Dexmedetomidine-mediated neuroprotection against sevoflurane-induced neurotoxicity extends to several brain regions in neonatal rats.

BACKGROUND: Exposure of infant animals to clinically used anaesthetics is associated with acute structural brain abnormalities and development functional alterations. The α 2 -adrenoceptor agonist dexmedetomidine (DEX) induces sedation, analgesia, and provides neuroprotection in experimental brain injury models. However, it is unknown whether DEX also affords protection in the developing brain against anaesthesia using sevoflurane (SEVO), which is commonly used in paediatric anaesthesia. METHODS: Infant rats were exposed on postnatal day seven for six h to 2.5% SEVO and were given i.p. injections of saline or DEX (1-50 µg kg -1 ) three times during the exposure. Level of anaesthesia, respiratory rates, and arterial blood gasses were assessed for each animal. Apoptosis was determined in brain slices immunostained for activated caspase-3 (AC-3) using a computerised approach. RESULTS: SEVO alone induced a surgical plane of anaesthesia, and all animals survived the study. SEVO induced an approximately 10-fold increase in AC-3 positive cells in several cortical and subcortical brain regions compared with untreated control animals. Co-administration of DEX 1 µg kg -1 with SEVO significantly reduced apoptosis in all brain areas, affording the highest protection in the thalamus (84% reduction) and lowest in the hippocampus and cortical areas (∼50% reduction). DEX 5-25 µg kg -1 plus SEVO dose-dependently increased infant rat mortality. CONCLUSIONS: SEVO anaesthesia induced widespread apoptosis in infant rat brain. Co-administration of DEX (1 µg kg -1 ) provided significant protection, whereas DEX (5 µg kg -1 or higher) plus SEVO increased mortality. Our findings suggest that DEX could be an attractive therapeutic for future studies investigating its neuroprotective potential in a translational animal model.

Histopathologic consequences of hyperglycemic cerebral ischemia during hypothermic cardiopulmonary bypass in pigs.

BACKGROUND: This study examined whether 34 degrees C or 31 degrees C hypothermia during global cerebral ischemia with hyperglycemic cardiopulmonary bypass (CPB) in surviving pigs improves electroencephalographic (EEG) recovery and histopathologic scores when compared with normothermic animals. METHODS: Anesthetized pigs were placed on CPB and randomly assigned to 37 degrees C (n = 9), 34 degrees C (n = 10), or 31 degrees C (n = 8) management. After increasing serum glucose to 300 mg/dL, animals underwent 15 minutes of global cerebral ischemia by temporarily occluding the innominate and left subclavian arteries. Following reperfusion, rewarming, and termination of CPB, animals were recovered for 24 (37 degrees C animals) or 72 hours (34 degrees C and 31 degrees C animals). Daily EEG signals were recorded, and brain histopathology from cortical, hippocampal, and cerebellar regions was graded by an independent observer. RESULTS: Before ischemia, serum glucose concentrations were similar in the 37 degrees C (307+/-9 mg/dL), 34 degrees C (311+/-14 mg/dL), and 31 degrees C (310+/-15) groups. By the first postoperative day, EEG scores in 31 degrees C animals (4.2+/-0.6) had returned to baseline and were greater than those in the 34 degrees C (3.4+/-0.5) and 37 degrees C (2.5+/-0.4) groups (p < 0.05, respectively, between groups). Cooling to 34 degrees C showed selective improvement over 37 degrees C in hippocampal, temporal cortical, and cerebellar regions, but the greatest improvement in all regions occurred with 31 degrees C. Cumulative neuropathology scores in 31 degrees C animals (13.5+/-2.2) exceeded 34 degrees C (6.8+/-2.2) and 37 degrees C (1.9+/-2.1) animals (p < 0.05, respectively, between groups). CONCLUSIONS: Hypothermia during CPB significantly reduced the morphologic consequences of severe, temporary cerebral ischemia under hyperglycemic conditions, with the greatest protection at 31 degrees C.

Differential NF-kappa B regulation of bcl-x gene expression in hippocampus and basal forebrain in response to hypoxia.

Cell death often occurs after hypoxic/ischemic injury to the central nervous system. Changes in levels of the anti-apoptotic Bcl-X(L) protein may be a determining factor in hypoxia-induced neuronal apoptosis. The transcription factor NF-kappa B regulates bcl-x gene expression. In this study, we examined the role of NF-kappa B in the regulation of bcl-x in hypoxia-induced cell death. Rat hippocampus and basal forebrain tissues were collected at different time points after hypoxia (7%O(2), 93% N(2) for 10 or 20 min). We found that 1) hypoxia induced apoptosis in the hippocampus and basal forebrain; 2) the NF-kappa B dimers c-Rel/p50 and p50/p50 bound to the bcl-x promoter NF-kappa B sequence (CS4) in the hippocampus, but only p50/p50 bound to the CS4 sequence in the basal forebrain and hypoxia-induced differential binding patterns of c-Rel/p50 and p50/p50 correlated with the bcl-x expression pattern in the hippocampus; 3) the hypoxia-induced patterns of binding of c-Rel/p50 to the bcl-x promoter CS4 sequence were different from those to the IgG-kappa B enhancer sequence, whereas those of p50/p50 were similar to both sequences; 4) nuclear protein levels of c-Rel, but not p50, correlated with the c-Rel/p50 DNA binding patterns to the bcl-x CS4 site; and 5) there were differential responses to hypoxia among the different NF-kappa B protein subunits. These results suggest that there is a tissue-specific regulation of bcl-x gene expression by NF-kappa B in hypoxia-induced cell death in the hippocampus. The absence of these regulating features in the basal forebrain may account for the early appearance of apoptosis in response to hypoxia as compared with that in hippocampus.

Effects of hypothermia and lamotrigine on trace-conditioned learning after global cerebral ischemia in rabbits.

Acquisition of the trace-conditioned eye blink response (CR) is mediated by a variety of brain structures, including the cerebellum, the hippocampus, and brain stem nuclei. We examined the effects of a neuronal sodium channel antagonist (lamotrigine) on the ability of rabbits to acquire an eye blink CR after 6.5 min of cerebral ischemia. New Zealand white rabbits (n = 31) were randomly assigned to sham (S), normothermic ischemia (N), hypothermic (30 degrees C) ischemia-(H), or lamotrigine (50 mg/kg) treated (L) groups. In the N, H, and L groups, 6.5 min of global cerebral ischemia was produced using an inflatable neck tourniquet. Trace conditioning was started on the 7th postischemic day. The conditioned stimulus consisted of a tone (85 dB, 6 kHz) presented for 100 ms. The unconditioned stimulus was an air puff (150 ms duration) directed at the cornea. The interval between the end of the conditioned stimulus and the start of the unconditioned stimulus (the trace interval, TI) was 300 ms in duration. A trace-conditioned response was defined as an eye blink that was initiated during the TI. Eighty trials were delivered daily for 15 days. Neurologic deficits were greatest in the N group, and these animals had fewer CRs (149 +/- 157) than animals in the S (509 +/- 214) or H (461 +/- 149) groups (P < 0.05 by analysis of variance). Animals in the L group had a total number of CRs (380 +/- 253) that was intermediate between the S and N groups. Histologic evidence of neural injury was greatest in the N group. This study demonstrates that a brief episode of cerebral ischemia results in the impairment of this test of neurobehavioral function. Both hypothermia and lamotrigine were able to attenuate the impairment of eye blink trace-conditioned responses produced by cerebral ischemia.

Asymptomatic intraplacental choriocarcinoma diagnosed on routine placental examination.

Asymptomatic intraplacental choriocarcinoma is a rare event with only a few case reports in the literature. The recognition of such a lesion on routine placental examination is important and prompts rapid clinical evaluation for identifying residual and/or metastatic disease followed by institution of chemotherapy. Failure to recognize such a lesion on gross inspection of the placenta can result in disseminated disease, which can be lethal. The following report describes the placental findings and clinical outcome in a recent case with a review of the relevant literature.

Testicular pathologic changes and the pituitary-testicular axis during human immunodeficiency virus infection.

OBJECTIVE: To chronicle pituitary-testicular axis dysfunction and its clinicopathologic features in homosexual men. METHODS: Between 1984 and 1992, 84 homosexual men underwent longitudinal follow-up for 4 years. At entry into the study, 28 were seronegative and 56 were seropositive for human immunodeficiency virus (HIV). Although 40 subjects remained asymptomatic (nonprogressors), 16 had progression to acquired immunodeficiency syndrome (AIDS). Of those 16 patients with progression, 8 had AIDS within 2 years (early progressors) and 8 demonstrated AIDS within 4 years after enrollment (late progressors), and all died. The testes of five patients were examined at autopsy. The control group had similar follow-up. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and bioavailable testosterone (bio-T) were measured in stored sera collected at 2-year intervals. The last hormonal measurement was between 3 and 24 months before autopsy. Comparison was made between autopsied and nonautopsied patients with AIDS as well as between HIV nonprogressors and control seronegative men. The correlation between pathologic findings and hormonal status was examined by regression analysis. RESULTS: At baseline, testosterone, bio-T, LH, and FSH were not significantly different among all patients and subjects. During the study period, testosterone, bio-T, and serum gonadotropin levels remained unchanged in the seronegative homosexual men. In nonprogressors, serum FSH and LH concentrations remained unchanged, whereas testosterone and bio-T levels decreased significantly during this 4-year period. After progression to AIDS (in both groups of progressors), the serum FSH and LH levels were higher and the serum testosterone and bio-T were lower in comparison with values in the seronegative men. In late progressors to AIDS, FSH and LH increased, whereas serum testosterone and bio-T decreased significantly from baseline. All five patients with AIDS on whom autopsy was done had boundary wall thickening of the seminiferous tubules and decreased spermatogenesis. No significant differences were found in serum testosterone, bio-T, and LH between those in whom autopsy was or was not done; however, FSH was significantly higher in the autopsied cases. The serum testosterone and bio-T levels were negatively correlated with the interstitial inflammation. A significant correlation was also observed between change of bio-T and weight loss. CONCLUSION: We conclude that dysfunction of the pituitary-gonadal axis is common in HIV-infected men. All patients in whom autopsy was done because of AIDS-related diseases had been hypogonadal 3 to 24 months before death. Decreased spermatogenesis, subacute interstitial inflammation, or both were seen at autopsy of patients with AIDS. Pathologic damage to the testes during AIDS was associated with decreased testosterone and bio-T as well as increased serum gonadotropin levels. In a substantial proportion of men with progression to AIDS, compensated hypogonadism (normal serum testosterone and increased serum LH levels) preceded the development of low serum testosterone level.

Serial determinations of cerebral water content by magnetic resonance imaging after an infusion of hypertonic saline.

OBJECTIVE: To determine regional cerebral water content in vivo by magnetic resonance imaging (MRI) after the administration of 7.5% saline in brain-lesioned rabbits. DESIGN: Randomized, controlled, intervention trial. SETTING: University animal laboratory. SUBJECTS: Eighteen male New Zealand white rabbits, randomly assigned to one of three groups. INTERVENTIONS: The animals were anesthetized (1% halothane), intubated, and mechanically ventilated to maintain end-tidal CO2 tension between 30 and 35 mm Hg (4 and 4.7 kPa). Arterial and central venous catheters were inserted and arterial blood samples were serially obtained during the experiment. Serum osmolality was measured. A cryogenic cerebral lesion was produced by pouring liquid nitrogen for 1 min into a funnel placed on the intact skull over the right hemisphere. One group of animals received 20 mL of 7.5% saline intravenously 150 mins after the cerebral lesion was generated (7.5% saline group, n = 7). A second group of animals received the same volume of 0.9% saline intravenously (0.9% saline group, n = 7). In a third group of animals (control group, n = 4) no lesion was created and no fluid administered. MEASUREMENTS AND MAIN RESULTS: Five spin-echo T2-weighted MRIs of the brain were acquired at 90 mins (Baseline 1), 120 mins (Baseline 2), 150 mins (Infusion), 180 mins (Infusion + 30 mins), and 210 mins (Infusion + 60 mins) after the generation of the cerebral lesion. In the control group, two scans separated by a time interval of 120 mins were performed. The percent changes in signal intensity between the first and the four following scans of a coronal slice of the central region were determined. Analysis of variance and the Mann-Whitney U test were used for statistical analysis. Data are presented as mean +/- SD; p < .05 was considered significant. Serum osmolality increased significantly from 308 +/- 13 mosm/L to 349 +/- 19 mosm/L after the infusion of 20 mL of 7.5% saline, but did not change after the administration of 0.9% saline. Signal intensity in the area between the caudal edge of the core of the lesion and the basal ganglia was 9 +/- 8% higher on the injured side than in the corresponding area on the contralateral side (p < .05). Compared with Baseline 1, signal intensity at Infusion + 60 mins decreased by 26.3 +/- 13.7% in the 7.5% saline group, whereas it decreased by 10.4 +/- 8.6% in the 0.9% saline group (p < .05 between groups). Signal intensity decreased only slightly and nonsignificantly by 0.6 +/- 4.4% between the two scans in the control group. CONCLUSIONS: The administration of a 7.5% saline solution causes a prompt and substantial decrease in cerebral water content as assessed by spin-echo T2-weighted MRI. Magnetic resonance imaging offers the opportunity for repeated, noninvasive in vivo determinations of cerebral water content.

High autopsy rates at a university medical center. What has gone right?

OBJECTIVE: Identification of factors that contribute to a high autopsy rate at our institution. DESIGN: An objective analysis of the Autopsy Service's organization, functions, and process flow to identify factors that impact the autopsy rate. SETTING: The University of Texas Medical Branch at Galveston, Tex. METHODS: Statistics were collected using the autopsy log book and computerized data bank. The events starting at the time of a patient's death through the completion of the autopsy report were reviewed. The role of each significant event was analyzed. RESULTS AND CONCLUSIONS: The annual autopsy rates between 1981 and 1995 ranged between 45% and 59%. The largest number of nonmedicolegal autopsies were received from the Department of Internal Medicine. The Texas Department of Criminal Justice Hospital contributed the largest number of medicolegal autopsies. We conclude that the following key factors contribute to our high autopsy rates: (1) the organization and multiple functions of the Autopsy Service, particularly the presence of a Decedent Affairs Office, dedicated resident assignments, and internal and external quality control of the autopsies; (2) close interactions with clinicians, including timely communication of autopsy results to clinicians and a fostering of positive attitude among clinical residents and faculty; and (3) other factors such as the contributions to hospital risk management, disproving the idea that there may be increased litigation related to high autopsy rates, and support by the hospital administration.

Spindle cell hemangioendothelioma of the spinal cord.

An intradural extramedullary spinal cord hemangioendothelioma at T10, T11 recurred twice and was irradiated after the third resection. This first reported case prompted a review of the neuropathology and natural history of this unusual tumor.

Recurrent chiasmatic-hypothalamic glioma treated with oral etoposide.

PURPOSE: Chiasmatic-hypothalamic gliomas are not amenable to surgical resection and therefore are treated with either radiotherapy or chemotherapy. Here we report the use of etoposide (VP-16) administered on a chronic oral schedule as a novel chemotherapeutic approach. PATIENTS AND METHODS: Fourteen patients, aged 2 to 15 years, were treated with VP-16 after clinical and neuroradiographic tumor progression. Thirteen patients had received prior radiotherapy, and 12 received prior nitrosourea-based chemotherapy. VP-16 was administered orally, each cycle consisting of 50 mg/m2/d on day 1 through 21 and 36 through 57. Clinical and neuroradiographic evaluations were performed during days 58 through 72 before initiation of each cycle of therapy. Complete blood counts were performed weekly. RESULTS: Treatment-related complications included the following: partial alopecia (seven patients); diarrhea (six); weight loss (five); neutropenia (four); and thrombocytopenia (four). Three patients required transfusion (three RBC; two platelet), and one patient required antibiotic treatment of neutropenic fever. There were no treatment-related deaths. Fourteen patients were assessable, five of whom demonstrated a radiographic response (one complete and four partial); and three patients demonstrated stable disease, with a median duration of response of 8 months. CONCLUSION: Chronic oral VP-16 is well tolerated, produces modest toxicity, and has apparent activity in this small cohort of patients with recurrent chiasmatic-hypothalamic gliomas.

Development of the olfactory nerve: its relationship to the craniofacies.

Although absence of the olfactory bulbs is a relatively common occurrence seen in holoprosencephaly, in Kallman syndrome, and in a number of malformation syndromes, the extent to which it determines olfactory nerve development, as well as the part it plays in the morphogenesis of the nasal structures, is unknown. Cases of arhinencephaly ascertained at autopsy were studied in an effort to better understand the relationships between the olfactory nerve, bulb, and facies. Based on these studies, it is concluded that both olfactory receptor cells and olfactory nerves are present in arhinencephaly, that the olfactory nerves did not make contact with the brain in these cases, that the presence of olfactory nerves is independent of the severity of the central nervous system malformation, and that the shape of the nasal structures is not dependent on the presence of the olfactory nerve.

Studies on the safety of chronically administered intrathecal neostigmine methylsulfate in rats and dogs.

BACKGROUND: The spinal delivery of the cholinesterase inhibitor neostigmine yields analgesia in rats and augments the analgesic effects of alpha 2 agonists in sheep. To assess its activity in humans, preclinical toxicology studies to define its safety were required in two species. METHODS: Rats with chronic intrathecal catheters received daily injections of saline (vehicle) or 5 micrograms/10 microliters or 10 micrograms/10 microliters neostigmine HCl (n = 6/group) for 4 days and were observed for general behavior and nociception (52.5 degrees C hot plate). On day 6, rats were anesthetized and submitted to whole body perfusion/fixation. For dog studies, male beagles were prepared following rigid aseptic precautions with catheters passed from the cisterna magna to the lumbar intrathecal space. Catheters were connected to an external vest-mounted pump. Based on preliminary studies, ten implanted dogs were randomly assigned to receive infusions of neostigmine for 28 days (4 mg/4 ml/day; n = 6) or saline (4 ml/day; n = 4). At 28 days, dogs were anesthetized, cisternal cerebrospinal fluid was obtained, and dogs were submitted to perfusion-fixation. Rat and dog spinal cords were embedded, sectioned, stained, and assessed by the pathologist without knowledge of treatment. RESULTS: In rats, neostigmine produced a dose-dependent increase in hot plate latency, and no tolerance was observed. Mild tremor was observed but was not debilitating. Histopathology revealed a mild fibrotic reaction to the catheter with mixed signs of moderate, acute, and chronic inflammation with no differences between saline or drug groups. In dogs, neostigmine had no effect on blood pressure or on the skin twitch response but produced bradycardia and an increase in muscle tone. At sacrifice, cerebrospinal fluid protein, specific gravity, and glucose were elevated in both saline and neostigmine groups. Histopathology displayed a local reaction to the spinal catheter and a mixed acute and chronic inflammatory reaction. No group differences were observed. These results suggest that, at the neostigmine concentration of 1 mg/ml in the rat and dog and in doses up to 4 mg/day in the dog, there is no evidence of spinal tissue toxicity that can be attributed to the drug. This result, observed in two species, suggests that intrathecal neostigmine given in this manner is without distinguishable toxicity in these two models.

Cephalocele detection in utero: sonographic and clinical features.

Sonographic and clinical features of 26 fetal cephaloceles were reviewed retrospectively. The most frequent reason for referral was elevated maternal serum alpha-fetoprotein levels. The smallest lesion identified was 0.4 x 0.5 cm (frontal, at 20 weeks); the largest was 9.0 x 10.0 cm (frontal, at 27 weeks). Twenty-four of 26 cephaloceles were detected on prenatal ultrasound examination; in 13 of these, more than 50% of the intracranial contents were exteriorized. Fifteen of 24 cephaloceles detected prenatally had a sulcal pattern (identified between 16 and 36 weeks' gestation); five were solid without a sulcal pattern (identified between 13 and 21 weeks' gestation), three were cystic, and one underwent a change in appearance from solid at 21 weeks to cystic at 26 weeks. Other cranial features were evaluated and included visible skull defect, seen in 23/24 (96%), ventriculomegaly, in 6/26 (23%); microcephaly, in 12/24 (50%); beaked tectal plate, in 6/16 (38%); and flattened basiocciput, in 9/24 (38%). Of the 26 cases, 14 had normal amniotic fluid volume, five had oligohydramnios and seven had polyhydramnios. Fetuses with oligohydramnios had the highest incidence of concurrent fetal abnormalities; four of five fetuses (80%) with oligohydramnios had additional structural abnormalities. In the overall population, a very high incidence of other abnormalities was found; 17/26 (65%) cases showed additional abnormalities, some of which were not detected by ultrasound. Five fetuses had Meckel-Gruber syndrome and three had amniotic band syndrome. Only one of the 18 karyotypes obtained was abnormal (trisomy 18). Survival was very poor; only two of the eight who survived until birth are currently living.

Herpes simplex virus brainstem encephalitis in an AIDS patient.

We report a case of a virulent, atypical herpes simplex infection in the brainstem of a patient with Acquired Immune Deficiency Syndrome (AIDS) which was characterized by demyelination and oligodendroglial tropism. At autopsy the brainstem showed demyelination. Immunocytochemistry, in situ hybridization, and electron microscopy confirmed the presence of herpes simplex virus (HSV). Viral cultures demonstrated HSV type 1. Neuroinvasiveness and neurovirulence were studied by intraperitoneal inoculation of susceptible mouse strains (A/J and Balb/cByJ) with different viral titers. The LD50 of the clinical isolate was 5 orders of magnitude greater than the LD50 of a laboratory HSV strain (HSV type 1 KOS). The brains of the mice inoculated with the clinical isolate showed brainstem and cerebellar demyelination.

Acute basal ganglia infarction in propionic acidemia.

An 8-year-old girl with propionic acidemia had acute and rapidly fatal symmetric necrosis of the caudate, globus pallidus, and putamen. Clinical presentation was with acute aphasia, generalized hypotonia, and muscle weakness. There was no evidence of metabolic decompensation, and analysis of the organic acids of the urine indicated good metabolic control. Organic acids in the cerebrospinal fluid were unremarkable. These observations indicate that the pathophysiology of "metabolic stroke" is more complicated than previously thought.

Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions.

Propionic acidemia is a rare genetic disorder of amino acid metabolism caused by deficient activity of propionyl coenzyme A carboxylase. Neuropathologic changes previously reported in infants have been white-matter vacuolization or spongiosis. In children who survive beyond infancy, abnormalities have been found primarily in the basal ganglia. We report neuropathologic findings in two patients with propionic acidemia diagnosed in infancy who survived 35 months and 9 years, respectively. Examination of the brain of the 35-month-old boy showed vascular and parenchymal mineralization, focal pallor and spongy change, and foci of acute neuronal injury. These changes were similar to those previously described. The 9-year-old girl was in good metabolic control when she died, and presented a neuropathologic picture not previously described. She was found at autopsy to have acute hemorrhagic lesions in the caudate, putamen, and globus pallidus bilaterally and in the left ventral thalamus. There was focal neuronal loss, but no acute hypoxic/ischemic neuronal injury. Vascular proliferation and swollen endothelial cells were seen in the basal ganglia, thalamus, and substantia nigra, but not in other regions of the brain. Electron microscopy showed swelling of endothelial cells with viable adjacent brain parenchyma. The endothelial changes suggest a breakdown of the blood-brain barrier.

Autopsy findings in AIDS patients with Mycobacterium avium complex bacteremia.

To study the pathogenesis of Mycobacterium avium complex (MAC) bacteremia, the extent of organ involvement was determined in a retrospective cohort of 44 AIDS patients with MAC bacteremia and complete autopsies between 1988 and 1992. Clinical and microbiologic histories were reviewed and lymph nodes, spleen, liver, bone marrow, small intestine, and colon from each autopsy were systematically evaluated for the presence of mycobacteria or foamy histiocytes. Of the patients, 30% had no histologic evidence of MAC. In the remaining 70%, reticuloendothelial and gastrointestinal involvement was most common, but the number and distribution of involved sites was highly variable. The risk of developing detectable histologic involvement was related to the duration of bacteremia. In contrast to the prevailing concept, our data suggest that MAC bacteremia may precede widespread tissue disease.

Spinal delivery of sufentanil, alfentanil, and morphine in dogs. Physiologic and toxicologic investigations.

BACKGROUND: This study examines the behavioral effects and potential neurotoxicity of sufentanil, alfentanil, and morphine after chronic daily epidural (15-day) and intrathecal (28-day) administration in dogs. METHODS: Dogs were chronically implanted with a lumbar intrathecal or epidural catheter and received daily injections for 28 or 15 days, respectively, of saline or one of three mu agonists: sufentanil (intrathecal 5, 25, or 50 micrograms/0.5 ml; epidural 10, 50, or 100 micrograms/2.0 ml), alfentanil (intrathecal 40 or 400 micrograms/0.5 ml; epidural 80 or 800 micrograms/2.0 ml), or morphine (intrathecal 0.5 or 5 mg/0.5 ml; epidural 1 or 10 mg/2.0 ml). Dogs were examined for antinociception (skin twitch) and neurobehavioral changes. When the animals were killed, cisternal cerebrospinal fluid was taken for clinical chemistry, and after perfusion fixation, spinal cord tissue was taken for histologic analysis. RESULTS: Bolus intrathecal and epidural injections of sufentanil, alfentanil, and morphine produced dose dependent antinociception, bradycardia, an initial tachypnea followed by a decrease in respiratory rate, hypothermia and somnolence. The order of potency was sufentanil > alfentanil > morphine on all measures. Over the extended period of drug delivery, a loss of response (tolerance) was observed on all measures. No abnormal morphologic or histologic effects were found when comparing the drug and dose groups. An inflammatory reaction secondary to the catheter was found in all animals. Intrathecal, but not epidural, catheters resulted in significant increases in cerebrospinal fluid protein and cell counts in vehicle animals. Values in drug treated animals did not differ significantly from the respective vehicle controls. A rapid systemic redistribution of all three drugs was observed. No differences were found in the pharmacokinetic parameters measured at day 1 and at the day of killing for any route. CONCLUSIONS: This large-animal model demonstrates the expected pharmacologic potency of these three agents and tolerance development. Based on cerebrospinal fluid and systematic histopathologic analyses, these three spinally administered agents showed no evidence of neurotoxicity over the range of doses/concentrations employed when given by the intrathecal or epidural route as compared to vehicle controls. Consideration of the toxicokinetics in this canine model suggests that it provides an appropriate test of the safety of these agents in concentrations which exceed those employed for daily intermittent epidural and intrathecal drug delivery in humans.

Developmental changes in the sensitivity of the neonatal rat brain to hypoxic/ischemic injury.

Developmental changes in the response of the neonatal rat brain to hypoxic/ischemic injury were examined. Hypoxic/ischemic injury was produced by unilateral carotid ligation followed by exposure to hypoxia in 1- (D1), 3- (D3), 5- (D5) and 7-day-old (D7) rats. Injury was produced in most D7 animals exposed to > or = 120 min of 7.6 or 8% oxygen after carotid ligation. The extent of neuronal injury was variable, ranging from focal neuronal death to massive infarction. In D5 and D3 animals, there was a progressive decline in the extent of neuronal injury in response to hypoxia/ischemia. In the younger animals, bilateral injury was occasionally seen. Sham-operated animals exposed to hypoxia alone had numbers of karyorrhectic neurons similar to normal control animals in all age groups. The underlying developmental changes which account for these differences are not yet known but are likely to be multiple.

The correlation of prenatal brain damage with placental pathology.

Several epidemiological studies have emphasized that prenatal factors are the best predictors for cerebral palsy. Many placental pathologists have anecdotally recognized an association between placental pathology and poor pregnancy outcome, including neurologic injury. This study was undertaken to determine if correlations exist between specific types of placental pathology and prenatal brain injury. Ninety-eight stillbirths and livebirths with < 1 hour survival and complete placental and neuropathologic exams were reviewed. Most brain damage was in three categories: germinal matrix/intraventricular hemorrhage (GMH), white matter gliosis/necrosis (WMG/N), and neuronal necrosis. Statistical analysis of contingency tables showed significant associations of WMN with placental chronic vascular changes (PCV), umbilical cord problems, old infarction/abruptio, and meconium staining of the placenta. Associations were found between neuronal necrosis and PCV, surface vessel thrombosis, and old infarction/abruptio. GMH was associated with funisitis, but no other factors. Fetuses with WMN or neuronal necrosis were older than fetuses with GMH or no neuropathology. It is likely that these types of placental pathology can also be correlated with prenatal brain injury in liveborn infants, and examination of the placenta may indicate which infants are at greater risk for neurologic injury.