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.

Magnetic resonance imaging and neurological recovery in acute spinal cord injury: observations from the National Acute Spinal Cord Injury Study 3.

STUDY DESIGN: Data are from a multicenter, randomized, double blind clinical trial of acute spinal cord injury. OBJECTIVES: To evaluate the prognostic value of magnetic resonance imaging (MRI) for randomized patients in the National Acute Spinal Cord Injury Study 3 (NASCIS). SETTING: Sixteen spinal cord injury centers throughout the United States and Canada. METHODS: Of 499 patients randomized in NASCIS 3 between December 1991 and September 1995, MRI was electively done on 191 patients within 72 h of injury. Indications of hemorrhage, edema, and contusion were recorded by standard protocol. Neurological impairment as determined by motor function, response to pin prick and light touch was assessed at admission to the participating center and 6 weeks after injury. Change in neurological function was obtained by subtracting the score of each neurological parameter at admission from that measured at 6 weeks. Spinal cord surgery performed within the 3 days after injury was noted. Data were analyzed by: chi square, analysis of variance, multiple logistic regression and linear regression models. RESULTS: Patients with hemorrhage were much more likely to have a complete injury (OR=2.88, 95 Cl 1.32, 6.23); however this association was much reduced when the initial neurological examination was taken into account (AOR=1.43, 95% Cl 0.55, 3.73) and was no longer a significant predictor of injury. MRI evidence of cord edema was the strongest predictor of reduced improvement in motor function (-3.34 points, P=0.06) and light touch sensation (-3.41 points, P=0.05) at 6 weeks. CONCLUSIONS: Cord hemorrhage, contusion, and edema on MRI were not associated with diagnosis of a complete cord injury after neurological assessment from the initial clinical examination was taken into account. Prediction of a worse 6 week neurological status was weakly associated with the presence of edema diagnosed by MRI. As MRI technology improves, these diagnostic and predictive capabilities need to be re-assessed. SPONSORSHIP: NASCIS 3 was funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, Washington, DC, USA. Pharmacia and Upjohn provided study drugs and placebos; they also monitored data quality, and funded additional tests, in accordance with Food and Drug Administration regulatory requirements. Dr Bracken has served as an occasional paid consultant to Pharmacia and Upjohn.

Stereotactic, automated, large-core needle biopsy of nonpalpable breast lesions: false-negative and histologic underestimation rates after long-term follow-up.

PURPOSE: To determine the rate and causes of false-negative findings and histologic underestimates at stereotactic biopsy of nonpalpable breast lesions. MATERIALS AND METHODS: Stereotactic, 14-gauge, automated, large-core needle biopsy (LCNB) was performed in 483 consecutive nonpalpable breast lesions. Excision was advised for the 143 carcinomas, 25 atypical ductal hyperplasia (ADH) lesions, and five radial scars. Mammographic follow-up was advised for the benign lesions without a repeat biopsy. RESULTS: Of the 310 benign lesions, 259 underwent mammographic follow-up at 6-85 months (median, 55 months) without repeat biopsy, 48 underwent repeat biopsy and three were lost to follow-up. On the basis of the histologic diagnosis of carcinoma at surgical biopsy, diagnosis with LCNB was not correct (i.e., disease was underestimated at histologic examination) in 14 (58%) of 24 ADH lesions and two (40%) of five radial scars. Two (1.2%) of 161 lesions with a final diagnosis of carcinoma were benign at LCNB but malignant at repeat biopsy (i.e., false-negative findings at LCNB). Repeat biopsy was prompted by mammographic progression at 6 and 18 months after LCNB. CONCLUSION: The false-negative rate with LCNB was 1.2% in this study and 4.0% in the literature. The presence of carcinoma in ADH and radial scar lesions was often underestimated.

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.

Maternal anthropometric factors and risk of primary cesarean delivery.

OBJECTIVES: This study examined absolute and proportional gestational weight gain and prepregnancy body mass index as predictors of primary cesarean delivery. METHODS: Data were derived from a prospective study of pregnancy outcome risk factors in 2301 women in greater New Haven, Conn, who had singleton deliveries by primary cesarean (n = 312) or vaginal delivery (n = 1989) and for whom height, prepregnancy weight, and weight gain were available. Women were divided into 4 body mass index groups (underweight, low average, high average, and obese) and further subdivided into 8 groups according to median proportional or absolute weight gain. RESULTS: Risk of cesarean delivery increased with increasing body mass index and gestational weight gain greater than the median for one's body mass index. Proportional weight gain was more predictive of cesarean delivery than absolute weight gain. Underweight women gaining more than 27.8% of their prepregnancy weight had a 2-fold adjusted relative risk of cesarean delivery. CONCLUSIONS: Proportional weight gain is an important predictor of cesarean delivery for underweight women; high body mass index is also predictive of increased risk.

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.

Maternal body mass, proportional weight gain, and fetal growth in parous women.

This study is designed to examine the impact of maternal body mass index (BMI), proportional weight gain, and other variables on fetal growth. From a 10% random sample of 5722 Norwegian and Swedish para one and two women (n = 561), three hundred and sixty-nine women for whom prepregnant weight and height were recorded and for whom four fetal ultrasound measurements were taken at 17, 25, 33, and 37 weeks of gestation, were divided into low, average, and high body mass index groups (weight/height2). Fetal growth rate (mm/day) was determined by taking the mean of three measurements of the sagital and transverse diameters of the fetal abdomen (MAD) in each of three study time periods: weeks 17 to 25, first period; weeks 25 to 33, second period; weeks 33 to 37, third period. Proportional weight gain (kilograms gained within a specific time period/prepregnant weight) was measured in those same intervals. Fetal growth rate was significantly slower in the first and second periods, and significantly faster in the third time period for women with a low BMI, compared with those of average BMI. Fetal growth also significantly increased with increases in proportional weight gain in the second and third periods, but not in the first. Fetal growth appears to be independently associated with maternal BMI and proportional maternal weight gain.

Stereotaxic large-core needle biopsy of 450 nonpalpable breast lesions with surgical correlation in lesions with cancer or atypical hyperplasia.

PURPOSE: To determine whether histologic findings of cancer or atypical hyperplasia at large-core needle biopsy (LCNB) of nonpalpable breast lesions match histologic findings at excision. MATERIALS AND METHODS: Stereotaxic LCNB was performed with an automated prone unit, biopsy gun, and 14-gauge cutting needles in 450 nonpalpable breast lesions. Lesions classified as carcinoma or atypical ductal hyperplasia (ADH) at histologic examination after LCNB were excised. A pathologist retrospectively compared core and excisional histologic findings. RESULTS: Histologic comparison was performed in 116 of 135 carcinomas after LCNB. Histologic findings were concordant in 99 carcinomas. Partial discordance in 17 carcinomas led to an additional surgical procedure in one case. Histologic comparison was performed in 16 of 19 ADHs diagnosed with LCNB. Histologic findings were concordant in five and discordant in 11 ADHs. CONCLUSION: LCNB findings of carcinoma are accurate and allow definitive therapeutic surgery, including mastectomy. LCNB findings of ADH are inaccurate, and excisional biopsy is necessary.

The effectiveness of surgery on the treatment of acute spinal cord injury and its relation to pharmacological treatment.

Using data from the Second National Acute Spinal Cord Injury Study (NASCIS II), the authors sought to characterize the role of surgery in the management of traumatic spinal cord injury and to examine the interaction between pharmacological treatment and surgery. Patients who did not undergo surgery had more severe spinal cord injuries initially than those who had surgery. However, no differences in neurological improvement at 1-year follow-up were found between those who underwent surgery and those who did not. The results suggest that either early surgery (< or = 25 hours after injury) or late surgery (> 200 hours) may be associated with increased neurological recovery, particularly motor function, but these results are equivocal. Surgery was not shown to interact with pharmacological treatments, indicating that the effect of drug treatment in NASCIS II, reported elsewhere, is not influenced by surgery. Other independent variables that best predicted improvement in motor score were age of 25 years or younger, incomplete injury, and lower baseline emergency department neurological scores. This study does not provide clinically relevant evidence concerning the efficacy of timing or the value of surgery in treating patients with spinal cord injuries. A randomized study on the timing and efficacy of spinal cord surgery is needed to obtain valid comparisons of the efficacy of surgical treatments.

The effect of methylprednisolone, naloxone, and spinal cord trauma on four liver enzymes: observations from NASCIS 2. National Acute Spinal Cord Injury Study.

In order to determine the impact of extremely large doses of methylprednisolone, naloxone, or of spinal cord injury itself, on liver enzymes, we examined the results of SGOT, SGPT, alkaline phosphatase and total bilirubin tests obtained 24 hours, 3 and 10 days after the end of the study drug infusions in spinal cord injured patients entered in the National Acute Spinal Cord Injury Study. The mean values of four liver enzymes, the amount of change between 24 hours and 3 and 10 days post infusion, and the proportion of liver enzyme levels considered to be abnormal did not appear to be affected by either drug protocol. Even when controlling for drug protocol and severity of injury (complete vs incomplete), variation in enzyme levels appeared to be the result of the spinal cord injury, not study drugs. Spinal cord injury is routinely treated with the NASCIS dose of methylprednisolone in many countries. It is reassuring to find no evidence of compromised liver function from this steroid protocol.

Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. Results of the second National Acute Spinal Cord Injury Study.

The 1-year follow-up data of a multicenter randomized controlled trial of methylprednisolone (30 mg/kg bolus and 5.4 mg/kg/hr for 23 hours) or naloxone (5.4 mg/kg bolus and 4.0 mg/kg/hr for 23 hours) treatment for acute spinal cord injury are reported and compared with placebo results. In patients treated with methylprednisolone within 8 hours of injury, increased recovery of neurological function was seen at 6 weeks and at 6 months and continued to be observed 1 year after injury. For motor function, this difference was statistically significant (p = 0.030), and was found in patients with total sensory and motor loss in the emergency room (p = 0.019) and in those with some preservation of motor and sensory function (p = 0.024). Naloxone-treated patients did not show significantly greater recovery. Patients treated after 8 hours of injury recovered less motor function if receiving methylprednisolone (p = 0.08) or naloxone (p = 0.10) as compared with those given placebo. Complication and mortality rates were similar in either group of treated patients as compared with the placebo group. The authors conclude that treatment with the study dose of methylprednisolone is indicated for acute spinal cord trauma, but only if it can be started within 8 hours of injury.

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.

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.

Radiation therapy for gliomas of the optic nerve and chiasm.

Thirty-three patients with optic glioma seen over a 30-year period were reviewed. Five patients (15%) had tumor confined to the optic nerve, 8 patients (24%) had optic nerve and chiasmal involvement, and the remaining 20 patients (61%) had invasion of contiguous structures as well as chiasmal involvement. Eleven patients (33%) had a history of neurofibromatosis. Two-thirds of the patients had either a biopsy or a partial resection of the tumor, with the remaining one-third being clinically diagnosed. All patients received irradiation to local fields. The median dose was 5040 cGy in 160 cGy fractions. Of patients alive at last follow-up, the median time of follow-up was 12.3 years. The 5-, 10-, and 15-year overall actuarial survivals were 94, 81, and 74%, respectively. Univariate and multivariate analysis were performed on the following clinical variables: extent of primary tumor, extent of surgery, dose of radiation, gender, race, age, and presence or absence of neurofibromatosis. Extension of the primary lesion to the optic chiasm and age less than or equal to 15 years were the only two variables to have statistically significantly inferior 15-year progression free survivals by multivariate analysis. Eighteen (55%) patients had treatment related complications with most involving the pituitary gland. We conclude that postoperative radiotherapy is beneficial in patients with chiasmal involvement and those with incomplete resections. A minimum tumor dose of 4000 cGy is recommended.

Proportional weight gain and complications of pregnancy, labor, and delivery in healthy women of normal prepregnant stature.

Detailed reproductive information was obtained through interview at early prenatal visits to hospital clinics, private medical groups, or health maintenance organizations for 4186 women delivered at Yale-New Haven Hospital. From these women, 1,396 were selected who had no preexisting chronic disease, were within their normal prepregnant weight for height as determined by Quetelet's Index (weight2/height2), and were delivered of single infants with no major congenital malformations between 37 and 42 weeks. These women were divided into four quartiles according to their proportional weight gain (weight gain/prepregnant weight): quartile 1 = gains less than or equal to 15%; quartile 2 = gains 16% to 25%; quartile 3 = gains 26% to 35%; quartile 4 = gains greater than 35%. Complications of pregnancy, labor, and delivery were recorded within 2 days of delivery. Compared with the women in quartile 2 those in quartile 4 were 3.8 times more likely to develop gestational hypertension and had a fourfold risk of becoming preeclamptic. They were also significantly more likely to require cesarean section. The size of the infant was a significant risk factor for prolonged second stage of labor in primigravid women (greater than 2 hours) but not in multigravid women (greater than 1 hour). Weight gains of more than 35% almost doubled the risk of a prolonged second stage of labor for multigravid women. High proportional gains were not associated with adverse neonatal outcomes. Clinicians should consider proportional weight gain when advising healthy women about weight gain during pregnancy.

Methylprednisolone and neurological function 1 year after spinal cord injury. Results of the National Acute Spinal Cord Injury Study.

A multi-center double-blind randomized clinical trial was conducted by the National Acute Spinal Cord Injury Study Group to examine the efficacy of high-dose methylprednisolone (1000-mg bolus and 1000 mg daily thereafter for 10 days) compared with that of a standard dose (100-mg bolus and 100 mg daily for 10 days). No significant difference was observed in neurological recovery of motor function, pinprick response, or touch sensation 1 year after injury between the two treatment groups, after adjustment for other potentially confounding factors. Analyses that specifically took into account the patients' total steroid dose and relative weight confirmed the lack of a steroid treatment effect. The case fatality rate was 10.7% during the 1st year after injury, and this was not associated with the steroid treatment protocol or the patient's gender. Deaths did occur significantly more frequently among patients who were completely (15.3%) and partially (8.6%) plegic than among those who were paretic (2.5%, p = 0.0005), and among patients aged 50 years or older (38.6%, p = 0.0001).

Efficacy of methylprednisolone in acute spinal cord injury.

A multicenter double-blind randomized trial was conducted to examine the efficacy of a high dose of methylprednisolone (1,000-mg bolus and daily thereafter for ten days) compared with a standard dose (100-mg bolus and daily thereafter for ten days) in 330 patients with acute spinal cord injury. No difference in neurological recovery of motor function or pinprick and light touch sensation was observed between the two treatment groups six weeks and six months after injury. The lack of a treatment effect was independent of the severity of the initial lesion or the time from injury to starting treatment. Although not statistically significant, early case fatality was greater in the high-dose protocol (relative risk of 3.1 and 1.9, less than or equal to 14 and 15 to 28 days after injury, respectively) but not from 29 to 210 days after injury. Wound infections of both trauma and operative sites were more prevalent in the high-dose regimen (relative risk of 3.6).

An evaluation of two equations for predicting fetal weight by ultrasound.

In an earlier study we presented a method of determining fetal weight from ultrasound measurements of abdominal circumference (AC) and biparietal diameter (BPD). From an equation with these two measurements as independent variables we generated tables of estimated fetal weights (E1). Although these tables have been very useful, we had the impression we were underestimating fetal weight. Therefore, we reconsidered an earlier unpublished table generated from a different equation (E2). While most estimates from E1 and E2 were likely to be within 10% of actual weight, there was significant underestimation with E1. E2 provides a better balance between the distribution of overestimations and underestimations.

Psychological response to acute spinal cord injury: an epidemiological study.

This study empirically examines psychological reactions to spinal cord injury from a coping and adaptation perspective. Ego defensive, affective and coping reactions, and long-term personality reactions are described at the time of discharge from the acute care hospital (n = 190). These psychological reactions are examined for their association with neurological function on admission, at discharge, and changes in neurological status during hospitalisation. Affective reactions to injury were still evident in this sample and related positively to severity of motor and, to a lesser degree, sensory disability. Affective reactions were also generally associated with negative coping responses which could interfere with successful rehabilitation therapy. The study indicates that intensive psychological counselling is required by many patients during acute hospitalisation and prior to transfer for rehabilitation.

Coping and adaptation following acute spinal cord injury: a theoretical analysis.

Coping and adaptation theory is used to synthesis existing data concerning psychological recovery from acute spinal cord injury. Psychological reactions to spinal cord trauma are similar to those of mourning and other situations of severe loss. Each reaction plays a specific role in fostering or hindering recovery depending upon when it occurs. Premorbid personality and the influence of significant others play a central role in coping with injury. These factors partly explain why some patients cope better than others to equally serious disability. A critique of research methodologies and suggestions for new studies are provided.