Effectiveness of Lumbar Cerebrospinal Fluid Drain Among Patients With Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial.

Importance: After aneurysmal subarachnoid hemorrhage, the use of lumbar drains has been suggested to decrease the incidence of delayed cerebral ischemia and improve long-term outcome. Objective: To determine the effectiveness of early lumbar cerebrospinal fluid drainage added to standard of care in patients after aneurysmal subarachnoid hemorrhage. Design, Setting, and Participants: The EARLYDRAIN trial was a pragmatic, multicenter, parallel-group, open-label randomized clinical trial with blinded end point evaluation conducted at 19 centers in Germany, Switzerland, and Canada. The first patient entered January 31, 2011, and the last on January 24, 2016, after 307 randomizations. Follow-up was completed July 2016. Query and retrieval of data on missing items in the case report forms was completed in September 2020. A total of 20 randomizations were invalid, the main reason being lack of informed consent. No participants meeting all inclusion and exclusion criteria were excluded from the intention-to-treat analysis. Exclusion of patients was only performed in per-protocol sensitivity analysis. A total of 287 adult patients with acute aneurysmal subarachnoid hemorrhage of all clinical grades were analyzable. Aneurysm treatment with clipping or coiling was performed within 48 hours. Intervention: A total of 144 patients were randomized to receive an additional lumbar drain after aneurysm treatment and 143 patients to standard of care only. Early lumbar drainage with 5 mL per hour was started within 72 hours of the subarachnoid hemorrhage. Main Outcomes and Measures: Primary outcome was the rate of unfavorable outcome, defined as modified Rankin Scale score of 3 to 6 (range, 0 to 6), obtained by masked assessors 6 months after hemorrhage. Results: Of 287 included patients, 197 (68.6%) were female, and the median (IQR) age was 55 (48-63) years. Lumbar drainage started at a median (IQR) of day 2 (1-2) after aneurysmal subarachnoid hemorrhage. At 6 months, 47 patients (32.6%) in the lumbar drain group and 64 patients (44.8%) in the standard of care group had an unfavorable neurological outcome (risk ratio, 0.73; 95% CI, 0.52 to 0.98; absolute risk difference, -0.12; 95% CI, -0.23 to -0.01; P = .04). Patients treated with a lumbar drain had fewer secondary infarctions at discharge (41 patients [28.5%] vs 57 patients [39.9%]; risk ratio, 0.71; 95% CI, 0.49 to 0.99; absolute risk difference, -0.11; 95% CI, -0.22 to 0; P = .04). Conclusion and Relevance: In this trial, prophylactic lumbar drainage after aneurysmal subarachnoid hemorrhage lessened the burden of secondary infarction and decreased the rate of unfavorable outcome at 6 months. These findings support the use of lumbar drains after aneurysmal subarachnoid hemorrhage. Trial Registration: ClinicalTrials.gov Identifier: NCT01258257.

Incidental findings of typical iNPH imaging signs in asymptomatic subjects with subclinical cognitive decline.

BACKGROUND: The etiology of idiopathic normal pressure hydrocephalus (iNPH) remains unclear. Little is known about the pre-symptomatic stage. This study aimed to investigate the association of neuropsychological data with iNPH-characteristic imaging changes compared to normal imaging and unspecific atrophy in a healthy population. METHODS: We extracted data from the community-dwelling Austrian Stroke Prevention Family Study (ASPS-Fam) database (2006-2010). All subjects underwent a baseline and identical follow-up examination after 3-5 years with MR imaging and an extensive neuropsychological test battery (Trail Making Test B, short physical performance balance, walking speed, memory, visuo-practical skills, composite scores of executive function and g-factor). We categorized the subjects into "iNPH"-associated, non-specific "atrophy," and "normal" based on the rating of different radiological cerebrospinal fluid (CSF) space parameters. We noted how the categories developed over time. We assessed the association of the image categories with the neuropsychological data, different demographic, and lifestyle parameters (age, sex, education, alcohol intake, arterial hypertension, hypercholesterolemia), and the extent of white matter hyperintensities. We investigated whether neuropsychological data associated with the image categories were independent from other parameters as confounders. RESULTS: One hundred and thirteen subjects, aged 50-70 years, were examined. The imaging category "iNPH" was only present at follow-up. A third of subjects with "atrophy" at baseline changed to the category "iNPH" at follow-up. More white matter hyperintensities (WMH) were present in later "iNPH" subjects. Subjects with "iNPH" performed worse than "normal" subjects on executive function (p = 0.0118), memory (p = 0.0109), and Trail Making Test B (TMT-B. p < 0.0001). Education, alcohol intake, diabetes, arterial hypertension, and hypercholesterolemia had no effect. Age, number of females, and the extent of white matter hyperintensities were higher in "iNPH" than in "normal" subjects but did not significantly confound the neuropsychological results. CONCLUSIONS: Apparent asymptomatic subjects with "iNPH" imaging characteristics presented with subclinical cognitive decline and showed worse executive function, memory, and TMT-B results than "normal" subjects. WMH seem to play a role in the etiology before ventriculomegaly. Clinical screening of individuals with incidental iNPH-characteristic imaging and conspicuous results sof these neurocognitive tests needs further validation.

Spinal meningioma surgery in the elderly: who can benefit from it?

BACKGROUND: With increasing life expectancy and increasing demands on quality of life more spinal meningiomas will limit quality of life in elderly in the coming decades. We investigated whether elderly can improve neurologically and gain self-dependence postoperatively. METHODS: Medical records of consecutive spinal meningioma patients from 2004-2015 were retrospectively analyzed. Age, gender, preoperative duration and quality of symptoms, pre- and postoperative McCormick score, Karnofsky Performance Status (KPS), American Society of Anesthesiologists Physical Status (ASA), modified Clinical Scoring System (mCSS) and tumor characteristics were included. Elderly were defined by ≥70 years. RESULTS: One hundred and twenty-nine patients were included, of whom 44 were 70 years or older. Younger patients were significantly better preoperatively in McCormick, KPS, ASA and mCSS within the first postoperative year. Both younger and elderly patients improved significantly postoperatively in McCormick, KPS and mCSS. Surgical complication rate was similar for younger and elderly patients (5.9 vs. 6.8%). Systemic complication rate was higher in elderly (0 vs. 6.8%). CONCLUSIONS: Surgery for spinal meningioma in elderly (KPS≥40 and ASA≤III) leads to a significant improvement of McCormick, KPS and mCSS postoperatively. This leads to a higher rate of self-dependency and thereby probably to an improvement of quality of life in elderly. However, special attention for systemic complications is necessary.

Central nervous system microbleeds in the acute phase are associated with structural integrity by DTI one year after mild traumatic brain injury: A longitudinal study.

INTRODUCTION: Several imaging modalities are under investigation to unravel the pathophysiological mystery of delayed performance deficits in patients after mild traumatic brain injury (mTBI). Although both imaging and neuropsychological studies have been conducted, only few data on longitudinal correlations of diffusion tensor imaging (DTI), susceptibility weighted imaging (SWI) and extensive neuropsychological testing exist. METHODS: MRI with T1- and T2-weighted, SWI and DTI sequences at baseline and 12 months of 30 mTBI patients were compared with 20 healthy controls. Multiparametric assessment included neuropsychological testing of cognitive performance and post-concussion syndrome (PCS) at baseline, 3 and 12 months post-injury. Data analysis encompassed assessment of cerebral microbleeds (Mb) in SWI, tract-based spatial statistics (TBSS) and voxel-based morphometry (VBM) of DTI (VBM-DTI). Imaging markers were correlated with neuropsychological testing to evaluate sensitivity to cognitive performance and post-concussive symptoms. RESULTS: Patients with Mb in SWI in the acute phase showed worse performance in several cognitive tests at baseline and in the follow-ups during the chronic phase and higher symptom severity in the post concussion symptom scale (PCSS) at twelve months post-injury. In the acute phase there was no statistical difference in structural integrity as measured with DTI between mTBI patients and healthy controls. At twelve months post-injury, loss of structural integrity in mTBI patients was found in nearly all DTI indices compared to healthy controls. CONCLUSIONS: Presence of Mb detected by SWI was associated with worse cognitive outcome and persistent PCS in mTBI patients, while DTI did not prove to predict neuropsychological outcome in the acute phase.

Overshunting-Associated Myelopathy (OSAM) in a Patient with Bilateral Jugular Vein Occlusion.

BACKGROUND: Overshunting-associated myelopathy (OSAM) is a very rare complication of ventricular shunt therapy, and only 11 previous cases have been reported in the literature. We report the successful surgical management of a case of OSAM in a patient with bilateral jugular vein occlusion and congenital hydrocephalus. CASE DESCRIPTION: A 45-year-old patient with shunt-dependent, congenital hydrocephalus presented to our department with an 8-year history of progressive tetraparesis and gait disturbance. The patient was wheelchair-dependent. A new magnetic resonance imaging scan of the head revealed slit ventricle syndrome and dural enhancement due to shunt overdrainage. Magnetic resonance imaging and a computed tomography-phlebography of the cervical spine revealed engorgement of the epidural venous plexus with secondary compression of the spinal cord and myelomalacia. Surgery was performed, during which we implanted a shunt valve. The patient recovered from surgery without any new deficits. The tetraparesis improved during the inpatient hospital stay. Computed tomography-phlebography was performed 5 days after surgery and showed that the epidural venous plexus anterior to the cervical spinal cord had returned to nearly normal size. On follow-up examination 3 months after surgery, the patient's strength had improved, and he was able to walk short distances with assistance and with ankle foot orthosis on the right side. CONCLUSIONS: OSAM has to be considered according to the Monro-Kellie doctrine and is affected by an engorgement of the epidural cervical venous plexus, which can produce cervical myelopathy. Because it can be treated simply by increasing the shunt resistance, surgeons should be aware of the rarely detected overdrainage complication.

Room Air Readings of Brain Tissue Oxygenation Probes.

OBJECTIVE: Brain tissue oxygenation (pbtO2) monitoring with microprobes is increasingly used as an important parameter in addition to intracranial pressure in acutely brain-injured patients. Data on accuracy and long-term drift after use are scarce. We investigated room air readings of used pbtO2 probes for their relationship with the duration of monitoring, geographic location of the center, and manufacturer type. METHODS: After finishing clinically indicated monitoring in patients, pbtO2 probes used in two centers in Berlin and Munich were explanted and cleaned to avoid blood contamination. Immediately afterward, room air readings of partial oxygen pressure (pairO2) from 44 Licox® and 10 Raumedic ® pbtO2 probes were recorded. Assumed height above sea level was 42 m for Berlin and 485 m for Munich; this resulted in assumed theoretical pairO2 readings of 157.8 mmHg in Berlin and 149.9 mmHg in Munich. RESULTS: Licox ® probes in Berlin showed a mean pairO2 of 160.5 (SD 14.4) mmHg and of 147.8 (11.9) mmHg in Munich. Raumedic ® probes in Berlin showed a mean pairO2 of 170.5 (12.2) mmHg and the single Raumedic ® probe used in Munich 155 mmHg. No significant drift was found over time for probes with up to 14 days of monitoring. Prolonged use of up to 20 days showed a clinically negligible drift of 1.2 mmHg per day of use for Licox® probes.Mean absolute deviation for pairO2 from expected values was 6.4% for Licox ® and 9.7% for Raumedic ® probes. CONCLUSION: Room air partial oxygen pressure pairO2 may be utilized to assess the proper function of a pbtO2 probe. It provides a tool for quality control which is easy to implement. Probe readings are stable in the clinically relevant range, even after prolonged use.

Three versus seven days to return-to-work after mild traumatic brain injury: a randomized parallel-group trial with neuropsychological assessment.

Although most patients with a mild traumatic brain injury (mTBI) recover within days to weeks, some experience persistent physical, cognitive and emotional symptoms, often described as post-concussion syndrome (PCS). The optimal recovery time including return-to-work (RTW) after mTBI is unclear. In this single-centre parallel-group trial, patients assigned three days (3D-group) or seven days (7D-group) sick leave were compared with a comprehensive neuropsychological test battery including the Post-Concussion Symptom Scale (PCSS) within one week, after three and 12 months post-injury. The influence of the effective time until RTW on post-concussional symptoms and cognitive performance was analysed. The 3D-group rated significantly higher mean scores in some PCSS symptoms, tended to fulfil diagnosis criteria of PCS more often and showed better cognitive performance in several neuropsychological test scores than the 7D-group at all three time-points of follow-up. Overall, patients returned to work 11.35 d post-injury, thus distinctly above both recommended sick leaves. There was a trend for longer sick leave in patients randomized into the 3D-group. Further analyses revealed that the group with an absolute RTW within one week showed lower symptom severity in fatigue at 3 and 12 months, less PCS and faster performance in fine motor speed at 12 months than the group with an absolute RTW after one week. Our data underline the heterogeneity of mTBI and show that acute and sub-acute symptoms are not prognostic factors for neuropsychological outcome at one year. Later, ability to work seems to be prognostic for long-term occurrence of PCS.

A basic model for training of microscopic and endoscopic transsphenoidal pituitary surgery: the Egghead.

BACKGROUND: Transsphenoidal endoscopic surgery has gained popularity in the last 2 decades and is becoming a standard technique for resection of pituitary adenomas. In contrast to their ENT colleagues, neurosurgical residents have practically no endoscopic experience when they reach the training stage for transsphenoidal procedures. We have developed an affordable method for repetitive training in endoscopic (and microscopic) work in a narrow channel, allowing training of the basic movements needed for resection of pituitary adenoma. METHODS: In collaboration with colleagues in the ENT Department, Cantonal Hospital St. Gall, and the Technical University of Zurich, a three-dimensional model of the nasal cavity was developed and patented. The Egghead model consists of a 3D synthetic reconstruction of the head nasal cavity and sphenoid sinus. A boiled egg represents the sella. For validation, 17 neurosurgical residents from the Department of Neurosurgery, University Hospital of Basel, and Department of Neurosurgery, Cantonal Hospital of St. Gall, St. Gall, Switzerland, and two experts performed a standardized procedure mimicking a transsphenoidal pituitary procedure by dissecting a corridor to the egg yolk and resecting it, respecting the surrounding egg white. This procedure was performed under both microscopic and video-endoscopic visualization. A score for the precision and speed of the surgical performance was developed and used. RESULTS: The model allows repetitive training of the resection of the egg yolk under sparing of the egg white after careful opening of the shell. The validation data showed a steeper learning curve using the endoscopic technique than performing the same task using the microscope. After three repetitions, the quality of resection was better with the endoscopic technique. CONCLUSIONS: Our model, the Egghead, is affordable, offers tactile feedback and allows infinite repetitions in basic training for pituitary surgery. It can be used for training of advanced neurosurgical residents, who thus far have very few possibilities of acquiring endoscopic experience.

Standardizing data collection in severe trauma: call for linking up.

Standardization of data collection in severely injured trauma patients in order to find the best performance and practice has been an issue for more than 20 years. The incidence of trauma has decreased and outcomes have improved over the past decades. Trauma still remains an important public health problem, however, and is listed by the World Health Organization as a leading cause of death and disability. Ringdal and colleagues prove the feasibility on a basic level in their prospective, intercontinental study showing the results of the Utstein Trauma Template. In-depth analysis is currently only partially possible. The future of standardizing data collection in trauma looks bright. However, bridging and cross-linking is necessary to a great extent in the future.

Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles.

RATIONALE: Stroke is the third most common cause of death in industrialized countries. The main therapeutic target is the ischemic penumbra, potentially salvageable brain tissue that dies within the first few hours after blood flow cessation. Hence, strategies to keep the penumbra alive until reperfusion occurs are needed. OBJECTIVE: To study the effect of inhaled nitric oxide on cerebral vessels and cerebral perfusion under physiological conditions and in different models of cerebral ischemia. METHODS AND RESULTS: This experimental study demonstrates that inhaled nitric oxide (applied in 30% oxygen/70% air mixture) leads to the formation of nitric oxide carriers in blood that distribute throughout the body. This was ascertained by in vivo microscopy in adult mice. Although under normal conditions inhaled nitric oxide does not affect cerebral blood flow, after experimental cerebral ischemia induced by transient middle cerebral artery occlusion it selectively dilates arterioles in the ischemic penumbra, thereby increasing collateral blood flow and significantly reducing ischemic brain damage. This translates into significantly improved neurological outcome. These findings were validated in independent laboratories using two different mouse models of cerebral ischemia and in a clinically relevant large animal model of stroke. CONCLUSIONS: Inhaled nitric oxide thus may provide a completely novel strategy to improve penumbral blood flow and neuronal survival in stroke or other ischemic conditions.

Standardizing data collection in traumatic brain injury.

Collaboration among investigators, centers, countries, and disciplines is essential to advancing the care for traumatic brain injury (TBI). It is thus important that we "speak the same language." Great variability, however, exists in data collection and coding of variables in TBI studies, confounding comparisons between and analysis across different studies. Randomized controlled trials can never address the many uncertainties concerning treatment approaches in TBI. Pooling data from different clinical studies and high-quality observational studies combined with comparative effectiveness research may provide excellent alternatives in a cost-efficient way. Standardization of data collection and coding is essential to this end. Common data elements (CDEs) are presented for demographics and clinical variables applicable across the broad spectrum of TBI. Most recommendations represent a consensus derived from clinical practice. Some recommendations concern novel approaches, for example assessment of the intensity of therapy in severely injured patients. Up to three levels of detail for coding data elements were developed: basic, intermediate, and advanced, with the greatest level of detail attained in the advanced version. More detailed codings can be collapsed into the basic version. Templates were produced to summarize coding formats, explanation of choices, and recommendations for procedures. Endorsement of the recommendations has been obtained from many authoritative organizations. The development of CDEs for TBI should be viewed as a continuing process; as more experience is gained, refinement and amendments will be required. This proposed process of standardization will facilitate comparative effectiveness research and encourage high-quality meta-analysis of individual patient data.

Common data elements for traumatic brain injury: recommendations from the interagency working group on demographics and clinical assessment.

Comparing results across studies in traumatic brain injury (TBI) has been difficult because of the variability in data coding, definitions, and collection procedures. The global aim of the Working Group on Demographics and Clinical Assessment was to develop recommendations on the coding of clinical and demographic variables for TBI studies applicable across the broad spectrum of TBI, and to classify these as core, supplemental, or emerging. The process was consensus driven, with input from experts over a broad range of disciplines. Special consideration was given to military and pediatric TBI. Categorizing clinical elements as core versus supplemental proved difficult, given the great variation in types of studies and their interests. The data elements are contained in modules, which are grouped together in categories. Three levels of detail for coding data elements were developed: basic, intermediate, and advanced, with the greatest level of detail in the advanced version. In every case, the more detailed coding can be collapsed into the basic version. Templates were produced to summarize coding formats, motivation of choices, and recommendations for procedures. Work is ongoing to include more international participation and to provide an electronic data entry format with pull-down menus and automated data checks. This proposed standardization will facilitate comparison of research findings across studies and encourage high-quality meta-analysis of individual patient data.

Changes of cerebral blood flow during the secondary expansion of a cortical contusion assessed by 14C-iodoantipyrine autoradiography in mice using a non-invasive protocol.

Although changes of cerebral blood flow (CBF) in and around traumatic contusions are well documented, the role of CBF for the delayed death of neuronal cells in the traumatic penumbra ultimately resulting in secondary contusion expansion remains unclear. The aim of the current study was therefore to investigate the relationship between changes of CBF and progressive peri-contusional cell death following traumatic brain injury (TBI). CBF and contusion size were measured in C57Bl6 mice under continuous on-line monitoring of (ETp)CO2 before, and at 15 min and 24 h following controlled cortical impact by 14C-iodoantipyrine autoradiography (IAP-AR; n = 5-6 per group) and by Nissl staining, respectively. Contused and ischemic (CBF < 10%) tissue volumes were calculated and compared over time. Cortical CBF in not injured mice varied between 69 and 93 mL/100mg/min depending on the anatomical location. Fifteen minutes after trauma, CBF decreased in the whole brain by approximately 50% (39 +/- 18 mL/100mg/min; p < 0.05), except in contused tissue where it fell by more than 90% (3 +/- 2 mL/100mg/min; p < 0.001). Within 24 h after TBI, CBF recovered to normal values in all brain areas except the contusion where it remained reduced by more than 90% (p < 0.001). Contusion volume expanded from 24.9 to 35.5 mm3 (p < 0.01) from 15 min to 24 h after trauma (+43%), whereas the area of severe ischemia (CBF < 10%) showed only a minimal (+13%) and not significant increase (22.3 to 25.1 mm3). The current data therefore suggest that the delayed secondary expansion of a cortical contusion following traumatic brain injury may not be caused by a reduction of CBF alone.

Aldolase C-positive cerebellar Purkinje cells are resistant to delayed death after cerebral trauma and AMPA-mediated excitotoxicity.

The cerebellum has been shown to be vulnerable to global ischemic damage in tightly controlled zones of Purkinje cells (PCs) that lack aldolase C, an enzyme critical for glycolysis. Here, we investigated whether aldolase C-negative PCs were more likely to die after cerebral trauma in vivo, and whether this death was mediated by excitotoxic [alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-mediated] means in vitro. Mice were subjected to controlled cortical impact, or remained uninjured, and were killed at 6 h, 24 h or 7 days after injury. Cerebellar sections (both ipsilateral and contralateral to the site of cerebral injury) were stained against aldolase C and calbindin (a marker of PCs). The number of viable, calbindin-positive PCs decreased significantly at 24 h and 7 days after injury, and the percentage of surviving, aldolase C-positive PCs significantly increased at those time-points. In addition, we subjected murine cerebellar cultures to AMPA (30 microm, 20 min), which killed a significant number of PCs at 24 h post-treatment. A similar number of PCs was lost after transfection with aldolase C siRNA, and this effect was exacerbated in transfected cultures treated with AMPA. The results from the present study indicate that aldolase C provides marked neuroprotection to PCs after trauma and excitotoxicity.

Prognostic value of demographic characteristics in traumatic brain injury: results from the IMPACT study.

Outcome following traumatic brain injury (TBI) is not only dependent on the nature and severity of injury and subsequent treatment, but also on constituent characteristics of injured individuals. We aimed to describe and quantify the relationship between demographic characteristics and six month outcome assessed by the Glasgow Outcome Scale (GOS) after TBI. Individual patient data on age (n = 8719), gender (n = 8720), race (n = 5320), and education (n = 2201) were extracted from eight therapeutic Phase III randomized clinical trials and three surveys in moderate or severe TBI, contained in the IMPACT database. The strength of prognostic effects was analyzed with binary and proportional odds regression analysis and expressed as an odds ratio. Age was analyzed as a continuous variable with spline functions, and the odds ratio calculated over the difference between the 75 th and 25 th percentiles. Associations with other predictors were explored. Increasing age was strongly related to poorer outcome (OR 2.14; 95% CI 2.00-2.28) in a continuous fashion that could be approximated by a linear function. No gender differences in outcome were found (OR: 1.01; CI 0.92-1.11), and exploratory analysis failed to show any gender/age interaction. The studies included predominantly Caucasians (83%); outcome in black patients was poorer relative to this group (OR 1.30; CI 1.09-1.56). This relationship was sustained on adjusted analyses, and requires further study into mediating factors. Higher levels of education were weakly related to a better outcome (OR: 0.70; CI 0.52-0.94). On multivariable analysis adjusting for age, motor score, and pupils, the prognostic effect of race and education were sustained. We conclude that outcome following TBI is dependent on age, race, to a lesser extent on education, but not on gender.

Prognostic value of secondary insults in traumatic brain injury: results from the IMPACT study.

We determined the relationship between secondary insults (hypoxia, hypotension, and hypothermia) occurring prior to or on admission to hospital and 6-month outcome after traumatic brain injury (TBI). A meta-analysis of individual patient data, from seven Phase III randomized clinical trials (RCT) in moderate or severe TBI and three TBI population-based series, was performed to model outcome as measured by the Glasgow Outcome Scale (GOS). Proportional odds modeling was used to relate the probability of a poor outcome to hypoxia (N = 5661), hypotension ( N = 6629), and hypothermia ( N = 4195) separately. We additionally analyzed the combined effects of hypoxia and hypotension and performed exploratory analysis of associations with computerized tomography (CT) classification and month of injury. Having a pre-enrollment insult of hypoxia, hypotension or hypothermia is strongly associated with a poorer outcome (odds ratios of 2.1 95% CI [1.7-2.6], 2.7 95% CI [2.1-3.4], and 2.2 95% CI [1.6-3.2], respectively). Patients with both hypoxia and hypotension had poorer outcomes than those with either insult alone. Radiological signs of raised intracranial pressure (CT class III or IV) were more frequent in patients who had sustained hypoxia or hypotension. A significant association was observed between month of injury and hypothermia. The occurrence of secondary insults prior to or on admission to hospital in TBI patients is strongly related to poorer outcome and should therefore be a priority for emergency department personnel.

Combined effects of mechanical and ischemic injury to cortical cells: secondary ischemia increases damage and decreases effects of neuroprotective agents.

Traumatic brain injury (TBI) involves direct mechanical damage, which may be aggravated by secondary insults such as ischemia. We utilized an in vitro model of stretch-induced injury to investigate the effects of mechanical and combined mechanical/ischemic insults to cultured mouse cortical cells. Stretch injury alone caused significant neuronal loss and increased uptake of the dye, propidium iodide, suggesting cellular membrane damage to both glia and neurons. Exposure of cultures to ischemic conditions for 24h, or a combination of stretch and 24h of ischemia, caused greater neuronal loss compared to stretch injury alone. Next, we tested the neuroprotective effects of superoxide dismutase (SOD), and the nitric oxide (NO) synthase inhibitors 7-nitroindazole (7-NINA) and lubeluzole. In general, these agents decreased neuronal loss following stretch injury alone, but were relatively ineffective against the combined injury paradigm. A combination of SOD with 7-NINA or lubeluzole offered no additional protection than single drug treatment against stretch alone or combined injury. These results suggest that the effects of primary mechanical damage and secondary ischemia to cortical neurons are cumulative, and drugs that scavenge superoxide or reduce NO production may not be effective for treating the secondary ischemia that often accompanies TBI.