Psychometric properties of the German version of the Diabetes Eating Problem Survey-Revised: additional benefit of disease-specific screening in adolescents with Type 1 diabetes.

AIM: To examine the psychometric properties of the German version of the abbreviated 16-item Diabetes Eating Problem Survey-Revised in a sample of young people with Type 1 diabetes. METHODS: A total of 246 young people, aged 11-19 years, with Type 1 diabetes from six pediatric diabetes centres in Germany were assessed using the Diabetes Eating Problem Survey-Revised. In addition, they underwent screening with two generic tools as well as the WHO five-question well-being index. A clinician's report was also obtained. RESULTS: The Diabetes Eating Problem Survey-Revised was found to have good internal consistency (Cronbach's α = 0.84). The Diabetes Eating Problem Survey-Revised scores significantly correlated with those provided by the non-specific screening tools (r = 0.37, P ≤ 0.000 and r = 0.50, P ≤ 0.000 for boys and r = 0.62, P ≤ 0.000 and r = 0.79, P ≤ 0.000 for girls), indicating convergent validity. The mean (sd) total of the scores was 12.0 (9.6). Criterion validity was confirmed against HbA1c value, BMI standard deviation score and expert (clinician) report. Of the boys included in the study, 11 scored higher than the threshold score on the Diabetes Eating Problem Survey-Revised, of whom only three (27%) were classified as 'suspected to have a disordered eating behaviour' by their clinicians. CONCLUSIONS: The Diabetes Eating Problem Survey-Revised delivered more specific information than generic screening instruments and identified more young people with eating disorders than did clinician report, especially regarding the detection of boys at risk. The results of this study support the utility of the German version of the Diabetes Eating Problem Survey-Revised to identify eating disorders in young people with Type 1 diabetes at an early stage. (German Clinical Trials Registry no.: DRKS00004699).

Multidirectional projectional rigid neuro-endoscopy: prototype and initial experience.

INTRODUCTION: The role of neuro-endoscopy is emerging. Traditional endoscopy is complicated by limited 2D views that make surgical interventions difficult. We have developed a rigid endoscope with a variable direction view that provides 3D visualization. MATERIALS AND METHODS: A prototype of the EndActive endoscope was used to examine 2 brain/intraventricular models. A 360-degree view is controlled via integrated joystick. Alternatively, the computer can volumetrically capture the ventricular surface. The captured video image can be viewed later or processed to create a flat projection map. The performance of this endoscope was compared to standard endoscopy with fixed directions of view. To simulate endoscopy, the center of the first brain model had eight labeled projections. The model was inspected with the multidirectional endoscope, standard rigid endoscopes (0-, 30- and 70-degree), and via a projection map. Ten neurosurgeons proficient in neuro-endoscopy were recruited for the experiments. The second brain model was labeled with 32 intraventricular tumors. RESULTS: With a 0-degree endoscope, only the number directly opposite the site of entry was visualized. With increasing angles, additional numbers were visualized. The 70-degree endoscope allowed 4 of 8 numbers to be visualized. Using the multidirectional endoscope, all 8 numbers were visualized. The multidirectional endoscope was more accurate in identifying markers compared to standard endoscopy (p = 0.031). The mean endoscopy times using the multidirectional endoscope and standard endoscopy were 143 and 117 seconds, respectively (p = 0.243). The best performance was obtained when the flat projection map was read (p < 0.01). Using the endoscope prototype, an average of 30.8 (96%) tumors was identified on the brain model. CONCLUSION: The EndActive endoscope is a rigid endoscope that provides complete visualization of a 3D space by controlling an adjustable viewing direction. In our study, the multidirectional endoscope provided superior visualization compared to standard endoscopy.

Lessons from epidemiologic studies in clinical trials of traumatic brain injury.

Lessions from epidemiological studies. The Clinical Trial Group for Neurosurgery of the University of California San Diego (UCSD) is involved in epidemiological studies and trials of new pharmacological agents in traumatic brain injury. A great number (> 10,000) of patients has been prospectively analyzed forming an integrated database for further purposes. The development of these databases is based on earlier work by the European Neurosurgeons Jennett and Braakmann and the US-Traumatic Coma Data Bank Study. These studies allowed for the development of sophisticated data collection instruments which were used in the international Tirilizad Trials which enrolled over 1,100 patients. A major observation from that trial was that pretreatment hypotension or hypoxia could be unbalanced even in a large two arm blinded study. Another issue of the tirilazad trial was the influence of gender affecting not only outcome but also drug metabolism. Similar experiences were gathered with the phase-III trial on the competitive NMDA-receptor antagonist selfotel, which interferes with the excitotoxic amino acid glutamate as mediator of secondary brain damage, as ischemia-induced neuronal degeneration. Unfortunately, the trial, already underway, had to be prematurely aborted, since concurrent stroke studies with enrollment of nonintubated patients on low-dose selfotel revealed an increased number of deaths and other adverse events. A retrospective analysis did not confirm that Selfotel was associated with an increased mortality in TBI, but there was also no evidence that the drug was efficacious. A problem here was that a major portion of patients did not have intracranial mass lesions (contusion, subdural haematoma) on CT, questioning whether these had a treatment responsive brain injury. Both studies on tirilazad or selfotel underscore the significance of well designed and conducted phase-I and -II trials to characterize the pharmacokinetics of the agent, to confirm availability of drug in the brain, and to identify a sufficient number of patients with lesions responding to the drug. A major issue is the blood-brain barrier permeability of the agent under study. Further, the phenomenon of secondary deterioration - neurological worsening - turned out as a powerful predictor of poor outcome. The findings and conclusions of both clinical trials (tirilazad, selfotel) were utilized for a subsequent patient study on CP101-606 in consultation with the Pfizer company, the US Brain Injury Consortium, and the San Diego Clinical Trial Group. The patient population was a priori selected towards responsiveness of the brain lesions to the treatment. The major conclusions are: I Development of therapeutic regimens targeted towards the mechanisms of brain injury. II Availability of adequate preclinical data. III Directing treatment towards an appropriate patient population. IV Central gathering and interpretation of the neuroradiological findings. V Monitoring of trial center performance. VI Stratification and pre-trial prognostic analysis for identification of subgroups.

Head injury: recent past, present, and future.

There is no question that substantial progress has been made over the last 30 years, since the pioneering multinational studies of Jennett and colleagues, in our understanding of the mechanisms involved in the production, progression, and amelioration of brain damage. The introduction of computed tomography and simple but elegant classifications of the severity of injury (e.g., the Glasgow Coma Scale and the Glasgow Outcome Scale) were seminal milestones in neurotraumatology. When neurosurgeons such as Langfitt, Becker, and Miller took advantage of the pioneering investigations of intracranial hypertension by Janny and Lundberg and combined them with imaging, classification of brain damage, and improvements in emergency medical services, substantial gains were soon made. However, given the perspective of the beginning of the 21 st century, one can see those gains as relatively straightforward, as they have required the consolidation of concepts and ideas that fit together relatively easily. Better attention to easily delineated abnormalities, such as shock, hypoxia, and hypercarbia, and the early evacuation of mass lesions coupled with the concurrent development of modern principles of critical care account for substantial reductions in mortality and a reduction in the number of vegetative, contracted, spastic survivors. Future improvement in the care of patients with head injuries will increasingly be dependent on advances in molecular neurobiology and psychology, our ability to successfully modulate genetic expression, and progress in the treatment of related illnesses, such as stroke, subarachnoid hemorrhage, depression, and Alzheimer's disease.

Clinical measurement, statistical analysis, and risk-benefit: controversies from trials of spinal injury.

BACKGROUND: The National Acute Spinal Cord Injury Studies have been a series of trials assessing the role of pharmacologic agents in the prevention of secondary neuronal damage after acute spinal cord injury. METHODS: The trials were multicenter randomized, controlled studies. RESULTS: Two trials have demonstrated the efficacy of high-dose methylprednisolone in improving neurologic and functional recovery and have shown a reassuring safety profile. CONCLUSION: This study responds to a recent commentary on these trials and examines in particular the roles of clinical measurement, statistical analysis, and risk benefit in assembling evidence for or against innovative therapies.

Intracranial hypertension and cerebral perfusion pressure: influence on neurological deterioration and outcome in severe head injury. The Executive Committee of the International Selfotel Trial.

OBJECT: Recently, a renewed emphasis has been placed on managing severe head injury by elevating cerebral perfusion pressure (CPP), which is defined as the mean arterial pressure minus the intracranial pressure (ICP). Some authors have suggested that CPP is more important in influencing outcome than is intracranial hypertension, a hypothesis that this study was designed to investigate. METHODS: The authors examined the relative contribution of these two parameters to outcome in a series of 427 patients prospectively studied in an international, multicenter, randomized, double-blind trial of the N-methyl-D-aspartate antagonist Selfotel. Mortality rates rose from 9.6% in 292 patients who had no clinically defined episodes of neurological deterioration to 56.4% in 117 patients who suffered one or more of these episodes; 18 patients were lost to follow up. Correspondingly, favorable outcome, defined as good or moderate on the Glasgow Outcome Scale at 6 months, fell from 67.8% in patients without neurological deterioration to 29.1% in those with neurological deterioration. In patients who had clinical evidence of neurological deterioration, the relative influence of ICP and CPP on outcome was assessed. The most powerful predictor of neurological worsening was the presence of intracranial hypertension (ICP > or = 20 mm Hg) either initially or during neurological deterioration. There was no correlation with the CPP as long as the CPP was greater than 60 mm Hg. CONCLUSIONS: Treatment protocols for the management of severe head injury should emphasize the immediate reduction of raised ICP to less than 20 mm Hg if possible. A CPP greater than 60 mm Hg appears to have little influence on the outcome of patients with severe head injury.

Neuromuscular blocking agents in neurointensive care.

INTRODUCTION: Intensive care treatment of patients with severe head injury is aimed at preventing secondary injury. One of the cornerstones in this treatment is sedation and ventilation. Use of Neuromuscular Blocking Agents (NBA) has gained widespread use as part of the protocol for maintaining normal intracranial pressure values, without class 1 evidence for the efficacy of the treatment. METHODS: We examined data of the use of NBA as infusion during ventilator treatment, and IntraCranial Pressure (ICP) measurements in the database from the international multicenter randomized double blind trial of the NMDA receptor antagonist Selfotel. No specific mode of sedation was recommended in the study protocol. RESULTS: Of the 427 patients enrolled in the study 326 had a full data set, 138 received NBA during their stay in the ICU. There were no statistical difference in demographic data between the two groups. During their stay in the ICU, patients who received NBA had a median of 13.5 hours with a recorded ICP above 20 mm Hg, patients who did not receive NBA had a median of 6.5 hours with ICP above 20 mm Hg (p < 0.05). CONCLUSION: Our data challenges the concept of using NBA as part of a routine sedation strategy in treatment of patients with severe head injury.

Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials. The Selfotel Investigators.

OBJECT: Excessive activity of excitatory amino acids released after head trauma has been demonstrated to contribute to progressive injury in animal models and human studies. Several pharmacological agents that act as antagonists to the glutamate receptor have shown promise in limiting this progression. The efficacy of the N-methyl-D-aspartate receptor antagonist Selfotel (CGS 19755) was evaluated in two parallel studies of severely head injured patients, defined as patients with post resuscitation Glasgow Coma Scale scores of 4 to 8. METHODS: A total of 693 patients were prospectively enrolled in two multicenter double-blind studies. Comparison between the treatment groups showed no significant difference with regard to demographic data, previous incidence of hypotension, and severity of injury. As the study progressed, the Safety and Monitoring Committee became concerned about possible increased deaths and serious brain-related adverse events in the treatment arm of the two head injury trials, as well as deaths in the two stroke trials being monitored concurrently. The Selfotel trials were stopped prematurely because of this concern and because an interim efficacy analysis indicated that the likelihood of demonstrating success with the agent if the studies had been completed was almost nil. CONCLUSIONS: Subsequently, more complete data analysis revealed no statistically significant difference in mortality rates in all cases between the two treatment groups in the head injury trials. In this report the authors examine the studies in detail and discuss the potential application of the data to future trial designs.

The frequency, antecedent events, and causal relationships of neurologic worsening following severe head injury. Executive Committee of the international Selfotel Trial.

Neurologic deterioration observed following head injury is recognized as having a deleterious effect on outcome. The present study examines this occurrence in detail to determine the frequency of these episodes, their antecedent events and causal relationships in order to identify patients who are at risk. Data was collected prospectively from a consecutive series of 427 patients entered into the international trial of the NMDA receptor antagonist Selfotel. Using a definition of neurologic worsening based upon objective criteria, 117 patients were identified who suffered 164 episodes of deterioration. The occurrence of a single episode of neurologic worsening increased mortality by more than five-fold and reduced favorable outcomes (good or moderate on the Glasgow Outcome Scale), by more than 50%. Increased intracranial volume resulting in intracranial hypertension was the single most frequent cause of neurologic worsening. This serves to emphasize the importance of more adequate treatments of intracranial hypertension in improving the outcome of patients with severe head injury.

Neurological deterioration as a potential alternative endpoint in human clinical trials of experimental pharmacological agents for treatment of severe traumatic brain injuries. Executive Committee of the International Selfotel Trial.

OBJECTIVE: A recently improved understanding of the pathophysiological features of head injuries has led to the development of new drug therapies. Accurate human clinical trials remain necessary to document the efficacy and safety of new agents. It would be helpful to decrease the time from drug development to clinical use and general availability for drugs found to be effective. Conversely, ineffective agents could be abandoned in a timely fashion. RATIONALE: A new endpoint measure, defined as neuroworsening (NW), is an objective observable event that is identifiable during hospitalization. This may enable the efficacy of drugs to be demonstrated or disproved much earlier than with 6-month outcome assessments. The prospective, double-blind, multicenter trial of the N-methyl-D-aspartate receptor antagonist Selfotel was used to acquire data on the efficacy of NW in predicting neurological outcomes. The 6-month Glasgow Outcome Scale scores, which were the primary endpoints of that trial, were compared with the frequency of NW. NW was an observable event that could be objectively defined after head injuries. Patients who suffered one or more episodes of NW demonstrated significantly higher morbidity and mortality rates than did patients who did not. CONCLUSION: Future trials should consider the use of NW as an outcome measure that can be included with more traditional measures in the study design. If the strong correlation demonstrated between NW and 6-month Glasgow Outcome Scale scores can be prospectively demonstrated in a successful trial, the time to approval of future agents could be decreased.

Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the third National Acute Spinal Cord Injury randomized controlled trial.

OBJECT: A randomized double-blind clinical trial was conducted to compare neurological and functional recovery and morbidity and mortality rates 1 year after acute spinal cord injury in patients who had received a standard 24-hour methylprednisolone regimen (24MP) with those in whom an identical MP regimen had been delivered for 48 hours (48MP) or those who had received a 48-hour tirilazad mesylate (48TM) regimen. METHODS: Patients for whom treatment was initiated within 3 hours of injury showed equal neurological and functional recovery in all three treatment groups. Patients for whom treatment was delayed more than 3 hours experienced diminished motor function recovery in the 24MP group, but those in the 48MP group showed greater 1-year motor recovery (recovery scores of 13.7 and 19, respectively, p=0.053). A greater percentage of patients improving three or more neurological grades was also observed in the 48MP group (p=0.073). In general, patients treated with 48TM recovered equally when compared with those who received 24MP treatments. A corresponding recovery in self care and sphincter control was seen but was not statistically significant. Mortality and morbidity rates at 1 year were similar in all groups. CONCLUSIONS: For patients in whom MP therapy is initiated within 3 hours of injury, 24-hour maintenance is appropriate. Patients starting therapy 3 to 8 hours after injury should be maintained on the regimen for 48 hours unless there are complicating medical factors.

A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury.

OBJECT: The authors prospectively studied the efficacy of tirilazad mesylate, a novel aminosteroid, in humans with head injuries. METHODS: A cohort of 1120 head-injured patients received at least one dose of study medication (tirilazad or placebo). Eighty-five percent (957) of the patients had suffered a severe head injury (Glasgow Coma Scale [GCS] score 4-8) and 15% (163) had sustained a moderate head injury (GCS score 9-12). Six-month outcomes for the tirilazad- and placebo-treated groups for the Glasgow Outcome Scale categories of both good recovery and death showed no significant difference (good recovery in the tirilazad-treated group was 39% compared with the placebo group in which it was 42% [p=0.461]; death in the tirilazad-treated group occurred in 26% of patients compared with the placebo group, in which it occurred in 25% [p=0.750]). Subgroup analysis suggested that tirilazad mesylate may be effective in reducing mortality rates in males suffering from severe head injury with accompanying traumatic subarachnoid hemorrhage (death in the tirilazad-treated group occurred in 34% of patients; in the placebo group it occurred in 43% [p=0.026]). No significant differences in frequency or types of serious adverse events were shown between the treatment and placebo groups. CONCLUSIONS: Striking problems with imbalance concerning basic prognostic variables were observed in spite of the large population studied. These imbalances concerned pretreatment hypotension, pretreatment hypoxia, and the incidence of epidural hematomas. In future trials of pharmacological therapy for severe head injury, serious consideration must be given to alternative randomization strategies. Given the heterogeneous nature of head injury and the identification of populations that do relatively well with standard therapy, target populations with a higher risk for mortality and morbidity may be more suitable for clinical trials of such agents.

Neurogenic hypotension in patients with severe head injuries.

OBJECTIVE: To examine the occurrence of hypotensive episodes in patients with severe traumatic brain injuries that are not of hypovolemic origin and to investigate possible neurogenic or iatrogenic causes of such episodes. METHODS: We reviewed Traumatic Coma Data Bank (TCDB) records of the 248 patients with early hypotension. We attempted to eliminate episodes related to hemorrhagic hypovolemia by excluding patients with (1) extracranial injuries of Abbreviated Injury Scale scores > 3 (n = 99, 40%); (2) postresuscitation hematocrit levels < 35% (n = 76, 30.6%); (3) hematocrit levels decreasing to < 35% during the first 24 hours after injury (n = 47, 19%); and (4) patients with conflicting data (n = 5, 2%). This left 21 patients (8.5%) without discernible extracranial causes for their hypotension. RESULTS: Of these 21 patients, 4 had no extracranial injuries and 4 had only a single injury with Abbreviated Injury Scale score = 1. Hypotensive episodes were not associated with terminal or unsalvageable status. Mortality was 43%. Of the multiple factors investigated, the only two that were strongly associated with these "unexplained" hypotensive episodes were the presence of a diffuse injury pattern on computed tomography (n = 15, 71%) and the early use of mannitol or furosemide (n = 16, 76%) (It was policy at TCDB centers that hypotensive patients not receive diuretics until they were resuscitated.) CONCLUSIONS: (1) Some episodes of severe traumatic brain injury-related hypotension may be of neurogenic origin. (2) The risk/benefit ratio of early diuretic use in patients with severe traumatic brain injuries may be too high to support liberal use. These data strongly support the need for a study involving prospective collection of data describing the early blood pressure courses in such patients.

Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study.

OBJECTIVE: To compare the efficacy of methylprednisolone administered for 24 hours with methyprednisolone administered for 48 hours or tirilazad mesylate administered for 48 hours in patients with acute spinal cord injury. DESIGN: Double-blind, randomized clinical trial. SETTING: Sixteen acute spinal cord injury centers in North America. PATIENTS: A total of 499 patients with acute spinal cord injury diagnosed in National Acute Spinal Cord Injury Study (NASCIS) centers within 8 hours of injury. INTERVENTION: All patients received an intravenous bolus of methylprednisolone (30 mg/kg) before randomization. Patients in the 24-hour regimen group (n=166) received a methylprednisolone infusion of 5.4 mg/kg per hour for 24 hours, those in the 48-hour regimen group (n=167) received a methylprednisolone infusion of 5.4 mg/kg per hour for 48 hours, and those in the tirilazad group (n=166) received a 2.5 mg/kg bolus infusion of tirilazad mesylate every 6 hours for 48 hours. MAIN OUTCOME MEASURES: Motor function change between initial presentation and at 6 weeks and 6 months after injury, and change in Functional Independence Measure (FIM) assessed at 6 weeks and 6 months. RESULTS: Compared with patients treated with methylprednisolone for 24 hours, those treated with methylprednisolone for 48 hours showed improved motor recovery at 6 weeks (P=.09) and 6 months (P=.07) after injury. The effect of the 48-hour methylprednisolone regimen was significant at 6 weeks (P=.04) and 6 months (P=.01) among patients whose therapy was initiated 3 to 8 hours after injury. Patients who received the 48-hour regimen and who started treatment at 3 to 8 hours were more likely to improve 1 full neurologic grade (P=.03) at 6 months, to show more improvement in 6-month FIM (P=.08), and to have more severe sepsis and severe pneumonia than patients in the 24-hour methylprednisolone group and the tirilazad group, but other complications and mortality (P=.97) were similar. Patients treated with tirilazad for 48 hours showed motor recovery rates equivalent to patients who received methylprednisolone for 24 hours. CONCLUSIONS: Patients with acute spinal cord injury who receive methylprednisolone within 3 hours of injury should be maintained on the treatment regimen for 24 hours. When methylprednisolone is initiated 3 to 8 hours after injury, patients should be maintained on steroid therapy for 48 hours.