Jonathan Z. Pan

Cytokine activity contributes to induction of inflammatory cytokine mRNAs in spinal cord following contusion

Injury of the spinal cord leads to an inflammatory tissue response, probably mediated in part by cytokines. Because a common therapy for acute spinal cord injury is the use of an antiinflammatory synthetic glucocorticoid (methylprednisolone), we sought to determine mechanisms contributing to inflammation shortly after acute injury. Cytokine mRNAs [interleukin (IL)‐1α, IL‐1β, tumor necrosis factor (TNF)‐α, and IL‐6] were increased during the first 2 hr following weight‐drop compression injury by RNase protection assay, prior to the reported appearance of circulating lymphocytes. This immediate pattern of cytokine mRNA induction could be replicated in cultured, explanted spinal cord slices but not in whole blood of injured animals, which is consistent with a tissue source of cytokine mRNAs. Western blotting detected IL‐1β‐like immunoreactivity released into culture medium following explantation and pro‐IL‐1β‐like immunoreactivity in freshly dissected spinal cord tissue. Pharmacologically blocking IL‐1 and TNF‐α receptors significantly reduced expression of IL‐1α, IL‐1β, and TNF‐α mRNAs. Finally, mice lacking both IL‐1 and TNF‐α receptors exhibited diminished induction of TNF‐α, IL‐6, and IL‐1ra mRNAs following injury. Therefore, we conclude that contusion injury induces an immediate release of cytokines, which then contributes to the induction of cytokine mRNAs.

Differential General Anesthetic Effects on Microglial Cytokine Expression

Post-operative cognitive dysfunction has been widely observed, especially in older patients. An association of post-operative cognitive dysfunction with the neurodegenerative diseases, such as Alzheimers disease, has been suggested. Neuroinflammation contributes to Alzheimer pathology, through elevated pro-inflammatory cytokines and microglial activation in the CNS leading to neuronal damage, synaptic disruption and ultimately cognitive dysfunction. We compare the effects of three different, clinically-used, anesthetics on microglial activation with, and without, the prototypical inflammatory trigger, lipopolysaccharide (LPS). Microglial BV-2 cell cultures were first exposed to isoflurane, sevoflurane (each at 2 concentrations) or propofol for 6 h, and cytokine levels measured in lysates and media. The same experiments were repeated after 1 h LPS pre-treatment. We found; 1) anesthetics alone have either no or only a small effect on cytokine expression; 2) LPS provoked a large increase in microglia cytokine expression; 3) the inhaled anesthetics either had no effect on LPS-evoked responses or enhanced it; 4) propofol nearly eliminated the LPS pro-inflammatory cytokine response and improved cell survival as reflected by lactate dehydrogenase release. These data suggest that propofol may be a preferred anesthetic when it is desirable to minimize neuroinflammation.

Inhaled anesthetics elicit region-specific changes in protein expression in mammalian brain

Inhaled anesthetics bind specifically to many proteins in the mammalian brain. Within the subgroup of proteins whose activity is substantially modulated by anesthetic binding, it is reasonable to expect anesthetic‐induced alterations in host expression level. Thus, in an attempt to define the group of functional targets for these commonly used drugs, we examined changes in protein expression after anesthetic exposure in both intact rodent brains and in neuronal cell culture. Differential in‐gel electrophoresis was used to minimize variance, in order to detect small changes. Quantitative analysis shows that 5 h exposures to 1 minimum alveolar concentration (1 MAC) halothane caused changes in the expression of ∼2% of detectable proteins, but only at 2–24 h after awakening, and only in the cortex. An equipotent concentration of isoflurane altered the expression of only ∼1% of detectable proteins, and only in the hippocampus. Primary cortical neurons were exposed to three‐fold higher concentrations of anesthetics with no evidence of cytotoxicity. Small changes in protein expression were elicited by both drugs. Despite the fact that anesthetics produce profound changes in neurobiology and behavior, we found only minor changes in brain protein expression. A pronounced degree of regional selectivity was noted, indicating an under appreciated degree of specificity for these promiscuous drugs.

Complications and outcomes of vasopressor usage in acute traumatic central cord syndrome

OBJECT The optimal mean arterial pressure (MAP) for spinal cord perfusion after trauma remains unclear. Although there are published data on MAP goals after spinal cord injury (SCI), the specific blood pressure management for acute traumatic central cord syndrome (ATCCS) and the implications of these interventions have yet to be elucidated. Additionally, the complications of specific vasopressors have not been fully explored in this injury condition. METHODS The present study is a retrospective cohort analysis of 34 patients with ATCCS who received any vasopressor to maintain blood pressure above predetermined MAP goals at a single Level 1 trauma center. The collected variables were American Spinal Injury Association (ASIA) grades at admission and discharge, administered vasopressor and associated complications, other interventions and complications, and timing of surgery. The relationship between the 2 most common vasopressors-dopamine and phenylephrine-and complications within the cohort as a whole were explored, and again after stratification by age. RESULTS The mean age of the ATCCS patients was 62 years. Dopamine was the most commonly used primary vasopressor (91% of patients), followed by phenylephrine (65%). Vasopressors were administered to maintain MAP goals fora mean of 101 hours. Neurological status improved by a median of 1 ASIA grade in all patients, regardless of the choice of vasopressor. Sixty-four percent of surgical patients underwent decompression within 24 hours. There was no observed relationship between the timing of surgical intervention and the complication rate. Cardiogenic complications associated with vasopressor usage were notable in 68% of patients who received dopamine and 46% of patients who received phenylephrine. These differences were not statistically significant (OR with dopamine 2.50 [95% CI 0.82-7.78], p = 0.105). However, in the subgroup of patients > 55 years, dopamine produced statistically significant increases in the complication rates when compared with phenylephrine (83% vs 50% for dopamine and phenylephrine, respectively; OR with dopamine 5.0 [95% CI 0.99-25.34], p = 0.044). CONCLUSIONS Vasopressor usage in ATCCS patients is associated with complication rates that are similar to the reported literature for SCI. Dopamine was associated with a higher risk of complications in patients > 55 years. Given the increased incidence of ATCCS in older populations, determination of MAP goals and vasopressor administration should be carefully considered in these patients. While a randomized control trial on this topic may not be practical, a multiinstitutional prospective study for SCI that includes ATCCS patients as a subpopulation would be useful for examining MAP goals in this population.

Higher Mean Arterial Pressure Values Correlate with Neurologic Improvement in Patients with Initially Complete Spinal Cord Injuries

BACKGROUND Traumatic spinal cord injury (SCI) guidelines recommend to maintain mean arterial pressures (MAPs) above 85 mm Hg for 7 days following SCI to minimize spinal cord ischemia. Some physicians doubt that patients with initially complete injuries benefit. OBJECTIVE To assess the relationship between MAP augmentation and neurologic improvement in SCI patients stratified by initial American Spinal Injury Association Impairment Scale (AIS) score. METHODS High-frequency MAP values of acute SCI patients admitted over a 6-year period were recorded, and values were correlated with degree of neurologic recovery in an analysis stratified by postresuscitation AIS score. RESULTS Sixty-two patients with SCI were analyzed. Thirty-three patients were determined to have complete injuries, and of those 11 improved at least 1 AIS grade by discharge. The average MAP of initially AIS A patients who improved versus those who did not was significantly higher (96.6 ± 0.07 mm Hg vs. 94.4 ± 0.06 mm Hg, respectively; P < 0.001), and the proportion of MAP values <85 mm Hg was significantly lower (13.5% vs. 25.6%, respectively; P < 0.001). A positive correlation between MAP values and outcome was also observed in AIS B and C patients but was not observed in patients who were initially AIS D. CONCLUSION A positive correlation was observed between MAP values and neurologic recovery in AIS A, B, and C patients but not AIS D patients. These data raise the possibility that patients with an initially complete SCI may derive greater benefit from MAP augmentation than patients with initial AIS D injuries.

Failure of Mean Arterial Pressure Goals to Improve Outcomes Following Penetrating Spinal Cord Injury.

BACKGROUND Increased spinal cord perfusion and blood pressure goals have been recommended for spinal cord injury (SCI). Penetrating SCI is associated with poor prognosis, but there is a paucity of literature examining the role of vasopressor administration for the maintenance of mean arterial pressure (MAP) goals in this patient population. OBJECTIVE To elucidate this topic and to determine the efficacy of vasopressor administration in penetrating SCI by examining a case series of consecutive penetrating SCIs. METHODS We reviewed consecutive patients with complete penetrating SCI who met inclusion and exclusion criteria, including the administration of vasopressors to maintain MAP goals. We identified 14 patients with complete penetrating SCIs with an admission American Spinal Injury Association grade of A from 2005 to 2011. The neurological recovery, complications, interventions, and vasopressor administration strategies were reviewed and compared with those of a cohort with complete blunt SCI. RESULTS In our patient population, only 1 patient with penetrating SCI (7.1%) experienced neurological recovery, as determined by improvement in the American Spinal Injury Association grade, despite the administration of vasopressors for supraphysiological MAP goals for an average of 101.07 ± 34.96 hours. Furthermore, 71.43% of patients with penetrating SCI treated with vasopressors experienced associated cardiogenic complications. CONCLUSION Given the decreased likelihood of neurological improvement in penetrating injuries, it may be important to re-examine intervention strategies in this population. Specifically, the use of vasopressors, in particular dopamine, with their associated complications is more likely to cause complications than to result in neurological improvement. Our experience shows that patients with acute penetrating SCI are unlikely to recover, despite aggressive cardiopulmonary management. ABBREVIATIONS ASIA, American Spinal Injury AssociationMAP, mean arterial pressureSCI, spinal cord injury.

Multidimensional Analysis of Magnetic Resonance Imaging Predicts Early Impairment in Thoracic and Thoracolumbar Spinal Cord Injury.

Literature examining magnetic resonance imaging (MRI) in acute spinal cord injury (SCI) has focused on cervical SCI. Reproducible systems have been developed for MRI-based grading; however, it is unclear how they apply to thoracic SCI. Our hypothesis is that MRI measures will group as coherent multivariate principal component (PC) ensembles, and that distinct PCs and individual variables will show discriminant validity for predicting early impairment in thoracic SCI. We undertook a retrospective cohort study of 25 patients with acute thoracic SCI who underwent MRI on admission and had American Spinal Injury Association Impairment Scale (AIS) assessment at hospital discharge. Imaging variables of axial grade, sagittal grade, length of injury, thoracolumbar injury classification system (TLICS), maximum canal compromise (MCC), and maximum spinal cord compression (MSCC) were collected. We performed an analytical workflow to detect multivariate PC patterns followed by explicit hypothesis testing to predict AIS at discharge. All imaging variables loaded positively on PC1 (64.3% of variance), which was highly related to AIS at discharge. MCC, MSCC, and TLICS also loaded positively on PC2 (22.7% of variance), while variables concerning cord signal abnormality loaded negatively on PC2. PC2 was highly related to the patient undergoing surgical decompression. Variables of signal abnormality were all negatively correlated with AIS at discharge with the highest level of correlation for axial grade as assessed with the Brain and Spinal Injury Center (BASIC) score. A multiple variable model identified BASIC as the only statistically significant predictor of AIS at discharge, signifying that BASIC best captured the variance in AIS within our study population. Our study provides evidence of convergent validity, construct validity, and clinical predictive validity for the sampled MRI measures of SCI when applied in acute thoracic and thoracolumbar SCI.

Multivariate Analysis of MRI Biomarkers for Predicting Neurologic Impairment in Cervical Spinal Cord Injury

BACKGROUND AND PURPOSE: Acute markers of spinal cord injury are essential for both diagnostic and prognostic purposes. The goal of this study was to assess the relationship between early MR imaging biomarkers after acute cervical spinal cord injury and to evaluate their predictive validity of neurologic impairment. MATERIALS AND METHODS: We performed a retrospective cohort study of 95 patients with acute spinal cord injury and preoperative MR imaging within 24 hours of injury. The American Spinal Injury Association Impairment Scale was used as our primary outcome measure to define neurologic impairment. We assessed several MR imaging features of injury, including axial grade (Brain and Spinal Injury Center score), sagittal grade, length of injury, maximum canal compromise, and maximum spinal cord compression. Data-driven nonlinear principal component analysis was followed by correlation and optimal-scaled multiple variable regression to predict neurologic impairment. RESULTS: Nonlinear principal component analysis identified 2 clusters of MR imaging variables related to 1) measures of intrinsic cord signal abnormality and 2) measures of extrinsic cord compression. Neurologic impairment was best accounted for by MR imaging measures of intrinsic cord signal abnormality, with axial grade representing the most accurate predictor of short-term impairment, even when correcting for surgical decompression and degree of cord compression. CONCLUSIONS: This study demonstrates the utility of applying nonlinear principal component analysis for defining the relationship between MR imaging biomarkers in a complex clinical syndrome of cervical spinal cord injury. Of the assessed imaging biomarkers, the intrinsic measures of cord signal abnormality were most predictive of neurologic impairment in acute spinal cord injury, highlighting the value of axial T2 MR imaging.

182 Ultra-Early (<12 Hours) Decompression Improves Recovery After Spinal Cord Injury Compared to Early (12-24 Hours) Decompression.

INTRODUCTION:Spinal cord injury (SCI) is a devastating condition with very few treatment options. Surgical decompression of the spine after injury has been shown to improve outcomes; however, the optimal timing of surgery is a matter of debate.METHODS:We collected data from 78 patients with SCI. Bas

Changes in the Bispectral Index in Response to Loss of Consciousness and No Somatic Movement to Nociceptive Stimuli in Elderly Patients

Background:Bispectral index (BIS) is considered very useful to guide anesthesia care in elderly patients, but its use is controversial for the evaluation of the adequacy of analgesia. This study compared the BIS changes in response to loss of consciousness (LOC) and loss of somatic response (LOS) to nociceptive stimuli between elderly and young patients receiving intravenous target-controlled infusion (TCI) of propofol and remifentanil. Methods:This study was performed on 52 elderly patients (aged 65–78 years) and 52 young patients (aged 25–58 years), American Society of Anesthesiologists physical status I or II. Anesthesia was induced with propofol administered by TCI. A standardized noxious electrical stimulus (transcutaneous electrical nerve stimulation, [TENS]) was applied (50 Hz, 80 mA, 0.25 ms pulses for 4 s) to the ulnar nerve at increasing remifentanil predicted effective-site concentration (Ce) until patients lost somatic response to TENS. Changes in awake, prestimulus, poststimulus BIS, heart rate, mean arterial pressure, pulse oxygen saturation, predicted plasma concentration, Ce of propofol, and remifentanil at both LOC and LOS clinical points were investigated. Results:BISLOC in elderly group was higher than that in young patient group (65.4 ± 9.7 vs. 57.6 ± 12.3) (t = 21.58, P < 0.0001) after TCI propofol, and the propofol Ce at LOC was 1.6 ± 0.3 &mgr;g/ml in elderly patients, which was significantly lower than that in young patients (2.3 ± 0.5 &mgr;g/ml) (t = 7.474, P < 0.0001). As nociceptive stimulation induced BIS to increase, the mean of BIS maximum values after TENS was significantly higher than that before TENS in both age groups (t = 8.902 and t = 8.019, P < 0.0001). With increasing Ce of remifentanil until patients lost somatic response to TENS, BISLOS was the same as the BISLOC in elderly patients (65.6 ± 10.7 vs. 65.4 ± 9.7), and there were no marked differences between elderly and young patient groups in BISawake, BISLOS, and Ce of remifentanil required for LOS. Conclusion:In elderly patients, BIS can be used as an indicator for hypnotic-analgesic balance and be helpful to guide the optimal administration of propofol and remifentanil individually. Trial Registration:CTRI Reg. No: ChiCTR-OOC-14005629; http://www.chictr.org.cn/showproj.aspx?proj=9875.