Lawrence F. Marshall

A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: Results of the second national acute spinal cord injury study

In 1990, the Second National Acute Spinal Cord Injury Study reported that high-dosage methylprednisolone improves neurologic recovery in spinal-injured humans. The study showed that patients who received the drug within 8 hr after injury improved, whereas those who received the drug later did not. The drug significantly increased recovery even in severely injured patients who were admitted with no motor or sensory function below the lesion, contradicting a long-held dogma that such patients would not recover. Some researchers, however, have questioned the stratification of the patient population, the use of summed neurologic change scores, and the absence of functional assessments. The stratification by injury severity and treatment time was planned a priori and based on objective criteria. Detailed analyses revealed no differences between groups attributable to stratification or randomization. While multivariate analyses of the summed neurologic scores were used, the conclusions were corroborated by other analytical approaches that did not rely on summed scores. For example, treatment with methylprednisolone more than doubled the probability that patients would convert from quadriplegia or paraplegia to quadriparesis or paraparesis, analgesia to hypalgesia, and anesthesia to hypesthesia. The treatment also significantly improved neurologic scores in lumbosacral segments, indicating that beneficial effects were not limited to segments close to the lesion site. The treatment did not significantly affect mortality or morbidity. The study strongly suggests that methylprednisolone has significant beneficial effects in human spinal cord injury, that these effects occur only when the drug is given within 8 hr, and that it helps even in patients with severe spinal cord injuries. These conclusions have important implications for spinal cord injury care and research.

The role of secondary brain injury in determining outcome from severe head injury

As triage and resuscitation protocols evolve, it is critical to determine the major extracranial variables influencing outcome in the setting of severe head injury. We prospectively studied the outcome from severe head injury (GCS score < or = 8) in 717 cases in the Traumatic Coma Data Bank. We investigated the impact on outcome of hypotension (SBP < 90 mm Hg) and hypoxia (Pao2 < or = 60 mm Hg or apnea or cyanosis in the field) as secondary brain insults, occurring from injury through resuscitation. Hypoxia and hypotension were independently associated with significant increases in morbidity and mortality from severe head injury. Hypotension was profoundly detrimental, occurring in 34.6% of these patients and associated with a 150% increase in mortality. The increased morbidity and mortality related to severe trauma to an extracranial organ system appeared primarily attributable to associated hypotension. Improvements in trauma care delivery over the past decade have not markedly altered the adverse influence of hypotension. Hypoxia and hypotension are common and detrimental secondary brain insults. Hypotension, particularly, is a major determinant of outcome from severe head injury. Resuscitation protocols for brain injured patients should assiduously avoid hypovolemic shock on an absolute basis.

A Randomized, Controlled Trial of Methylprednisolone or Naloxone in the Treatment of Acute Spinal-Cord Injury

Abstract Studies in animals indicate that methylprednisolone and naloxone are both potentially beneficial in acute spinal-cord injury, but whether any treatment is clinically effective remains uncertain. We evaluated the efficacy and safety of methylprednisolone and naloxone in a multicenter randomized, double-blind, placebo-controlled trial in patients with acute spinal-cord injury, 95 percent of whom were treated within 14 hours of injury. Methylprednisolone was given to 162 patients as a bolus of 30 mg per kilogram of body weight, followed by infusion at 5.4 mg per kilogram per hour for 23 hours. Naloxone was given to 154 patients as a bolus of 5.4 mg per kilogram, followed by infusion at 4.0 mg per kilogram per hour for 23 hours. Placebos were given to 171 patients by bolus and infusion. Motor and sensory functions were assessed by systematic neurologic examination on admission and six weeks and six months after injury. After six months the patients who were treated with methylprednisolone within eigh...

Clinical Trials in Head Injury

Secondary brain damage, following severe head injury is considered to be a major cause for bad outcome. Impressive reductions of the extent of brain damage in experimental studies have raised high expectations for cerebral neuroprotective treatment, in the clinic. Therefore multiple compounds were and are being evaluated in trials. In this review we discuss the pathomechanisms of traumatic brain damage, based upon their clinical importance. The role of hypothermia, mannitol, barbiturates, steroids, free radical scavengers, arachidonic acid inhibitors, calcium channel blockers, N-methyl-D-aspartate (NMDA) antagonists, and potassium channel blockers, will be discussed. The importance of a uniform strategic approach for evaluation of potentially interesting new compounds in clinical trials, to ameliorate outcome in patients with severe head injury, is proposed. To achieve this goal, two nonprofit organizations were founded: the European Brain Injury Consortium (EBIC) and the American Brain Injury Consortium (ABIC). Their aim lies in conducting better clinical trials, which incorporate lessons learned from previous trials, such that the succession of negative, or incomplete studies, as performed in previous years, will cease.

Prediction of outcome in traumatic brain injury with computed tomographic characteristics: a comparison between the computed tomographic classification and combinations of computed tomographic predictors.

BACKGROUND AND OBJECTIVE: The Marshall computed tomographic (CT) classification identifies six groups of patients with traumatic brain injury (TBI), based on morphological abnormalities on the CT scan. This classification is increasingly used as a predictor of outcome. We aimed to examine the predictive value of the Marshall CT classification in comparison with alternative CT models. METHODS: The predictive value was investigated in the Tirilazad trials (n = 2269). Alternative models were developed with logistic regression analysis and recursive partitioning. Six month mortality was used as outcome measure. Internal validity was assessed with bootstrapping techniques and expressed as the area under the receiver operating curve (AUC). RESULTS: The Marshall CT classification indicated reasonable discrimination (AUC = 0.67), which could be improved by rearranging the underlying individual CT characteristics (AUC = 0.71). Performance could be further increased by adding intraventricular and traumatic subarachnoid hemorrhage and by a more detailed differentiation of mass lesions and basal cisterns (AUC = 0.77). Models developed with logistic regression analysis and recursive partitioning showed similar performance. For clinical application we propose a simple CT score, which permits a more clear differentiation of prognostic risk, particularly in patients with mass lesions. CONCLUSION: It is preferable to use combinations of individual CT predictors rather than the Marshall CT classification for prognostic purposes in TBI. Such models should include at least the following parameters: status of basal cisterns, shift, traumatic subarachnoid or intraventricular hemorrhage, and presence of different types of mass lesions.

Prolonged hypernatremia controls elevated intracranial pressure in head-injured pediatric patients

Objective: To determine the effects continuous infusions of hypertonic saline (3% NaCl) on intracranial pressure (ICP) control and describe the physiologic effects of hypertonic saline administered to closed head injury children. Design: Retrospective chart review. Settings: Pediatric intensive care unit of a childrens hospital. Patients: Sixty‐eight children with closed head injury. Intervention: Intravenous infusion of 3% hypertonic saline to increase serum sodium to levels necessary to reduce ICP ≤20 mm Hg. Measurements and Main Results: The patients enrolled had similar Injury Severity Scores. Treatment effectively lowered ICP in these patients and ICP was under good control a majority of the time. Only three patients (4%) died of uncontrolled elevation of ICP. No adverse effects of supraphysiologic hyperosmolarity such as renal failure, pulmonary edema, or central pontine demyelination, were noted. Conclusions: Hypertonic saline administration to children with closed head injury appears to be a promising therapy for control of cerebral edema. Further controlled trials are required to determine the optimal duration of treatment before widespread use is advocated.

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 Alzheimers disease.

Severe Head Injury in Children: Experience of the Traumatic Coma Data Bank

The outcome at discharge, 6 months, and 1 year after they had sustained severe head injuries was investigated in children (0-15 yr old at injury) who were admitted to the neurosurgery service at one of four centers participating in the Traumatic Coma Data Bank. Of 103 eligible children, the quality of recovery was assessed by the Glasgow Outcome Scale (GOS) at 6 months after injury in 92 patients (86% of series) and at 1 year in 82 patients (73% of series). The lowest post-resuscitation Glasgow Coma Scale score and pupillary reactivity were predictive of the 6-month GOS as were their interaction. Analysis of the first computed tomographic scan disclosed that bilateral swelling with/without midline shift was related to a poor outcome as was the presence of mass lesions. Comparison of age-defined subgroups of patients revealed that outcome was poorest in the 0- to 4-year-old patients, as reflected by their mortality, which increased to 62% by 1 year. Distinctive features of the injuries in the 0- to 4-year-olds included evacuated subdural hematomas (20% of patients) and hypotension (32% of patients). The most favorable outcome was attained by 5- to 10-year-olds (2/3 had a good recovery by 1 yr), whereas the GOS distribution of adolescents was intermediate between the children and adults. In summary, the GOS data reflect heterogeneity in the quality of outcome after severe head injury depending on age, neurological indices, and computed tomographic scan diagnostic category.

Predictors of outcome following severe head trauma: follow-up data from the traumatic coma data bank

Outcome as a function of employment status or return to school was evaluated in severely head-injured patients. A priori we selected the most salient demographic, physiological, neuropsychological and psychosocial outcome predictors with the aim of identifying which of there variables captured at baseline or 6 months would best predict employability at 6 or 12 months. Based on the patients evaluated at 6 months, 18% of former workers had returned to gainful employment and 62% of former students had returned to school. For those not back to work or school at 6 months, 31% of the former workers and 66% of the former students had returned by 12 months. Age, length of coma, speed for both attending and motor movements, spatial integration, and intact vocabulary were all significantly related to returning to work or school. The three most potent predictors for returning to work or school were intactness of the patients verbal intellectual power, speed of information processing and age.

Determinants of head injury mortality: importance of the low risk patient.

Data were obtained prospectively for 7,912 head-injured patients admitted from 1980 to 1981 to 41 hospitals in 3 U.S. metropolitan areas. Highly significant independent predictors of mortality were motor score, number of reactive eyes, systolic blood pressure, abdominal injury, chest injury, age, and hospital unit (hospital or group of hospitals). The difference between the number of deaths observed and the number expected, by hospital unit, ranged from 43% below expectation to 52% above expectation. The 2 hospital units with the lowest mortality had only 1 death, where 9.4 would be expected, in patients whose risk of death was estimated to be less than 10%. In the single hospital with clearly excess mortality, however, the standardized mortality ratios were 208, 135, and 144% for the risk groups whose probabilities of death were 0 to 50, 50 to 80, and 80 to 100%, respectively. The lack of deaths in those hospitals with the best mortality experience and the excess mortality in the hospital with the worst mortality experience appear to be explained largely by differences in patients who, by clinical criteria, seem to be at low risk for death, and not by severely injured patients.