Venous Thromboembolism Risk and Thromboprophylaxis in Pediatric Neurosurgery and Spinal Injury: Current Trends and Literature Review.

Although the entities of venous thromboembolism (VTE), deep venous thrombosis, pulmonary embolus, and thromboprophylaxis in adult patients undergoing brain tumor and spine surgery, traumatic brain injury and elective neurosurgical procedures are widely elucidated, the same is not valid when pediatric patients are under consideration. An attempt to review the peculiarities of these patients through a comprehensive bibliographic review is undertaken. We performed a narrative summary of the relevant literature dedicated to pediatric patients, centered on traumatic brain injury, the general incidence of thromboembolic disease in this patient population, the role of low molecular weight heparin (LMWH) in the treatment and prophylaxis of VTE, and its role in elective neurosurgical procedures, including spinal operations. Additionally, the risk of deep venous thrombosis in elective neurosurgical procedures is reviewed. Due to inherent limitations of the current studies, particularly a restricted number of patients, our data are underpowered to give a definitive protocol and guidelines for all the affected patients. Our current conclusions, based only on pediatric patients, argue that there is limited risk of VTE in pediatric patients suffering from brain tumors and that the possibility of VTE is very low in children undergoing elective neurosurgical procedures. There is no consensus regarding the exact incidence of VTE in traumatic brain injury patients. LMWH seems to be a safe and effective choice for the "at risk" pediatric patient population defined as being older than 15 years, venous catheterization, nonaccidental trauma, increased length of hospital stays, orthopaedic (including spinal) surgery, and cranial surgery.

Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats.

We have recently reported that a short course of morphine, starting 10days after sciatic chronic constriction injury (CCI), prolonged the duration of mechanical allodynia for months after morphine ceased. Maintenance of this morphine-induced persistent sensitization was dependent on spinal NOD-like receptor protein 3 (NLRP3) inflammasomes-protein complexes that proteolytically activate interleukin-1ß (IL-1ß) via caspase-1. However, it is still unclear how NLRP3 inflammasome signaling is maintained long after morphine is cleared. Here, we demonstrate that spinal levels of the damage associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1) and biglycan are elevated during morphine-induced persistent sensitization in male rats; that is, 5weeks after cessation of morphine dosing. We also show that HMGB1 and biglycan levels are at least partly dependent on the initial activation of caspase-1, as well as Toll like receptor 4 (TLR4) and the purinergic receptor P2X7R-receptors responsible for priming and activation of NLRP3 inflammasomes. Finally, pharmacological attenuation of the DAMPs HMGB1, biglycan, heat shock protein 90 and fibronectin persistently reversed morphine-prolonged allodynia. We conclude that after peripheral nerve injury, morphine treatment results in persistent DAMP release via TLR4, P2X7R and caspase-1, which are involved in formation/activation of NLRP3 inflammasomes. These DAMPs are responsible for maintaining persistent allodynia, which may be due to engagement of a positive feedback loop, in which NLRP3 inflammasomes are persistently activated by DAMPs signaling at TLR4 and P2X7R.

Clinical study of ganglioside (GM) combined with methylprednisolone (MP) for early acute spinal injury.

This paper aims to make an analysis of the effects of ganglioside (GM) combined with methylprednisolone (MP) in early acute spinal injury. Fifty-three patients with acute spinal cord injury were included in this study and they were randomly divided into experimental and control group. Twenty-seven patients in the control group were treated with MP, while the rest 26 patients received more GM based on that. By observing and comparing the clinical responses from patients and recovery time of all indexes, results came out: the curative rates in the experimental and control group were 50.0%, 40.7% respectively, and the total effective rates were 92.3%, 85.2% respectively. There was a remarkable difference between the two groups (P<0.05). Patients in the experimental group took 6.2 ± 1.9d to restore their sphincter function, 11.2 ± 2.8d to recover their muscle forces to over grade II, and 13.8 ± 3.9d to return general activity, while the patients in the other group clearly spent longer time on recovery, that were 12.1 ± 3.2, 19.2 ± 4.6 and 23.9 ± 5.6 respectively. The distinct difference between the two groups was of statistical significance (P<0.05). We conclude that GM has better curative effects than MP, for it is able to promote the recovery of nerve function for patients and greatly improve the prognosis.

Impact of intravenous acetaminophen therapy on the necessity of cervical spine imaging in patients with cervical spine trauma.

OBJECTIVE: We evaluated a new hypothesis of acetaminophen therapy to reduce the necessity of imaging in patients with probable traumatic cervical spine injury. METHODS: Patients with acute blunt trauma to the neck and just posterior midline cervical tenderness received acetaminophen (15 mg/kg) intravenously after cervical spine immobilization. Then, all the patients underwent plain radiography and computerized tomography of the cervical spine. The outcome measure was the presence of traumatic cervical spine injury. Sixty minutes after acetaminophen infusion, posterior midline cervical tenderness was reassessed. RESULTS: Of 1 309 patients, 41 had traumatic cervical spine injuries based on imaging. Sixty minutes after infusion, posterior midline cervical tenderness was eliminated in 1 041 patients, none of whom had abnormal imaging. CONCLUSION: Patients with cervical spine trauma do not need imaging if posterior midline cervical tenderness is eliminated after acetaminophen infusion. This analgesia could be considered as a diagnostic and therapeutic intervention.

Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury.

Axon regeneration failure causes neurological deficits and long-term disability after spinal cord injury (SCI). Here, we found that the α2δ2 subunit of voltage-gated calcium channels negatively regulates axon growth and regeneration of corticospinal neurons, the cells that originate the corticospinal tract. Increased α2δ2 expression in corticospinal neurons contributed to loss of corticospinal regrowth ability during postnatal development and after SCI. In contrast, α2δ2 pharmacological blockade through gabapentin administration promoted corticospinal structural plasticity and regeneration in adulthood. Using an optogenetic strategy combined with in vivo electrophysiological recording, we demonstrated that regenerating corticospinal axons functionally integrate into spinal circuits. Mice administered gabapentin recovered upper extremity function after cervical SCI. Importantly, such recovery relies on reorganization of the corticospinal pathway, as chemogenetic silencing of injured corticospinal neurons transiently abrogated recovery. Thus, targeting α2δ2 with a clinically relevant treatment strategy aids repair of motor circuits after SCI.

Lower Mortality and Morbidity with Low-Molecular-Weight Heparin for Venous Thromboembolism Prophylaxis in Spine Trauma.

STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: The objective of this study was to evaluate outcomes between patients receiving LMWH versus UH in a retrospective cohort of patients with spine trauma. SUMMARY OF BACKGROUND DATA: Although multiple clinical trials have been conducted, current guidelines do not have enough evidence to suggest low-molecular-weight heparin (LMWH) or unfractionated heparin (UH) for venous thromboembolism (VTE) prophylaxis in spine trauma. METHODS: Patients with spine trauma in the Trauma Quality Improvement Program datasets were identified. Those who died, were transferred within 72 hours, were deemed to have a fatal injury, were discharged within 24 hours, suffered from polytrauma, or were missing data for VTE prophylaxis were excluded. A propensity score was created using age, sex, severity of injury, time to prophylaxis, presence of a cord injury, and altered mental status or hypotension upon arrival, and inverse probability weighted logistic regression modeling was used to evaluate mortality, venous thromboembolic, return to operating room, and total complication rates. E values were used to calculate the likelihood of unmeasured confounders. RESULTS: Those receiving UH (n = 7172) were more severely injured (P < 0.0001), with higher rates of spinal cord injury (32.26% vs. 25.32%, P < 0.0001) and surgical stabilization (29.52% vs. 22.94%, P < 0.0001) compared to those receiving LMWH (n = 20,341). Patients receiving LMWH had lower mortality (odds ratio [OR]: 0.47; 95% CI: 0.42-0.53; P < 0.001; E = 3.68), total complication (OR: 0.92; 95% CI: 0.88-0.95; P < 0.001; E = 1.39), and VTE event (OR: 0.80; 95% CI: 0.72-0.88; P < 0.001; E = 1.81) rates than patients receiving UH. There were no differences in rates of unplanned return to the operating room (OR: 1.01; 95% CI: 0.80-1.27; P = 0.93; E = 1.11). CONCLUSION: There is an association between lower mortality and receiving LMWH for VTE prophylaxis in patients with spine trauma. A large randomized clinical trial is necessary to confirm these findings. LEVEL OF EVIDENCE: 3.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Evaluation and Treatment of Patients With Thoracolumbar Spine Trauma: Pharmacological Treatment.

QUESTION: Does the administration of a specific pharmacologic agent (eg, methylprednisolone) improve clinical outcomes in patients with thoracic and lumbar fractures and spinal cord injury? RECOMMENDATION: There is insufficient evidence to make a recommendation; however, the task force concluded, in light of previously published data and guidelines, that the complication profile should be carefully considered when deciding on the administration of methylprednisolone. Strength of recommendation: Grade Insufficient The full version of the guideline can be reviewed at: https://www.cns.org/guideline-chapters/congress-neurological-surgeons-systematic-review-evidence-based-guidelines/chapter_5.

Operative spinal trauma: Thromboprophylaxis with low molecular weight heparin or a direct oral anticoagulant.

Essentials Operative spine trauma patients are at increased risk of venous thromboembolism (VTE). Direct oral anticoagulants (DOACs) may have a favorable efficacy and safety in spine trauma. Patients on DOACs had lower rates of VTE in comparison to low molecular weight heparin. DOACs did not augment the risk of surgical bleeding (transfusion, decompressive procedures). BACKGROUND: Spinal trauma patients are at high risk for venous thromboembolism (VTE). OBJECTIVE: To compare the impacts of direct oral anticoagulants (DOACs) and low molecular weight heparin (LMWH) as thromboprophylactic agents on outcomes in operative spinal trauma patients. METHODS: A 2-year (2015-2016) retrospective cohort analysis of such patients (spine Abbreviated Injury Scale [AIS] ≥ 3 and other AIS < 3) who received LMWH or DOACs was performed. Propensity score matching (1:2 ratio) followed stratification into two groups. Outcomes included rates of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), packed red blood cell (pRBC) transfusion, operative interventions for spinal cord decompression, and mortality. RESULTS: Of 6036 patients, 810 (270 receiving DOACs; 540 receiving LMWH) were matched. The mean age was 62 ± 15 years, 58% were male, and the median Injury Severity Score was 12 (10-18). Matched groups were similar in demographics, injury parameters, emergency department vital signs, hospital stay, rates of inferior vena cava filter placement, and timing of initiation of thromboprophylaxis. The overall rate of in-hospital DVT was 5.6%, the overall rate of in-hospital PE was 1.6%, and the mortality rate was 2.5%. DOAC patients were less likely to develop DVT (1.8% vs 7.4%) and PE (0.3% vs 2.1%). There were no differences in postprophylaxis pRBC transfusion requirements, postprophylaxis decompressive procedures on the spinal cord, or mortality. CONCLUSION: In operative spinal trauma patients, thromboprophylaxis with DOACs appears to be associated with lower rates of DVT and PE. Further prospective clinical trials should evaluate the role of DOACs in preventing VTE events in spinal trauma patients.

Efficacy of low molecular weight heparin in spinal trauma patients after part concentrated screw surgery and its influence on blood parameters and the incidence of deep venous thrombosis.

This study was to investigate the efficacy of low molecular weight heparin (LMWH) therapy in patients with spinal trauma after part concentrated screw (PCS) pedicle screw surgery (PSS) and its influence on blood parameters and the incidence of deep venous thrombosis. Prospectively, 36 patients with spinal trauma who underwent PSS were randomly divided into an experimental group (n = 18) and a control group (n = 18). The experimental group was treated with LMWH after the operation. Changes in the vascular endothelial function, inflammatory factors and other blood indexes, and the incidence of deep venous thrombosis in lower extremities were compared between the two groups before and after the surgery. Compared to pre-surgery, the levels of endothelin (ET) and tissue plasminogen activator (tPA) in the experimental group decreased significantly after surgery (all P < 0.001), while the levels of ET increased and tPA decreased significantly in the control group (all P < 0.001). In addition, compared with pre-surgical levels, interleukin-8 (IL-8), IL-6 and procalcitonin (PCT) decreased significantly in the experimental group after surgery while there was a significant increase in these cytokines in the control group (all P < 0.001), with a significant difference in the cytokine levels between the two groups post-surgery (P < 0.01). After the surgery, plasma viscosity, erythrocyte electrophoresis time and platelet aggregation rate in the control group were significantly increased from pre-surgery levels (all P < 0.001), and these levels were also significantly higher than in the experimental group (P < 0.01). The D-dimer (D-D) level in both groups also increased significantly after surgery (all P < 0.001), and the level post-surgery was significantly higher in the experimental group as compared to the control group (P < 0.01). Finally, the incidence of deep venous thrombosis in the experimental group was significantly lower than in the control group (P < 0.05). LMWH is beneficial in reducing the degree of hypercoagulability, hyperviscosity and inflammatory reaction in patients with spinal trauma who underwent PSS. It also effectively reduced the occurrence of deep vein thrombosis in lower limbs after surgery. Thus, it is a candidate for further clinical development.

Cervical lordosis after subaxial spinal trauma surgery: relationship with neck pain and stiffness.

BACKGROUND: The objective of this retrospective study is to evaluate how neck pain is influenced by post-operative cervical alignment in patients operated for cervical spinal trauma. PATIENTS AND METHODS: From January 2013 to June 2017, at our department we operated 34 patients with cervical spinal trauma, 22 males and 12 females. Age, sex, level and type of fractures, surgical approach, fixation levels (cervical or cervico-dorsal), preoperative and postoperative CT scan, cervical (C2-C7) Cobb angle (lordotic > +10°, straight 0 /+10°, kyphotic < 0°) at X-rays on sitting position 3 months after surgery, postoperative self-reported neck stiffness scale, preoperative and follow-up ASIA score, pre and postoperative VAS value were evaluated for each patient. Statistical analysis was performed according to the Mann-Whitney and T-test. RESULTS: In this series, 22 patients were operated by anterior approach, 7 patients by posterior approach and 5 by combined approach. Postoperative chronic cervical pain was not correlated with cervical sagittal alignment after surgery, fracture type, surgical approach, fixation level and postoperative ASIA score but is correlated with the presence of neck stiffness (P=0,001). Patients treated with posterior approach (P=0,022) and fracture type C (P=0,026) had higher significantly neck stiffness compared to patients who underwent anterior approach for type B fractures. CONCLUSIONS: The presence of abnormal cervical lordosis after surgery for cervical spinal trauma does not correlate with neck pain. Patients treated with posterior fixation had higher neck stiffness and related chronic pain.

Effect of Jisuikang () on kinetic dysfunction in patients after spinal injury.

OBJECTIVE: To explore the effect of Jisuikang (, JSK) on kinetic dysfunction in patients after spinal injury. METHODS: Eighty-four patients with spinal injury were assigned equally, according to a randomizing digital table to the treated group and the control group. Conventional treatment was given to both groups, and JSK was additionally given to the treated group. Changes of various kinetic function concerning parameters including kinetic score, grades of spinal injury, effectiveness of the treatment and available recovery rate in patients allocated in the treated group and the control group were observed and compared in the way issued by Association of Spinal Injury of America (ASIA). RESULTS: Better effects were shown in the treated group than those in the control group in improving kinetic score (92.00+/-9.95 scores vs 83.76+/-24.12 scores), ASIA overall improvement rate (69.05% vs 45.24%) and grades of effectiveness (P<0.05). However, the difference of available recovery rate between the two groups was insignificant (P>0.05). CONCLUSION: JSK could prevent secondary alteration of spinal injury, promote the recovery and regeneration of nerve tissues, but could not restore the function of a necrotic spine.

Corticosteroid use in management of pediatric emergency conditions.

Corticosteroids have been used for over half a century to treat various inflammatory disorders; however, their use in many pediatric conditions remains controversial. This issue reviews evidence on corticosteroid treatment in acute asthma exacerbations, croup, acute pharyngitis, anaphylaxis, acute spinal injury, and bacterial meningitis. While corticosteroids are clearly indicated for management of asthma exacerbations and croup, they are not universally recommended for potential spinal cord injury. Due to insufficient data or conflicting data, corticosteroids may be considered in children with acute pharyngitis, anaphylaxis, and bacterial meningitis.

Progestins and neuroprotection: are all progestins created equal?

Our understanding of the biology of gonadal steroids has expanded such that we now appreciate that the effects of gonadal steroid hormones, including estradiol and progesterone, extend beyond the strict confines of reproductive function and exert their effects on a wide range of tissue targets including, but not limited to, the bone, the heart and the brain. With respect to the brain, an increasing body of literature supports the protective effects of estradiol and progesterone. However, results from the Women's Health Initiative (WHI) underscored the fact that there may be important caveats to these protective effects and include the choice of hormone used. Here, we describe our current understanding of the neurobiology of progesterone and the synthetic progestin used in most formulations of hormone therapy, medroxyprogesterone acetate, and provide a review of the basic and clinical literature that address the importance of progestins in neuroprotection. In addition, we caution that the effects and mechanisms underlying the neurobiological effects of progestins may not be identical to those seen in non central nervous systems. And though additional research is certainly needed to explore the neurobiology of progesterone and its related progestins more completely, we provide evidence that, at least with respect to the brain, not all progestins are created equal.

Management of spinal injury.

Spinal injury often affects young adults and results in debilitating neurological status, which in turn places a significant burden on society. This review article describes the current practice and controversies surrounding the management of spinal injury. General principles of pre-hospital management, resuscitation, medical treatment, surgical intervention and future advancement are reviewed.

Fentanyl in a pectin gel treating breakthrough pain in vertebral compression fracture due to multiple myeloma: A descriptive study of three cases.

Breakthrough pain (BTP) currently represents a challenge for health professionals dedicated to the treatment of pain. In this descriptive 1-year follow-up study on three patients with BTP from vertebral crush, in the context of multiple myeloma, the authors have observed the great either efficacy or tolerability profile of fentanyl pectin nasal spray. The most relevant findings in this study were better adherence to treatment compared to previously opioids and also great personal satisfaction. Because of common pathophysiological mechanism for noncancerous pain of bone origin, these good results could open the door to investigation of the use of this drug in this patient's group.

Spinal Astrocytic Thrombospondin-4 Induced by Excitatory Neuronal Signaling Mediates Pain After Facet Capsule Injury.

Thrombospondin-4 (TSP4) is a synaptogenic molecule that is upregulated in the spinal cord after painful facet joint injury and may contribute to spinal hyperexcitability. However, the mechanisms leading to increased spinal TSP4 are unclear. Because primary afferent activity is critical in the development of spinal hyperexcitability after facet joint injury, this study evaluated the role of afferent firing in the increase of spinal TSP4 and excitatory synapses. Intra-articular bupivacaine was administered immediately or 4 days after painful facet joint injury in male Holtzman rats, and TSP4 and excitatory synapses were quantified in the spinal cord at day 7. Immediate, but not delayed bupivacaine treatment, prevents the injury-induced increase in TSP4 and excitatory synapses in the dorsal horn (p < 0.0001). Preliminary in vitro experiments suggest that the excitatory signaling molecules ATP and glutamate may stimulate astrocytic TSP4 expression (p ≤ 0.04). Collectively, these results suggest that afferent activity early after facet joint injury is critical for the induction of spinal TSP4. This study advances the understanding of the timing and role of afferent activity in TSP4 expression after injury, which is critical for the therapeutic targeting of TSP4 to treat persistent pain conditions.

Synthes Award for Resident Research on Spinal Cord and Spinal Column Injury: granulocyte macrophage colony stimulating factor (GM-CSF) prevents apoptosis and improves functional outcome in experimental spinal cord contusion injury.

OBJECTIVE: Granulocyte macrophage colony stimulating factor (GM-CSF) is a potent hematopoietic cytokine, which stimulates stem cell proliferation in the bone marrow and inhibits apoptotic cell death in leukocytes. However, the effects of GM-CSF in the central nervous system are still unclear. The present study was undertaken to determine if GM-CSF can rescue neuronal cells from apoptosis and improve neurologic function in a spinal cord injury (SCI) model. METHODS: To study the effect of GM-CSF on apoptotic neuronal death, we used a staurosporine-induced neuronal death model in a Neuro 2A (N2A) cell line (in vitro) and in a rat SCI model (in vivo). N2A cells were preincubated with GM-CSF for 60 minutes before being exposed to staurosporine for 24 hours. To inhibit GM-CSF, we pretreated N2A cells with antibodies of the GM-CSF receptor for 60 minutes. SCI was made by clip compression. Rats were treated with daily GM-CSF (20 microg/d) for 5 days. The number of apoptotic cells in the spinal cord and neurologic improvements were checked. RESULTS: GM-CSF pretreatment was found to significantly protect N2A cells from apoptosis, and neutralizing antibodies for the GM-CSF receptors inhibited the rescuing effect of GM-CSF on apoptosis. In the rat SCI model, neurologic functions improved significantly in the GM-CSF-administered group versus the phosphate buffered saline (PBS)-treated control. TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeled) staining showed that GM-CSF administration reduced apoptosis in the injured spinal cord. CONCLUSION: Treatment of SCI with GM-CSF showed some beneficial effects. Neuronal protection against apoptosis is viewed as a likely mechanism underlying the therapeutic effect of GM-CSF in SCI.

Exogenous Crosslinking Restores Intradiscal Pressure of Injured Porcine Intervertebral Discs: An In Vivo Examination Using Quantitative Discomanometry.

STUDY DESIGN: In vivo examination of intradiscal pressure by quantitative discomanometry (QD). OBJECTIVE: To determine whether an injectable, exogenous crosslinking could acutely restore intradiscal pressure of stab-injured discs in vivo by short-term treatment. SUMMARY OF BACKGROUND DATA: Disc biomechanical performance depends on its integrity associated with the intradiscal pressure and mechanical properties. Genipin crosslink augmentation has demonstrated the in vitro biomechanical capability to improve intervertebral joint stability and increase mechanical properties of the annulus fibrosus. METHODS: 4 lumbar discs on each of 8 swine were randomly assigned to 4 groups: intact, injured, untreated, and crosslinked. A 16G needle was stabbed into the annulus fibrosus to create the disc injury model. An injection of 0.33% genipin solution was delivered into the annulus to treat the injury. QD technique was performed to examine the intradiscal pressure for the intact and injured discs at the time of surgery, while untreated and crosslinked discs were measured 1-week postsurgery. 4 QD parameters were analyzed and compared across the 4 groups: leakage pressure and volume, and saturation pressure and volume. RESULTS: The leakage and saturation pressures of the injured group were significantly lower than those of the intact group (P = 0.004 and P = 0.01, respectively). The leakage and saturation pressures of untreated discs were statistically equivalent to the injured levels, but with a 2-times higher saturation volume. Relative to the untreated group, the leakage pressure and saturation pressure of genipin-crosslinked discs had a 617% (P = 0.008) and a 473% increase (P = 0.007), respectively. CONCLUSION: A large disc injury produced by annular puncture immediately lowered intradiscal pressure when left untreated. Genipin crosslinking can restore intradiscal pressure acutely in vivo without any obvious morbidity associated with the injection.