Two patients underwent thoracotomy for resection of pulmonary or esophageal carcinoma. Postoperatively, epidural catheters were inserted for pain management. Complaints of severe injection pain over the abdomen or lower extremities were made during one administration of pain medication. Progressive weakness and numbness developed over the lower trunk and lower extremities, with subsequent respiratory difficulties. Potassium chloride (KCl) was suspected to have been mistaken for normal saline as the diluent for morphine. In addition to endotracheal intubation and ventilatory support, steroids were administered both intravenously and epidurally to suppress spinal cord irritation. The two patients regained motor and sensory functions 14 and 18 hours later, respectively, without sequelae.

Report of two cases

Background There is evidence that medications or vitamins that increase the levels of brain catecholamines and protect against oxidative damage may reduce the neuronal damage and slow the progression of Alzheimer's disease. Methods We conducted a double-blind, placebo-controlled, randomized, multicenter trial in patients with Alzheimer's disease of moderate severity. A total of 341 patients received the selective monoamine oxidase inhibitor selegiline (10 mg a day), alpha-tocopherol (vitamin E, 2000 IU a day), both selegiline and alpha-tocopherol, or placebo for two years. The primary outcome was the time to the occurrence of any of the following: death, institutionalization, loss of the ability to perform basic activities of daily living, or severe dementia (defined as a Clinical Dementia Rating of 3). Results Despite random assignment, the base-line score on the Mini–Mental State Examination was higher in the placebo group than in the other three groups, and this variable was highly predictive of the pr...

https://www.nejm.org/doi/pdf/10.1056/NEJM199704243361704

A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study

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 neurological examination on admission and six weeks and six months after injury. After six months the patients who were treated with methylprednisolone within eight hours of their injury had significant improvement as compared with those given placebo in motor function (neurologic change scores of 16.0 and 11.2, respectively; P = 0.03) and sensation to pinprick (change scores of 11.4 and 6.6; P = 0.02) and touch (change scores, 8.9 and 4.3; P = 0.03). Benefit from methylprednisolone was seen in patients whose injuries were initially evaluated as neurologically complete, as well as in those believed to have incomplete lesions. The patients treated with naloxone, or with methylprednisolone more than eight hours after their injury, did not differ in their neurologic outcomes from those given placebo. Mortality and major morbidity were similar in all three groups. We conclude that in patients with acute spinal-cord injury, treatment with methylprednisolone in the dose used in this study improves neurologic recovery when the medication is given in the first eight hours. We also conclude that treatment with naloxone in the dose used in this study does not improve neurologic recovery after acute spinal-cord injury.

https://www.nejm.org/doi/pdf/10.1056/NEJM199005173222001

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 Second National Acute Spinal Cord Injury Study.

In patients with spinal cord injury, the primary or mechanical trauma seldom causes total transection, even though the functional loss may be complete. In addition, biochemical and pathological changes in the cord may worsen after injury. To explain these phenomena, the concept of the secondary injury has evolved for which numerous pathophysiological mechanisms have been postulated. This paper reviews the concept of secondary injury with special emphasis on vascular mechanisms. Evidence is presented to support the theory of secondary injury and the hypothesis that a key mechanism is posttraumatic ischemia with resultant infarction of the spinal cord. Evidence for the role of vascular mechanisms has been obtained from a variety of models of acute spinal cord injury in several species. Many different angiographic methods have been used for assessing microcirculation of the cord and for measuring spinal cord blood flow after trauma. With these techniques, the major systemic and local vascular effects of acute spinal cord injury have been identified and implicated in the etiology of secondary injury. The systemic effects of acute spinal cord injury include hypotension and reduced cardiac output. The local effects include loss of autoregulation in the injured segment of the spinal cord and a marked reduction of the microcirculation in both gray and white matter, especially in hemorrhagic regions and in adjacent zones. The microcirculatory loss extends for a considerable distance proximal and distal to the site of injury. Many studies have shown a dose-dependent reduction of spinal cord blood flow varying with the severity of injury, and a reduction of spinal cord blood flow which worsens with time after injury. The functional deficits due to acute spinal cord injury have been measured electrophysiologically with techniques such as motor and somatosensory evoked potentials and have been found proportional to the degree of posttraumatic ischemia. The histological effects include early hemorrhagic necrosis leading to major infarction at the injury site. These posttraumatic vascular effects can be treated. Systemic normotension can be restored with volume expansion or vasopressors, and spinal cord blood flow can be improved with dopamine, steroids, nimodipine, or volume expansion. The combination of nimodipine and volume expansion improves posttraumatic spinal cord blood flow and spinal cord function measured by evoked potentials. These results provide strong evidence that posttraumatic ischemia is an important secondary mechanism of injury, and that it can be counteracted.

Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms

Therapeutic potential of the lazaroids (21-aminosteroids) in acute central nervous system trauma, ischemia and subarachnoid hemorrhage.

Beginning 30 minutes after compression trauma of the upper lumbar (L-2) spinal cord, cats were treated with either a high-dose regimen of methylprednisolone (MP) administered as the sodium salt of the 21-succinate ester (Solu-Medrol sterile powder) or the MP vehicle. Animals were randomly assigned to either treatment group (10 cats per group), and all personnel were blind as to which animals received vehicle or drug. The intensive 48-hour dosing regimen was designed to maintain therapeutic tissue levels of MP and consisted of an initial 30 mg/kg intravenous bolus of MP; 2 and 6 hours later additional 15 mg/kg MP doses were administered by intravenous bolus. Immediately following the bolus given at 6 hours, a continuous MP infusion of 2.5 mg/kg/hr was started. The infusion was stopped abruptly at 48 hours with no dose tapering. Animals in the vehicle group received an equivalent volume of MP vehicle. The total MP dose administered over 48 hours was 165 mg/kg. Animals were evaluated weekly for neurological recovery based upon a 12-point functional scale which assessed general mobility, running, and stair-climbing. Mean recovery scores at 1 month after injury (+/- standard error of the mean) were: vehicle group (seven cats) 3.7 +/- 0.9, and MP group (10 cats) 8.7 +/- 0.2; (p less than 0.001). Histological evaluation of the spinal cords revealed a strong negative correlation between neurological recovery and size of the spinal cord cavity at 1 month (r = -0.88). Three of 10 animals in the vehicle group became ill and had to be dropped from the study, whereas all of the 10 MP-treated animals survived in excellent health. The results demonstrate the therapeutic effectiveness and low incidence of side effects associated with an intensive MP dose regimen for treatment of experimental spinal cord injury.

Evaluation of an intensive methylprednisolone sodium succinate dosing regimen in experimental spinal cord injury

Compression trauma of the cat spinal cord induces a very rapid alteration in the lipid metabolism of cellular membranes, including lipid hydrolysis with release of fatty acids including arachidonate, production of biologically active eicosanoids, and loss of cholesterol This disturbance of cellular membranes can directly damage cells and can lead to the secondary development of tissue ionic imbalance, ischemia, edema, and inflammation with neuronophagia Pretreatment with either the synthetic glucocorticoid methylprednisolone sodium succinate (MPSS) or the antioxidants vitamin E and selenium (Se) completely prevented the loss of cholesterol and partially inhibited lipolysis and prostanoid production Treatment with MPSS significantly reduced the postinjury tissue necrosis and paralysis Preliminary evidence indicates that pretreatment with vitamin E and Se also protected against the effects of spinal cord injury (SCI) We speculate that the ability of these agents to preserve function after SCI 

Lipid hydrolysis and peroxidation in injured spinal cord: partial protection with methylprednisolone or vitamin E and selenium.

The purpose of this study was to determine the effect of methylprednisolone sodium succinate on clincal recovery and tissue preservation following compression trauma of feline spinal cord. Cats were anesthetized with pentobarbital and injured by placing a 170-gm weight on the spinal cord for 5 minutes. One hour after injury, the animals were given intravenous steroid (15 mg/kg/day) for 2 days in three devided doses, 15 mg/kg/day for 1 day intramuscularly, 7.5 mg/kg/day intramuscularly for 3 days, and 3.75 mg/kg/day intramuscularly for 3 days, for a total of 9 days. In a control group, the animals were injured but untreated. At 60 days after injury, the animals were sacrifieced by perfusion fixation with 10% formalin. The spinal cord was removed and evaluated for a number of morphometric parameters, including percentage of spinal cord cross-sectional area containing the cavity (%area) and percentage of spinal cord volume occupied by the cavity (%volume). A clinical recovery score (recovery index) was devised to evaluate neurological recovery. Steroid-treated cats showed significantly greater recovery than the untreated controls (p less than 0.001). Moreover, the spinal cord of treated cats displayed greater tissue preservation as measured by %area (p leass than 0.005) and %volume (p less than 0.004). Correlation coefficients comparing the recovery index with morphometric parameters revealed a negative correlation between cavity size and recovery. These data provide evidence for a beneficial effect of methylprednisolone in promoting recovery and preserving spinal cord tissue following blunt injury to the feline spinal cord.

Effect of methylprednisolone in compression trauma to the feline spinal cord

The purpose of this study was to determine the effect of treatment with the synthetic glucocorticoid, methylprednisolone, on the microvasulature and metabolism of the traumatized spinal cord. Spinal cords of cats were compressed with a 170-gm weight for 5 minutes and were treated with either high-dose methylprednisolone (HDMP, 15 mg/kg/24 hrs) or megadose methylprednisolone (MDMP,60 mg/kg/24 hrs). Animals were sacrificed at 2, 8, or 24 hours following injury. Treatment with HDMP resulted in substantial preservation of injured spinal cord microvascular perfusion at 8 hours as compared with injured untreated cats. Compression trauma caused a partial derangement of energy metabolism and a shift toward anaerobic glycolysis in both treated and untreated groups for the entire 24-hour postinjury period. Tissue levels of adenosine triphosphate, phosphocreatine, and total adenylates in the HDMP-treated cats sacrificed at 8 hours after trauma were significantly elevated over untreated controls, but those in the 2- and 24-hour groups were not. Concentration of energy intermediates in MDMP-treated cat were either equal to or below those of injured untreated animals al all three postinjury time period. The postinjury metabolite pattern and concentrations seen in this study possibly result from differing levels of blood flow and neuronal activity in the injured untreated, HDMP-, and MDMP-treated spinal cords. Better tissue perfusion in the HDMP-treated cats might be expected to result in an improved tissue energy state in these animals. However, intensive high-dose glucocorticoid treatment has been demonstrated to augment spinal cord monosynaptic and polysynaptic reflex transmission and primary afferent excitability. Furthermore, acute single intravenous dose studies have shown this direct neuronal action to be dose-related. Thus, additional high-energy phosphate molecules that may be reformed as a result of HDMP treatment were perhaps used as the energy source for any increased neuronal activity caused by steroid administration. The beneficial effects of glucocorticoid treatment in experimental spinal cord trauma might derive from preserved cellular structural integrity. This could result in increased levels of neuronal activity, energy utilization, and production in treated as compared with untreated tissue.

Eugene D. Means

Papers

Therapeutic potential of the lazaroids (21-aminosteroids) in acute central nervous system trauma, ischemia and subarachnoid hemorrhage.

Evaluation of an intensive methylprednisolone sodium succinate dosing regimen in experimental spinal cord injury

Lipid hydrolysis and peroxidation in injured spinal cord: partial protection with methylprednisolone or vitamin E and selenium.

Effect of methylprednisolone in compression trauma to the feline spinal cord

Microvascular perfusion and metabolism in injured spinal cord after methylprednisolone treatment