A Pragmatic Randomized Trial Comparing Surgical Clipping and Endovascular Treatment of Unruptured Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Surgical clipping and endovascular treatment are commonly used in patients with unruptured intracranial aneurysms. We compared the safety and efficacy of the 2 treatments in a randomized trial. MATERIALS AND METHODS: Clipping or endovascular treatments were randomly allocated to patients with one or more 3- to 25-mm unruptured intracranial aneurysms judged treatable both ways by participating physicians. The study hypothesized that clipping would decrease the incidence of treatment failure from 13% to 4%, a composite primary outcome defined as failure of aneurysm occlusion, intracranial hemorrhage during follow-up, or residual aneurysms at 1 year, as adjudicated by a core lab. Safety outcomes included new neurologic deficits following treatment, hospitalization of >5 days, and overall morbidity and mortality (mRS > 2) at 1 year. There was no blinding. RESULTS: Two hundred ninety-one patients were enrolled from 2010 to 2020 in 7 centers. The 1-year primary outcome, ascertainable in 290/291 (99%) patients, was reached in 13/142 (9%; 95% CI, 5%-15%) patients allocated to surgery and in 28/148 (19%; 95% CI, 13%-26%) patients allocated to endovascular treatments (relative risk: 2.07; 95% CI, 1.12-3.83; P = .021). Morbidity and mortality (mRS >2) at 1 year occurred in 3/143 and 3/148 (2%; 95% CI, 1%-6%) patients allocated to surgery and endovascular treatments, respectively. Neurologic deficits (32/143, 22%; 95% CI, 16%-30% versus 19/148, 12%; 95% CI, 8%-19%; relative risk: 1.74; 95% CI, 1.04-2.92; P = .04) and hospitalizations beyond 5 days (69/143, 48%; 95% CI, 40%-56% versus 12/148, 8%; 95% CI, 5%-14%; relative risk: 0.18; 95% CI, 0.11-0.31; P < .001) were more frequent after surgery. CONCLUSIONS: Surgical clipping is more effective than endovascular treatment of unruptured intracranial aneurysms in terms of the frequency of the primary outcome of treatment failure. Results were mainly driven by angiographic results at 1 year.

Stent-Assisted Coiling in the Treatment of Unruptured Intracranial Aneurysms: A Randomized Clinical Trial.

BACKGROUND AND PURPOSE: Stent-assisted coiling may improve angiographic results of endovascular treatment of unruptured intracranial aneurysms compared with coiling alone, but this has never been shown in a randomized trial. MATERIALS AND METHODS: The Stenting in the Treatment of Aneurysm Trial was an investigator-led, parallel, randomized (1:1) trial conducted in 4 university hospitals. Patients with intracranial aneurysms at risk of recurrence, defined as large aneurysms (≥10 mm), postcoiling recurrent aneurysms, or small aneurysms with a wide neck (≥4 mm), were randomly allocated to stent-assisted coiling or coiling alone. The composite primary efficacy outcome was "treatment failure," defined as initial failure to treat the aneurysm; aneurysm rupture or retreatment during follow-up; death or dependency (mRS > 2); or an angiographic residual aneurysm adjudicated by an independent core laboratory at 12 months. The primary hypothesis (revised for slow accrual) was that stent-assisted coiling would decrease treatment failures from 33% to 15%, requiring 200 patients. Primary analyses were intent to treat. RESULTS: Of 205 patients recruited between 2011 and 2021, ninety-four were allocated to stent-assisted coiling and 111 to coiling alone. The primary outcome, ascertainable in 203 patients, was reached in 28/93 patients allocated to stent-assisted coiling (30.1%; 95% CI, 21.2%-40.6%) compared with 30/110 (27.3%; 95% CI, 19.4%-36.7%) allocated to coiling alone (relative risk = 1.10; 95% CI, 0.7-1.7; P = .66). Poor clinical outcomes (mRS >2) occurred in 8/94 patients allocated to stent-assisted coiling (8.5%; 95% CI, 4.0%-16.6%) compared with 6/111 (5.4%; 95% CI, 2.2%-11.9%) allocated to coiling alone (relative risk = 1.6; 95% CI, 0.6%-4.4%; P = .38). CONCLUSIONS: The STAT trial did not show stent-assisted coiling to be superior to coiling alone for wide-neck, large, or recurrent unruptured aneurysms.

Flow Diversion in the Treatment of Intracranial Aneurysms: A Pragmatic Randomized Care Trial.

BACKGROUND AND PURPOSE: Flow diversion is a recent endovascular treatment for intracranial aneurysms. We compared the safety and efficacy of flow diversion with the alternative standard management options. MATERIALS AND METHODS: A parallel group, prerandomized, controlled, open-label pragmatic trial was conducted in 3 Canadian centers. The trial included all patients considered for flow diversion. A Web-based platform 1:1 randomly allocated patients to flow diversion or 1 of 4 alternative standard management options (coiling with/without stent placement, parent vessel occlusion, surgical clipping, or observation) as prespecified by clinical judgment. Patients ineligible for alternative standard management options were treated with flow diversion in a registry. The primary safety outcome was death or dependency (mRS > 2) at 3 months. The composite primary efficacy outcome included the core lab-determined angiographic presence of a residual aneurysm, aneurysm rupture, progressive mass effect during follow-up, or death or dependency (mRS > 2) at 3-12 months. RESULTS: Between May 2011 and November 2020, three hundred twenty-three patients were recruited: Two hundred seventy-eight patients (86%) had treatment randomly allocated (139 to flow diversion and 139 to alternative standard management options), and 45 (14%) received flow diversion in the registry. Patients in the randomized trial frequently had unruptured (83%), large (52% ≥10 mm) carotid (64%) aneurysms. Death or dependency at 3 months occurred in 16/138 patients who underwent flow diversion and 12/137 patients receiving alternative standard management options (relative risk, 1.33; 95% CI, 0.65-2.69; P = .439). A poor primary efficacy outcome was found in 30.9% (43/139) with flow diversion and 45.6% (62/136) of patients receiving alternative standard management options, with an absolute risk difference of 14.7% (95% CI, 3.3%-26.0%; relative risk, 0.68; 95% CI, 0.50-0.92; P = .014). CONCLUSIONS: For patients with mostly unruptured, large, anterior circulation (carotid) aneurysms, flow diversion was more effective than the alternative standard management option in terms of angiographic outcome.

Metameric spinal AVM: Long-term symptomatic relief achieved by embolization of the extradural component.

BACKGROUND: Metameric spinal cord arteriovenous malformations (AVMs) are rare lesions characterized by an intradural and extradural component. They are difficult to treat surgically by the endovascular route. We report a case in which symptomatic relief was achieved by embolization of the extradural component only. CASE PRESENTATION: A 35-year-old woman presented with acute worsening of back pain, weakness in the left leg and urinary retention. Spinal angiography showed a metameric spinal cord AVM with partial common venous drainage of the extradural and intradural components. CONCLUSIONS: Targeted embolization of the extradural component led to dramatic improvement of the patient's symptoms, probably by achieving venous decongestion. She remains neurologically stable at two years' follow-up.

Stent-assisted coiling of posterior inferior cerebellar artery aneurysm complicated by arterial avulsion.

BACKGROUND: Rapid development of new devices and techniques in endovascular neurosurgery allows treatment of complex intracranial vascular lesions. These treatments, however, are not without risk. We report a case of unusual vascular laceration during stent-assisted coiling of a posterior inferior cerebellar artery (PICA) aneurysm. CASE PRESENTATION: A 75-year-old female with a recurrent, previously coiled PICA aneurysm developed avulsion of the parent vessel followed by fatal bleeding while an attempt was made to place a microcatheter across the aneurysmal neck for stent-assisted coiling. CONCLUSIONS: Pathological examination was performed to understand the mechanism of the rupture. The most likely mechanism was straightening of the significant vascular tortuosity, excessive tension on the vessel origin and avulsion upon advancement of the microcatheter over the microguidewire.

Spontaneous resolution of posttraumatic middle meningeal artery pseudoaneurysm.

We present a case of traumatic pseudoaneurysm of the middle meningeal artery (demonstrated on CT angiogram) associated with epidural hematoma that spontaneously resolved without treatment. Follow-up CT angiogram and conventional angiogram done 2 weeks later demonstrated complete resolution of the pseudoaneurysm. The literature suggests that these lesions require urgent treatment because they have a high mortality rate. We highlight the lack of proper data regarding the natural history of this disease and therefore lack of treatment guidelines.

The Canadian C-spine rule for radiography in alert and stable trauma patients.

CONTEXT: High levels of variation and inefficiency exist in current clinical practice regarding use of cervical spine (C-spine) radiography in alert and stable trauma patients. OBJECTIVE: To derive a clinical decision rule that is highly sensitive for detecting acute C-spine injury and will allow emergency department (ED) physicians to be more selective in use of radiography in alert and stable trauma patients. DESIGN: Prospective cohort study conducted from October 1996 to April 1999, in which physicians evaluated patients for 20 standardized clinical findings prior to radiography. In some cases, a second physician performed independent interobserver assessments. SETTING: Ten EDs in large Canadian community and university hospitals. PATIENTS: Convenience sample of 8924 adults (mean age, 37 years) who presented to the ED with blunt trauma to the head/neck, stable vital signs, and a Glasgow Coma Scale score of 15. MAIN OUTCOME MEASURE: Clinically important C-spine injury, evaluated by plain radiography, computed tomography, and a structured follow-up telephone interview. The clinical decision rule was derived using the kappa coefficient, logistic regression analysis, and chi(2) recursive partitioning techniques. RESULTS: Among the study sample, 151 (1.7%) had important C-spine injury. The resultant model and final Canadian C-Spine Rule comprises 3 main questions: (1) is there any high-risk factor present that mandates radiography (ie, age >/=65 years, dangerous mechanism, or paresthesias in extremities)? (2) is there any low-risk factor present that allows safe assessment of range of motion (ie, simple rear-end motor vehicle collision, sitting position in ED, ambulatory at any time since injury, delayed onset of neck pain, or absence of midline C-spine tenderness)? and (3) is the patient able to actively rotate neck 45 degrees to the left and right? By cross-validation, this rule had 100% sensitivity (95% confidence interval [CI], 98%-100%) and 42.5% specificity (95% CI, 40%-44%) for identifying 151 clinically important C-spine injuries. The potential radiography ordering rate would be 58.2%. CONCLUSION: We have derived the Canadian C-Spine Rule, a highly sensitive decision rule for use of C-spine radiography in alert and stable trauma patients. If prospectively validated in other cohorts, this rule has the potential to significantly reduce practice variation and inefficiency in ED use of C-spine radiography.

Canadian CT head rule study for patients with minor head injury: methodology for phase II (validation and economic analysis).

Prospective validation on a new set of patients is an essential test of a new decision rule. However, many clinical decision rules are not prospectively assessed to determine their accuracy, reliability, clinical sensibility, or potential impact on practice. This validation process is important because many statistically derived rules or guidelines do not perform well when tested in a new population. The methodologic standards for a validation study are similar to those described in the article on phase I for derivation studies in the August 2001 issue of Annals of Emergency Medicine. The goal of phase II is to prospectively assess the accuracy, reliability, and acceptability of the decision rule in a new set of patients with minor head injury. This will determine the clinical utility of the rule and is essential if such a rule is to be widely adopted into clinical practice.

The Canadian CT Head Rule Study for patients with minor head injury: rationale, objectives, and methodology for phase I (derivation).

Head injuries are among the most common types of trauma seen in North American emergency departments, with an estimated 1 million cases seen annually. "Minor" head injury (sometimes known as "mild") is defined by a history of loss of consciousness, amnesia, or disorientation in a patient who is conscious and talking, that is, with a Glasgow Coma Scale score of 13 to 15. Although most patients with minor head injury can be discharged without sequelae after a period of observation, in a small proportion, their neurologic condition deteriorates and requires neurosurgical intervention for intracranial hematoma. The objective of the Canadian CT Head Rule Study is to develop an accurate and reliable decision rule for the use of computed tomography (CT) in patients with minor head injury. Such a decision rule would allow physicians to be more selective in their use of CT without compromising care of patients with minor head injury. This paper describes in detail the rationale, objectives, and methodology for Phase I of the study in which the decision rule was derived. [Stiell IG, Lesiuk H, Wells GA, McKnight RD, Brison R, Clement C, Eisenhauer MA, Greenberg GH, MacPhail I, Reardon M, Worthington J, Verbeek R, Rowe B, Cass D, Dreyer J, Holroyd B, Morrison L, Schull M, Laupacis A, for the Canadian CT Head and C-Spine Study Group. The Canadian CT Head Rule Study for patients with minor head injury: rationale, objectives, and methodology for phase I (derivation). Ann Emerg Med. August 2001;38:160-169.]

The Canadian CT Head Rule for patients with minor head injury.

BACKGROUND: There is much controversy about the use of computed tomography (CT) for patients with minor head injury. We aimed to develop a highly sensitive clinical decision rule for use of CT in patients with minor head injuries. METHODS: We carried out this prospective cohort study in the emergency departments of ten large Canadian hospitals and included consecutive adults who presented with a Glasgow Coma Scale (GCS) score of 13-15 after head injury. We did standardised clinical assessments before the CT scan. The main outcome measures were need for neurological intervention and clinically important brain injury on CT. FINDINGS: The 3121 patients had the following characteristics: mean age 38.7 years); GCS scores of 13 (3.5%), 14 (16.7%), 15 (79.8%); 8% had clinically important brain injury; and 1% required neurological intervention. We derived a CT head rule which consists of five high-risk factors (failure to reach GCS of 15 within 2 h, suspected open skull fracture, any sign of basal skull fracture, vomiting >2 episodes, or age >65 years) and two additional medium-risk factors (amnesia before impact >30 min and dangerous mechanism of injury). The high-risk factors were 100% sensitive (95% CI 92-100%) for predicting need for neurological intervention, and would require only 32% of patients to undergo CT. The medium-risk factors were 98.4% sensitive (95% CI 96-99%) and 49.6% specific for predicting clinically important brain injury, and would require only 54% of patients to undergo CT. INTERPRETATION: We have developed the Canadian CT Head Rule, a highly sensitive decision rule for use of CT. This rule has the potential to significantly standardise and improve the emergency management of patients with minor head injury.

The use-dependent sodium channel blocker mexiletine is neuroprotective against global ischemic injury.

Mechanisms responsible for anoxic/ischemic cell death in mammalian CNS grey and white matter involve an increase in intracellular Ca2+, however the routes of Ca2+ entry appear to differ. In white matter, pathological Ca2+ influx largely occurs as a result of reversal of Na+-Ca2+ exchange, due to increased intracellular Na+ and membrane depolarization. Na+ channel blockade has therefore been logically and successfully employed to protect white matter from ischemic injury. In grey matter ischemia, it has been traditionally presumed that activation of agonist (glutamate) operated and voltage dependent Ca2+ channels are the primary routes of Ca2+ entry. Less attention has been directed towards Na+-Ca2+ exchange and Na+ channel blockade as a protective strategy in grey matter. This study investigates mexiletine, a use-dependent sodium channel blocker known to provide significant ischemic neuroprotection to white matter, as a grey matter protectant. Pentobarbital (65 mg/kg) anesthetized, mechanically ventilated Sprague-Dawley rats were treated with mexiletine (80 mg/kg, i.p.). Then 25 min later the animals were subjected to 10 min of bilateral carotid occlusion plus controlled hypotension to 50 Torr by temporary partial exsanguination. Animals were sacrificed with perfusion fixation after 7 days. Ischemic and normal neurons were counted in standard H&E sections of hippocampal CA1 and the ratio of ischemic to total neurons calculated. Mexiletine pre-treatment reduced hippocampal damage by approximately half when compared to control animals receiving saline alone (45 vs. 88% damage, respectively; P<0.001). These results suggest that mexiletine (and perhaps other drugs of this class) can provide protection from ischemia to grey matter as well as white matter.

The spectrin skeleton of newly-invaginated plasma membrane.

As a cell's shape and volume change. its surface area must re-adjust. How is the plasma membrane's spectrin skeleton implicated? For erythrocytes, cells of fixed surface area, spectrin responses to mechanical disturbances have been studied, but for more typical cells with changeable surface areas, they have not. In rapidly shrinking cells, surface membrane at an adherent substratum invaginates, forming transient vacuole-like dilations (VLDs). We exploited this readily inducible surface area perturbation to pose a simple question: is newly invaginated plasma membrane naked or is it supported by a spectrin skeleton? The spectrin skeleton was examined immunocytochemically in L6 cells (rat skeletal muscle) before and after VLD formation, using fixation in cold methanol and 4112, an antibody against beta-fodrin and beta-spectrin. 4112 was visualized by confocal fluorescence microscopy, while paired phase contrast images independently located the VLDs. To generate VLDs, cells were hypotonically swelled then reshrunk in isotonic medium. Swollen L6 cells maintained their plasma membrane (sarcolemma) spectrin skeleton. Within minutes of subsequent shrinkage, VLDs of 1-2 microm diameter invaginated at the substratum surface of myotubes. Both sarcolemma and VLDs were lined by a relatively uniform spectrin skeleton. Z-series suggested that some of the spectrin skeleton-lined sarcolemma became internalized as vacuoles.

Evidence that brain-derived neurotrophic factor neuroprotection is linked to its ability to reverse the NMDA-induced inactivation of protein kinase C in cortical neurons.

Several lines of evidence indicate that a rapid loss of neuronal protein kinase C (PKC) activity is a characteristic feature of cerebral ischemia and is a necessary step in the NMDA-induced death of cultured neurons. Exposing embryonic day 18 primary rat cortical neurons to 50 microM NMDA or 50 microM glutamate for 10 min caused approximately 80% cell death over the next 24 h, but excitotoxic death was largely averted, i.e., by 70-80%, in cells pretreated with brain-derived neurotrophic factor (BDNF). An 8-h preexposure to BDNF (50-100 ng/ml) maximally protected cortical cells from the effects of NMDA and glutamate, although the transient application of BDNF between 8 and 4 h before NMDA was equally protective. These effects of BDNF were abolished at supralethal, i.e., >100 microM, NMDA concentrations. It is significant that BDNF pretreatment prevented the inactivation of PKC in cortical cells normally seen 30 min to 2 h following lethal NMDA or glutamate exposure. This BDNF effect did not arise from changes in NMDA channel activity because neither whole-cell NMDA current amplitudes nor increases in intracellular free Ca2+ concentration were altered by the 8-h BDNF pretreatment. Furthermore, BDNF offered no neuroprotection to cells treated with the PKC inhibitors staurosporine (10-20 nM), calphostin C (1-2.5 microM), or GF-109203X (100 nM) at the time of NMDA addition. These results underscore the importance of PKC inactivation in glutamate-induced neuronal death. They also suggest that BDNF neuroprotection arises, at least in part, via its ability to block the mechanism by which pathophysiological Ca2+ influx through the NMDA receptor causes membrane PKC inactivation.

Selective coupling of mu-calpain activation with the NMDA receptor is independent of translocation and autolysis in primary cortical neurons.

Excessive mu-calpain activation has been linked to several cellular pathologies including excitotoxicity and ischemia. In erythrocytes and other non-central nervous system (CNS) cells, calpain activation is thought to occur following a Ca2+-induced translocation of inactive cytosolic enzyme to membranes and subsequent autolysis. In the present report, we show that transiently exposing primary rat cortical neurons to lethal (50 microM) N-methyl-D-aspartic acid (NMDA) caused protracted calpain activation, measured as increased spectrin hydrolysis, but this was independent of translocation or autolysis of the protease. An anti-mu-calpain antibody showed that calpain was largely membrane associated in cortical neurons, and, consequently, neither translocation nor autolysis of the protease was observed following ionomycin or lethal NMDA treatment. By contrast, in rat erythrocytes, calpain was largely cytosolic and underwent rapid translocation and autolysis in response to ionomycin. Calpain-mediated spectrin hydrolysis was specifically coupled to Ca2+ entry through the NMDA receptor because nonspecific Ca2+ influx via ionomycin or KCl-mediated depolarization failed to activate the enzyme. Thus, calpain appears selectively linked to glutamate receptors in cortical neurons and regulated by mechanisms distinct from that occurring in many non-CNS cells. The data suggest that intracellular signals coupled to the NMDA receptor are responsible for activating calpain already associated with cellular membranes in cortical cells.

Prognostic factors derived from recursive partition analysis (RPA) of Radiation Therapy Oncology Group (RTOG) brain metastases trials applied to surgically resected and irradiated brain metastatic cases.

PURPOSE: (a) To identify the prognostic factors that determine survival after surgical resection and irradiation of tumors metastatic to brain. (b) To determine if the prognostic factors used in the recursive partition analysis (RPA) of brain metastases cases from Radiation Therapy Oncology Group (RTOG) studies into three distinct survival classes is applicable to surgically resected and irradiated patients. METHOD: The medical records of 125 patients who had surgical resection and radiotherapy for brain metastases from 1985 to 1997 were reviewed. The patients' disease and treatment related factors were analyzed to identify factors that independently determine survival after diagnosis of brain metastasis. The patients were also grouped into three classes using the RPA-derived prognostic parameters which are: age, performance status, state of the primary disease, and presence or absence of extracranial metastases. Class 1: patients < or = 65 years of age, Karnofsky performance status (KPS) of > or =70, with controlled primary disease and no extracranial metastases; Class 3: patients with KPS < 70. Patients who do not qualify for Class 1 or 3 are grouped as Class 2. The survival of these patients was determined from the time of diagnosis of brain metastases to the time of death. RESULTS: The median survival of the entire group was 9.5 months. The three classes of patients as grouped had median survivals of 14.8, 9.9, and 6.0 months respectively (p=0.0002). Age of < 65 years, KPS of > or = 70, controlled primary disease, absence of extracranial metastases, complete surgical resection of the brain lesion(s) were found to be independent prognostic factors for survival; the total dose of radiation was not. CONCLUSION: Based on the results of this study, the patients and disease characteristics have significant impact on the survival of patients with brain metastases treated with a combination of surgical resection and radiotherapy. These parameters could be used in selecting patients who would benefit most from such treatment.

Variation in ED use of computed tomography for patients with minor head injury.

STUDY OBJECTIVE: To determine the frequency of utilization, yield for brain injury, incidence of missed injury, and variation in the use of computed tomography (CT) for ED patients with minor head injury. METHODS: This retrospective health records survey was conducted over a 12-month period in the EDs at seven Canadian teaching institutions. Included in this review were adult patients who sustained acute minor head injury, defined as witnessed loss of consciousness or amnesia and a Glasgow Coma Scale score of 13 or greater. Data were collected by research assistants who were trained to select cases and abstract data in a standardized fashion according to a resource manual. Subsequently, patient eligibility was reviewed by the study coordinator and principal investigator. RESULTS: Of the 1,699 patients seen, 521 (30.7%) were referred for CT, and 418 (79.8%) of these scans were negative for any type of brain injury. Overall, 105 (6.2%) of these patients sustained acute brain injury, including 9 (.5%) with an epidural hematoma Cochran's Q test for homogeneity demonstrated significant variation between the seven centers for rate of ordering CT (P < .0001), from a low of 15.9% to a high of 70.4%. All five cases of "missed" hematoma occurred at the institutions with the highest and third highest rates of CT use. After controlling for possible differences in case severity and patient characteristics at each hospital, logistic regression analysis revealed that five of seven hospitals were significantly associated with the use of CT (respected odds ratios [OR], .4, .5, .5, 3.2, and 4.7). Three of the centers (two with the highest ordering rates) showed significant heterogeneity in the ordering of CT among their attending staff physicians, from a low of 6.5% to a high of 80.0%. CONCLUSION: There was considerable variation among institutions and individual physicians in the ordering of CT for patients with minor head injury. Although emergency physicians were selective when ordering CT, the yield of radiography was very low at all hospitals. None of the cases of "missed" intracranial hematoma came from the lowest ordering institutions, indicating that patients may be managed safely with a selective approach to CT use. These findings suggest great potential for more standardized and efficient use of CT of the head, possibly through the use of a clinical decision rule.

Variation in emergency department use of cervical spine radiography for alert, stable trauma patients.

OBJECTIVE: To, assess the emergency department use of cervical spine radiography for alert, stable adult trauma patients in terms of utilization, yield for injury and variation in practices among hospitals and physicians. DESIGN: Retrospective survey of health records. SETTING: Emergency departments of 6 teaching and 2 community hospitals in Ontario and British Columbia. PATIENTS: Consecutive alert, stable adult trauma patients seen with potential cervical spine injury between July 1, 1994, and June 30, 1995. MAIN OUTCOME MEASURES: Total number of eligible patients, referral for cervical spine radiography (overall, by hospital and by physician), presence of cervical spine injury, patient characteristics and hospitals associated with use of radiography. RESULTS: Of 6855 eligible patients, cervical spine radiography was ordered for 3979 (58.0%). Only 60 (0.9%) patients were found to have an acute cervical spine injury (fracture, dislocation or ligamentous instability); 98.5% of the radiographic films were negative for any significant abnormality. The demographic and clinical characteristics of the patients were similar across the 8 hospitals, and no cervical spine injuries were missed. Significant variation was found among the 8 hospitals in the rate of ordering radiography (p < 0.0001), from a low of 37.0% to a high of 72.5%. After possible differences in case severity and patient characteristics at each hospital were controlled for, logistic regression analysis revealed that 6 of the hospitals were significantly associated with the use of radiography. At 7 hospitals, there was significant variation in the rate of ordering radiography among the attending emergency physicians (p < 0.05), from a low of 15.6% to a high of 91.5%. CONCLUSIONS: Despite considerable variation among institutions and individual physicians in the ordering of cervical spine radiography for alert, stable trauma patients with similar characteristics, no cervical spine injuries were missed. The number of radiographic films showing signs of abnormality was extremely low at all hospitals. The findings suggest that cervical spine radiography could be used more efficiently, possibly with the help of a clinical decision rule.

Correlation between electrophysiological effects of mexiletine and ischemic protection in central nervous system white matter.

Protection of CNS white matter tracts in brain and spinal cord is essential for maximizing clinical recovery from disorders such as stroke or spinal cord injury. Central myelinated axons are damaged by anoxia/ischemia in a Ca(2+)-dependent manner. Leakage of Na+ into the axoplasm through Na+ channels causes Ca2+ overload mainly by reverse Na(+)-Ca2+ exchange. Na+ channel blockers have thus been shown to be protective in an in vitro anoxic rat optic nerve model. Mexiletine (10 microM-1 mM), an antiarrhythmic and use-dependent Na+ channel blocker, was also significantly protective, as measured by recovery of the compound action potential after a 60 min anoxic exposure in vitro. More importantly, mexiletine (80 mg/kg, i.p.) also significantly protected optic nerves from injury in a model of in situ ischemia. This in situ model is more clinically relevant as it addresses drug pharmacokinetics, toxicity and CNS penetration. Optic nerve recovery cycles (defined as shifts in latency of compound action potentials with paired stimulation) were used to measure the concentration of mexiletine in optic nerves after systemic administration, estimated at approximately 42 microM 1 h after a single dose of 80 mg/kg, i.p. These results indicate that mexiletine is able to penetrate into the CNS at concentrations sufficient to confer significant protection. Na+ channel blockers such as mexiletine may prove to be effective clinical therapeutic agents for protecting CNS white matter tracts against anoxic/ischemic injury.

A selective N-type Ca(2+)-channel blocker prevents CA1 injury 24 h following severe forebrain ischemia and reduces infarction following focal ischemia.

SNX-111 (NEUREX Corporation, Menlo Park, CA, U.S.A.) an omega-conopeptide, was tested for cytoprotection following normothermic ischemia using both a four-vessel occlusion model of severe forebrain ischemia and a model of transient middle cerebral artery occlusion focal ischemia. Adult male Wistar rats were subjected to 10 min of forebrain ischemia followed by 7 days of reperfusion. A single dose of SNX-111 (5 mg/kg) was injected intravenously following delays of either 6 or 24 h after reperfusion. For 11 rats treated with saline, there was 78 +/- 13% CA1 neuronal injury (mean +/- SD); for 11 given SNX-111 delayed by 6 h, injury was reduced to 35 +/- 30% (p < 0.01); and remarkably, treatment delayed by 24 h (n = 10), still resulted in protection, with only 50 +/- 29% injury (p < 0.05). Adult male spontaneously hypertensive rats had transient occlusion of the right middle cerebral artery of 1.5- or 2-h duration followed by 22.5 or 22 h of reperfusion, respectively. Rats were randomly assigned to receive either saline or SNX-111 (5 mg/kg i.v.), with treatment starting immediately after reperfusion (1.5-h ischemic group) or at 1 h following the onset of ischemia (2-h ischemic group). In the 1.5-h ischemic group, saline-treated animals sustained 138 +/- 32 mm3 of neocortical infarction (n = 9), and SNX-111 treatment resulted in an infarct reduction to 76 +/- 25 mm3 (n = 9; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)