeks after SCI (average difference 1.3 points). Mechanical allodynia elicited from the hindpaw decreased by up to 25%. The PDE4-I treatment also increased white matter volume near the lesion at 8 weeks after SCI. In conclusion, the PDE4-I reduced key markers of oxidative stress and leukocyte infiltration, producing cellular protection, locomotor improvements, and a reduction in neuropathic pain. Early inhibition of PDE4 is neuroprotective after SCI when given acutely and briefly at sufficient doses.

Anti-alpha4beta1 integrin antibody induces receptor internalization and does not impair the function of circulating neutrophilic leukocytes.

OBJECTIVE: A compelling strategy for treatment of spinal cord injury is the blockade of integrin-mediated leukocyte extravasation using a monoclonal antibody (mAb) against the alpha4 subunit of the alpha4beta1-integrin. However, little is known with respect to neutrophil function following anti-alpha4 mAb treatment. This study assessed the effects of anti-alpha4 mAb binding on neutrophil activation [reactive oxygen species (ROS) production], function (phagocytic activity) and anti-alpha4-mAb/alpha4beta1-integrin-complex internalization. METHODS: Resting, primed or stimulated rat neutrophils were incubated ex vivo with anti-alpha4 mAb or isotype-control antibody. ROS production, phagocytic activity, and anti-alpha4-mAb/alpha4beta1-integrin-complex internalization were determined by flow cytometry using dihydrorhodamine (DHR1,2,3), fluorescent microspheres, and indirect immunolabeling, respectively. RESULTS: Brief (0.5 h) incubation of resting, primed or activated neutrophils with anti-alpha4 mAb had no effect on ROS production and did not change neutrophil phagocytic activity. However, prolonged incubation (2 h), assessed only in resting neutrophils, increased ROS production. The anti-alpha4-mAb/alpha4beta1-integrin-complex was internalized after 1 h of anti-alpha4 mAb treatment and remained internalized up to 6 h. CONCLUSION: Neutrophil ROS production and phagocytic function remain unaltered after brief anti-alpha4 mAb exposure, demonstrating that use of this mAb as a treatment should not adversely affect important beneficial roles of these cells.

Timing and duration of anti-alpha4beta1 integrin treatment after spinal cord injury: effect on therapeutic efficacy.

OBJECT: After spinal cord injury (SCI) leukocytes infiltrate the injured cord, causing significant damage and further impairment of functional recovery. The leukocyte integrin alpha4beta1 is crucial for their entry. The authors previously demonstrated that an anti-alpha4 monoclonal antibody (mAb) treatment attenuates leukocyte infiltration, improves motor and autonomic function, and reduces neuropathic pain when administered at 2 hours and 24 hours after SCI. METHODS: The authors conducted 2 preclinical studies: the first determined effects of treatment commencing at 6 hours, a clinically relevant time after injury, and the second examined effects of long-lasting treatment (28 days) on neurological recovery after SCI, as current clinically used anti-inflammatory monoclonal antibodies have such longevity. In the first study (timing study), rats were treated with anti-alpha4 or control mAb (intravenously) at 6 hours and 48 hours after moderate (35 g) thoracic compression SCI. Effects on intraspinal inflammation and oxidative injury were assessed at 3 and 7 days after SCI; motor function and pain were examined for 6 weeks. In the second study (duration study), anti-alpha4 mAb was administered starting 2 hours after SCI and subsequently every 3 days for 4 weeks (total of 8 doses), using a schedule of decreasing doses to resemble the pharmacodynamics of long-lasting antibodies used clinically. Motor function and pain were examined for 6 weeks. Lesions were assessed for tissue sparing and inflammation at 6 weeks by histological examination and MR imaging. RESULTS: Anti-alpha4 mAb treatment at 6 hours and 48 hours after SCI (timing study) significantly decreased neutrophil and monocyte/macrophage influx at 3 days by 36% and 20%, respectively, but had no effect by at 7 days after SCI. Antibody treatment significantly reduced intraspinal myeloperoxidase activity by 48% and lipid peroxidation by 27% at 3 days post-injury. The treatment did not improve locomotor function but reduced mechanical allodynia elicited from the trunk and hind paw by ~50% at 3-6 weeks after SCI. In contrast, long-term mAb treatment commencing at 2 hours after SCI (duration study) significantly improved locomotor function at 2-6 weeks after SCI, (mean BBB scores +/- SE: treated rats, 8.3 +/- 0.16; controls, 7.3 +/- 0.2 at 6 weeks). At 3-6 weeks, mAb treatment decreased mechanical allodynia elicited from the trunk and hind paw by ~55%. This recovery correlated with 30% more myelin-containing white matter in treated rats than controls at 6 weeks. The lesion cavity was smaller in the treated rats when assessed by both histological (-37%) and imaging (-50%) methods. The accumulation of ED1-immunoreactive microglia/macrophages at the lesion was similar in treated and control rats. CONCLUSIONS: Although delayed treatment reduced intraspinal inflammation and pain, motor function was not improved, revealing decreased efficacy at the more clinically feasibly treatment onset. Long-term anti-alpha4 mAb treatment starting 2 hours after SCI improved neurological outcomes, with tissue sparing near the lesion and no impairment of the late immune response to injury. These findings reveal no disadvantage of long-lasting immunosuppression by the treatment but show that efficacy depends upon very early delivery.

Alpha4beta1 integrin blockade after spinal cord injury decreases damage and improves neurological function.

The extent of disability caused by spinal cord injury (SCI) relates to secondary tissue destruction arising partly from an intraspinal influx of neutrophils and monocyte/macrophages after the initial injury. The integrin alpha4beta1, expressed by these leukocytes, is a key to their activation and migration into/within tissue. Therefore, blocking this integrin's functions may afford significant neuroprotection. Rats were treated intravenously with a blocking monoclonal antibody (mAb) to the alpha4 subunit of alpha4beta1 at 2 and 24 h after thoracic clip-compression SCI. Anti-alpha4beta1 treatment significantly decreased neutrophil and monocyte/macrophage influx at 3 d by 47% and 53%, respectively, and decreased neutrophil influx by 61% at 7 d after SCI. Anti-alpha4beta1 treatment also significantly reduced oxidative activity in injured cord homogenates at 3 d. For example, myeloperoxidase activity decreased by 38%, inducible nitric oxide by 44%, dichlorofluorescein (marking free radicals) by 33% and lipid peroxidation (malondialdehyde) by 42%. At 2-8 weeks after SCI, motor function improved by up to 2 points on an open-field locomotor scale. Treated rats supported weight with their hind paws instead of sweeping. At 2-4 weeks after SCI, anti-alpha4beta1 treatment decreased blood pressure responses during autonomic dysreflexia by as much as 43% and, at 2-8 weeks, decreased mechanical allodynia elicited from the trunk and hind paw by up to 54% and 40%, respectively. This improved functional recovery correlated with spared myelin-containing white matter and >10-fold more bulbospinal serotonergic axons below the injury than were in controls. The significant neurological improvement offered by this neuroprotective strategy underscores the potential for an anti-integrin treatment for SCI.

The cellular inflammatory response in human spinal cords after injury.

Spinal cord injury (SCI) provokes an inflammatory response that generates substantial secondary damage within the cord but also may contribute to its repair. Anti-inflammatory treatment of human SCI and its timing must be based on knowledge of the types of cells participating in the inflammatory response, the time after injury when they appear and then decrease in number, and the nature of their actions. Using post-mortem spinal cords, we evaluated the time course and distribution of pathological change, infiltrating neutrophils, monocytes/macrophages and lymphocytes, and microglial activation in injured spinal cords from patients who were 'dead at the scene' or who survived for intervals up to 1 year after SCI. SCI caused zones of pathological change, including areas of inflammation and necrosis in the acute cases, and cystic cavities with longer survival (Zone 1), mantles of less severe change, including axonal swellings, inflammation and Wallerian degeneration (Zone 2) and histologically intact areas (Zone 3). Zone 1 areas increased in size with time after injury whereas the overall injury (size of the Zones 1 and 2 combined) remained relatively constant from the time (1-3 days) when damage was first visible. The distribution of inflammatory cells correlated well with the location of Zone 1, and sometimes of Zone 2. Neutrophils, visualized by their expression of human neutrophil alpha-defensins (defensin), entered the spinal cord by haemorrhage or extravasation, were most numerous 1-3 days after SCI, and were detectable for up to 10 days after SCI. Significant numbers of activated CD68-immunoreactive ramified microglia and a few monocytes/macrophages were in injured tissue within 1-3 days of SCI. Activated microglia, a few monocytes/macrophages and numerous phagocytic macrophages were present for weeks to months after SCI. A few CD8(+) lymphocytes were in the injured cords throughout the sampling intervals. Expression by the inflammatory cells of the oxidative enzymes myeloperoxidase (MPO) and nicotinamide adenine dinucleotide phosphate oxidase (gp91(phox)), and of the pro-inflammatory matrix metalloproteinase (MMP)-9, was analysed to determine their potential to cause oxidative and proteolytic damage. Oxidative activity, inferred from MPO and gp91(phox) immunoreactivity, was primarily associated with neutrophils and activated microglia. Phagocytic macrophages had weak or no expression of MPO or gp91(phox). Only neutrophils expressed MMP-9. These data indicate that potentially destructive neutrophils and activated microglia, replete with oxidative and proteolytic enzymes, appear within the first few days of SCI, suggesting that anti-inflammatory 'neuroprotective' strategies should be directed at preventing early neutrophil influx and modifying microglial activation.