The impact of gestational age and fetal weight on the risk of failure of spinal anesthesia for cesarean delivery.

BACKGROUND: There are limited data about spinal dosing for cesarean delivery in preterm parturients. We investigated the hypothesis that preterm gestation is associated with an increased incidence of inadequate spinal anesthesia for cesarean delivery compared with term gestation. METHODS: We searched our perioperative database for women who underwent cesarean delivery under spinal or combined spinal-epidural anesthesia with hyperbaric bupivacaine ⩾10.5mg. The primary outcome was the incidence of inadequate surgical anesthesia needing conversion to general anesthesia or repetition or supplementation of the block. We divided patients into four categories: <28, 28 to <32, 32 to <37 and ⩾37weeks of gestation. The chi-square test was used to compare failure rates and a multivariable regression analysis was performed to investigate potential confounders of the relationship between gestational age and failure. RESULTS: A total of 5015 patients (3387 term and 1628 preterm) were included. There were 278 failures (5.5%). The incidence of failure was higher in preterm versus term patients (6.4% vs. 5.1%, P=0.02). Failure rates were 10.8%, 7.7%, 5.3% and 5% for <28, 28 to <32, 32 to <37 and ⩾37weeks of gestation, respectively. In the multivariable model, low birth weight (P<0.0001), gestational age (P=0.03), ethnicity (P=0.02) and use of combined spinal-epidural anesthesia (P<0.0001) were significantly associated with failure. CONCLUSIONS: At standard spinal doses of hyperbaric bupivacaine used in our practice (⩾10.5mg), there were higher odds of inadequate surgical anesthesia in preterm parturients. When adjusting for potential confounders, low birth weight was the main factor associated with failure.

The construction and characterization of new permeable rho antagonists and their roles after spinal cord injury

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Influence of fetal tissue transplant on the morphology of the neuromuscular junctions of tibialis anterior and medial gastrocnemius following spinal transection in the rat

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Stimulation électrique de la moelle épinière lombaire pour déclencher la marche chez le chat spinal

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Characterization of the glial scar tissue in a murine model of spinal cord compression, with focus on hyaluronan

Spinal cord injury (SCI) is a devastating neurological disorder that affects thousands of people each year. Although in recent decades significant progress has been made in relation to understanding the molecular and cellular events underlying the nervous damage, spinal cord injury is still a highly disabling condition for which there is no curative therapy. People affected by spinal cord injuries manifested dysfunction or loss, temporary or permanent, of motor, sensory and / or autonomic functions depending on the spinal lesion damaged. Currently, the incidence rate of this type of injury is approximately 15-40 cases per million people worldwide. At the origin of these lesions are: road accidents, falls, interpersonal violence and the practice of sports. In this work we placed the hypothesis that HA is one of the component of the scar tissue formed after a compressive SCI, that it is likely synthetised by the perilesional glial cells and that it might support the permeation of the glial scar during the late phase of SCI. Nowadays, much focus is drawn on the recovery of CNS function, made impossible after SCI due to the high content of sulfated proteoglycans in the extracellular matrix. Counterbalancing the ratio between these proteoglycans and hyaluronic acid could be one of the experimental therapy to re-permeate the glial scar tissue formed after SCI, making possible axonal regrowth and functional recovery. Therefore, we established a model of spinal cord compression in mice and studied the glial scar tissue, particularly through the characterization of the expression of enzymes related to the metabolism of HA and the subsequent concentration thereof at different distances of the lesion epicenter. Our results show that the lesion induced in mice shows results similar to those produced in human lesions, in terms of histologic similarities and behavioral results. but these animals demonstrate an impressive spontaneous reorganization mechanism of the spinal cord tissue that occurs after injury and allows for partial recovery of the functions of the CNS. As regards the study of the glial scar, changes were recorded at the level of mRNA expression of enzymes metabolizing HA i.e., after injury there was a decreased expression of HA synthases 1-2 (HAS 1-2) and an increase of the expression HAS3 synthase mRNA, as well as the enzymes responsible for the HA catabolism, HYAL 1-2. But the amount of HA measured through the ELISA test was found unchanged after injury, it is not possible to explain this fact only with the change of expression of enzymes. At two weeks and in response to SCI, we found synthesized HA by reactive astrocytes and probably by others like microglial cells as it was advanced by the HA/GFAP+ and HA/IBA1+ cells co-location.

Disseminated Cerebral and Intradural Extramedullary Spinal Nocardiosis in an Immunocompetent Patient

Disseminated nocardiosis of the central nervous system (CNS) has been rarely reported, especially in the immunocompetent patient. We report a case of cerebral and cervical intradural extramedullary nocardiosis likely to have been the result of disseminated spread from a pulmonary infective focus. Attempts at tissue biopsy and culture of the initial cerebral and pulmonary lesions both failed to yield the diagnosis. Interval development of a symptomatic intradural extramedullary cervical lesion resulted in open biopsy and an eventual diagnosis of nocardiosis was made. We highlight the diagnostic dilemma and rarity of spinal nocardial dissemination in an immunocompetent individual.

Development of novel therapeutics and in vitro models for spinal cord injury

Spinal cord injury (SCI) is a devastating condition, which results from trauma to the cord, resulting in a primary injury response which leads to a secondary injury cascade, causing damage to both glial and neuronal cells. Following trauma, the central nervous system (CNS) fails to regenerate due to a plethora of both intrinsic and extrinsic factors. Unfortunately, these events lead to loss of both motor and sensory function and lifelong disability and care for sufferers of SCI. There have been tremendous advancements made in our understanding of the mechanisms behind axonal regeneration and remyelination of the damaged cord. These have provided many promising therapeutic targets. However, very few have made it to clinical application, which could potentially be due to inadequate understanding of compound mechanism of action and reliance on poor SCI models. This thesis describes the use of an established neural cell co-culture model of SCI as a medium throughput screen for compounds with potential therapeutic properties. A number of compounds were screened which resulted in a family of compounds, modified heparins, being taken forward for more intense investigation. Modified heparins (mHeps) are made up of the core heparin disaccharide unit with variable sulphation groups on the iduronic acid and glucosamine residues; 2-O-sulphate (C2), 6-O-sulphate (C6) and N-sulphate (N). 2-O-sulphated (mHep6) and N-sulphated (mHep7) heparin isomers were shown to promote both neurite outgrowth and myelination in the SCI model. It was found that both mHeps decreased oligodendrocyte precursor cell (OPC) proliferation and increased oligodendrocyte (OL) number adjacent to the lesion. However, there is a difference in the direct effects on the OL from each of the mHeps; mHep6 increased myelin internode length and mHep7 increased the overall cell size. It was further elucidated that these isoforms interact with and mediate both Wnt and FGF signalling. In OPC monoculture experiments FGF2 treated OPCs displayed increased proliferation but this effect was removed when co-treated with the mHeps. Therefore, suggesting that the mHeps interact with the ligand and inhibit FGF2 signalling. Additionally, it was shown that both mHeps could be partially mediating their effects through the Wnt pathway. mHep effects on both myelination and neurite outgrowth were removed when co-treated with a Wnt signalling inhibitor, suggesting cell signalling mediation by ligand immobilisation and signalling activation as a mechanistic action for the mHeps. However, the initial methods employed in this thesis were not sufficient to provide a more detailed study into the effects the mHeps have on neurite outgrowth. This led to the design and development of a novel microfluidic device (MFD), which provides a platform to study of axonal injury. This novel device is a three chamber device with two chambers converging onto a central open access chamber. This design allows axons from two points of origin to enter a chamber which can be subjected to injury, thus providing a platform in which targeted axonal injury and the regenerative capacity of a compound study can be performed. In conclusion, this thesis contributes to and advances the study of SCI in two ways; 1) identification and investigation of a novel set of compounds with potential therapeutic potential i.e. desulphated modified heparins. These compounds have multiple therapeutic properties and could revolutionise both the understanding of the basic pathological mechanisms underlying SCI but also be a powered therapeutic option. 2) Development of a novel microfluidic device to study in greater detail axonal biology, specifically, targeted axonal injury and treatment, providing a more representative model of SCI than standard in vitro models. Therefore, the MFD could lead to advancements and the identification of factors and compounds relating to axonal regeneration.

A randomised controlled trial comparing the effect of adjuvant intrathecal 2 mg midazolam to 20 micrograms fentanyl on postoperative pain for patients undergoing lower limb orthopaedic surgery under spinal anaesthesia.

Background: Intrathecal adjuvants are added to local anaesthetics to improve the quality of neuraxial blockade and prolong the duration of analgesia during spinal anaesthesia. Used intrathecally, fentanyl improves the quality of spinal blockade as compared to plain bupivacaine and confers a short duration of post-operative analgesia. Intrathecal midazolam as an adjuvant has been used and shown to improve the quality of spinal anaesthesia and prolong the duration of post-operative analgesia. No studies have been done comparing intrathecal fentanyl with bupivacaine and intrathecal 2 mg midazolam with bupivacaine. Objective: To compare the effect of intrathecal 2 mg midazolam to intrathecal 20 micrograms fentanyl when added to 2.6 ml of 0.5% hyperbaric bupivacaine, on post-operative pain, in patients undergoing lower limb orthopaedic surgery under spinal anaesthesia. Methods: A total of 40 patients undergoing lower limb orthopaedic surgery under spinal anaesthesia were randomized to two groups. Group 1: 2.6mls 0.5% hyperbaric bupivacaine with 0.4mls (20micrograms) fentanyl Group 2: 2.6mls of 0.5% hyperbaric bupivacaine with 0.4mls (2mg) midazolam Results: The duration of effective analgesia was longer in the midazolam group (384.05 minutes) as compared to the fentanyl group (342.6 minutes). There was no significant difference (P 0.4047). The time to onset was significantly longer in midazolam group 17.1 minutes as compared to the fentanyl group 13.2 minutes (P 0.023). The visual analogue score at rescue was significantly lower in the midazolam group (5.55) as compared to the fentanyl group 6.35 (P - 0.043). Conclusion: On the basis of the results of this study, there was no significant difference in the duration of effective analgesia between adjuvant intrathecal 2 mg midazolam as compared to intrathecal 20 micrograms fentanyl for patients undergoing lower limb orthopaedic surgery.

Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury.

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

A randomised controlled trial comparing weight adjusted dose versus fixed dose prophylactic phenylephrine infusion on maintaining systolic blood pressure during caesarean section under spinal anaesthesia.

Background: Spinal anaesthesia is the standard of care for elective caesarean delivery. It has advantages over general anaesthesia. However the sympathetic blockade induced by spinal anaesthesia results in an 80 percent incidence of hypotension without prophylactic management. Current evidence supports co-loading with intravenous fluids in conjunction with the use of vasopressors as the most effective way to prevent and treat the hypotension. Phenylephrine is the accepted vasopressor of choice in the parturient. A prophylactic phenylephrine infusion combined with a fluid co-load is proven to be an effective and safe method of maintaining maternal hemodynamic stability. While most published studies have assessed the effectiveness of a prophylactic phenylephrine fixed dose infusion, few studies have assessed the effect of a prophylactic phenylephrine weight adjusted dose infusion on maintaining maternal hemodynamic stability following spinal anesthesia for a cesarean delivery. Objective: To compare the incidence of hypotension between women undergoing elective caesarean section under spinal anaesthesia, receiving prophylactic phenylephrine infusion at a fixed dose of 37.5 micrograms per minute versus a weight adjusted dose of 0.5 micrograms per kilogram per minute. Methods: One hundred and eight patients scheduled for non-urgent caesarean section under spinal anaesthesia were randomized into 2 groups; control group and intervention group using a computer generated table of numbers. Control group; Received prophylactic phenylephrine fixed dose infusion at 37.5 micrograms per minute. Intervention group; Received prophylactic phenylephrine weight adjusted dose infusion at 0.5 micrograms per kilogram per minute Results: The two groups had similar baseline characteristics in terms of ; Age, sex, weight and height. There was a 35.2% incidence of hypotension in the fixed dose group and an 18.6% incidence of hypotension in the weight adjusted dose group. This difference was found to be of borderline statistical significance p-value 0.05, and the difference in the incidence rates between the two groups was found to be statistically significant p= 0.03. The difference in the incidence of reactive hypertension and bradycardia between the two groups was not statistically significant: p-value of 0.19 for reactive hypertension and p-value of 0.42 for the incidence of bradycardia. There was also no statistically significant difference in the use of phenylephrine boluses, use of atropine, intravenous fluid used and the number of times the infusion was stopped. Conclusion: Among this population, the incidence of hypotension was significantly less in the weight adjusted dose group than in the fixed dose group. There was no difference in the number of physician interventions required to keep the blood pressure within 20% of baseline, and no difference in the proportion of reactive hypertension or bradycardia between the two groups. Administering prophylactic phenylephrine infusion at a weight adjusted dose of 0.5 micrograms per kilogram per minute results in a lower incidence of hypotension compared to its administration at a fixed dose of 37.5 micrograms per minute.

Effects of Load History on Ovine Spinal Range of Motion

Loading of spinal motion segment units alters biomechanical properties by modifying flexibility and range of motion. This study utilizes angular displacement due to an applied bending moment to assess biomechanical function during high-magnitude and prolonged compressive loading of ovine lumbar motion segments. High compressive loads, representative of physiological lifestyle and occupational behaviors, appear to limit fluid recovery of the intervertebral disc, thereby modifying spinal flexibility and increasing spinal instability. Intermittent extensions, or backwards bending movements, may provide a protective effect against the load-induced spinal instability. This study contributes a greater understanding of the effects of load history on the function and health of the lumbar spine. Findings may inform future efforts investigating adjustments in spinal posture to preserve or promote the recovery of lumbar spinal biomechanics.

Dipsacus asperoides (Xue Duan) inhibits spinal cord injury-induced inflammatory responses in rats

Purpose: To investigate the effect of Dipsacus asperoides (Xue Duan), a traditional Chinese medicine, on rats with spinal cord injury (SCI). Methods: In this study a total of 40 adult rats were used after inducing SCI where Xue Duan was applied on experimental group and phosphate-buffered saline (PBS) was administered in corresponding control groups. Intraperitoneal administration of both compounds for a period of four weeks (28 days) was carried out at a dose of 10 mg/kg/day. Bright field microscopy was performed on the tissues. Results: Bright Field microscopy of tissue sections showed significant reduction in cavity area that resulted from injury, that is from 0.19 ± 0.05 mm2 to 0.09 ± 0.03 mm2 (p < 0.01) in untreated and treated groups respectively. Similarly western blotting results showed a decrease in the expression of NF-kB p65 and I-kBα (p < 0.01). These two compounds are important in increasing secondary pathophysiology in SCI. The results for MPO activity also revealed significantly reduced infiltration of leukocytes to the injury site (p < 0.01). Conclusion: This study reveals the positive effect of the plant material in reducing inflammation in rats with traumatic SCI.

Dose-dependent protection of reseveratrol against spinal cord ischemic-reperfusion injury in rats

Purpose: To examine the protective effects of resveratrol (RESV) against spinal cord ischemic reperfusion (SCIR) injury. Methods: Forty-eight male rats were divided into six groups: sham-operated (control-I), SCIR-treated (SCIR-II), rats receiving 20 mg/kg of RESV with SCIR (RESV 20+SCIR-III), rats receiving 40 mg/kg of RESV with SCIR (RESV 40+SCIR-IV), rats receiving 60 mg/kg of RESV with SCIR (RESV 60+SCIR-V), and rats receiving 50 mg/kg of methylprednisolone (MP) with SCIR (MP + SCIR-VI), for 7 days prior to IR (pre-treatment) and 7 days after IR (post-treatment). Results: The levels of oxidative markers (TBARS, MPO) and inflammatory markers (IL-1β, IL-6, TNF-α, and NF-p65) were concomitantly suppressed in RESV-treated rats, which showed improved locomotor function. A pronounced increase in the activities of antioxidant enzymes (SOD, CAT and GSH) was noted in the RESV group compared with the MP and SCIR groups. RESV and MP supplementation increased neuronal count with decreased nuclear degeneration. RESV (40 mg) exhibited greater protective effect than 20 mg and 60 mg of RESV and 50 mg of MP. Conclusion: The results show the neurotherapeutic potential of RESV (40 mg) to attenuate oxidative stress and the inflammatory response to SCIR injury.

In situ epicatechin-loaded hydrogel implants for local drug delivery to spinal column for effective management of post-traumatic spinal injuries

Purpose: To prepare hydrogels loaded with epicatechin, a strong antioxidant, anti-inflammatory, and neuroprotective tea flavonoid, and characterise them in situ as a vehicle for prolonged and safer drug delivery in patients with post-traumatic spinal cord injury. Methods: Five in situ gel formulations were prepared using chitosan and evaluated in terms of their visual appearance, clarity, pH, viscosity, and in vitro drug release. In vivo anti-inflammatory activity was determined and compared with 2 % piroxicam gel as standard. Motor function activity in a rat model of spinal injury was examined comparatively with i.v. methylprednisolone as standard. Results: The N-methyl pyrrolidone solution (containing 1 % w/w epicatechin with 2 to 10 % w/w chitosan) of the in situ gel formulation had a uniform pH in the range of 4.01 ± 0.12 to 4.27 ± 0.02. High and uniform drug loading, ranging from 94.48 ± 1.28 to 98.08 ± 1.24 %, and good in vitro drug release (79.48 ± 2.84 to 96.48 ± 1.02 % after 7 days) were achieved. The in situ gel prepared from 1 % epicatechin and 2 % chitosan (E5) showed the greatest in vivo anti-inflammatory activity (60.58 % inhibition of paw oedema in standard carrageenan-induced hind rat paw oedema model, compared with 48.08 % for the standard). The gels showed significant therapeutic effectiveness against post-traumainduced spinal injury in rats. E5 elicited maximum motor activity (horizontal bar test) in the spinal injury rat model; the rats that received E5 treatment produced an activity score of 3.62 ± 0.02 at the end of 7 days, compared with 5.0 ± 0.20 following treatment with the standard. Conclusion: In situ epicatechin-loaded gel exhibits significant neuroprotective and anti-inflammatory effects, and therefore can potentially be used for prolonged and safe drug delivery in patients with traumatic spinal cord injury.