Beagle puppy model of intraventricular hemorrhage: randomized indomethacin prevention trial.

The newborn beagle puppy has been demonstrated to provide a good model for neonatal intraventricular hemorrhage (IVH). By randomized computerized design, indomethacin, a known inhibitor of prostaglandin synthetase, was administered to newborn beagle puppies, all of which underwent the experimental model of hemorrhagic hypotension followed by volume reexpansion for the production of IVH, to determine whether indomethacin can prevent intraventricular hemorrhage in this model. Nine percent of all pups receiving indomethacin experienced intraventricular hemorrhage, compared with 80% of animals who received the saline vehicle. In addition, significant alterations in the blood pressure responses to the hemorrhagic hypotension/volume reexpansion insult were noted in this group when compared with control animals.

Neurodevelopmental outcome at 36 months' corrected age of preterm infants in the Multicenter Indomethacin Intraventricular Hemorrhage Prevention Trial.

OBJECTIVES: Low-dose indomethacin has been shown to prevent intraventricular hemorrhage (IVH) in very low birth weight neonates, and long-term neurodevelopmental follow-up data are needed to validate this intervention. We hypothesized that the early administration of low-dose indomethacin would not be associated with adverse cognitive outcome at 36 months' corrected age (CA). METHODS: We enrolled 431 neonates of 600 to 1250 g birth weight with no IVH at 6 to 12 hours in a randomized, prospective trial to determine whether low-dose indomethacin would prevent IVH. A priori, neurodevelopmental follow-up examinations, including the Stanford-Binet Intelligence Scale and Peabody Picture Vocabulary Test-Revised, and standard neurologic examinations were planned at 36 months' CA. RESULTS: Three hundred eighty-four of the 431 infants survived (192 [92%] of 209 infants receiving indomethacin versus 192 [86%] of 222 infants receiving saline), and 343 (89%) children were examined at 36 months' CA. Thirteen (8%) of the 166 infants who received indomethacin and 14 (8%) of 167 infants receiving the placebo were found to have cerebral palsy. There were no differences in the incidence of deafness or blindness between the two groups. For the 248 English-monolingual children for whom IQ data follow, the mean gestational age was significantly younger for the infants who received indomethacin than for those who received the placebo. None of the 115 infants who received indomethacin was found to have ventriculomegaly on cranial ultrasound at term, compared with 5 of 110 infants who received the placebo. The mean +/- SD Stanford-Binet IQ score for the 126 English-monolingual children who had received indomethacin was 89.6 +/- 18.92, compared with 85.0 +/- 20.79 for the 122 English-monolingual children who had received the placebo. Although maternal education was strongly correlated with Stanford-Binet IQ at 36 months' CA, there was no difference in educational levels between mothers of the infants receiving indomethacin and the placebo. CONCLUSIONS: Indomethacin administered at 6 to 12 hours as prophylaxis against IVH in very low birth weight infants does not result in adverse cognitive or motor outcomes at 36 months' CA.

Low-dose indomethacin and prevention of intraventricular hemorrhage: a multicenter randomized trial.

OBJECTIVES: Parenchymal involvement of intraventricular hemorrhage (IVH) is a major risk factor for neurodevelopmental handicap in very low birth weight neonates. Previous trials have suggested that indomethacin would lower the incidence and severity of IVH in very low birth weight neonates. METHODS: We enrolled 431 neonates of 600- to 1250-g birth weight with no evidence for IVH at 6 to 11 hours of age in a prospective, randomized, placebo-controlled trial to test the hypothesis that low-dose indomethacin (0.1 mg/kg intravenously at 6 to 12 postnatal hours and every 24 hours for two more doses) would lower the incidence and severity of IVH. Serial cranial ultrasound examinations and echocardiographs were performed. RESULTS: There were no differences in the birth weight, gestational age, sex, Apgar scores, and percent of neonates treated with surfactant between the indomethacin and placebo groups. Within the first 5 days, 25 (12%) indomethacin-treated and 40 (18%) placebo-treated neonates developed IVH (P = .03, trend test). Only one indomethacin-treated patient experienced grade 4 IVH compared with 10 placebo-treated neonates (P = .01). Sixteen indomethacin-treated neonates and 29 control neonates died (P = .08); there was a difference favoring indomethacin with respect to survival time (P = .06). Eighty-six percent of all neonates had a patent ductus arteriosus on the first postnatal day; indomethacin was associated with significant ductal closure by the fifth day of life (P < .001). There were no differences in adverse events attributed to indomethacin between the two treatment groups. CONCLUSIONS: Low-dose prophylactic indomethacin significantly lowers the incidence and severity of IVH, particularly the severe form (grade 4 IVH). In addition, indomethacin closes the patent ductus arteriosus and is not associated with significant adverse drug events in very low birth weight neonates.

Results of a management protocol for premature rupture of the membranes.

The results of a management protocol for women with premature rupture of the membranes (PROM) between 27 and 36 weeks' gestation is presented. Prior to 33 weeks' gestation patients were hospitalized and observed for signs of infection; labor was induced if amnionitis was diagnosed. After 33 weeks patients with vertex presentations underwent elective induction of labor after 16 hours of PROM. Amniocentesis was not performed, corticosteroids were not administered, and tocolysis was not used. The overall perinatal mortality rate was 2.8%. There was only 1 death in the group of 44 patients between 33 and 36 weeks' gestation with PROM for more than 16 hours. This neonate had moderate respiratory distress syndrome and a severe intracranial hemorrhage. The cesarean section rate in the group that underwent labor induction after 16 hours of PROM was 22.7% but only 1 of the 10 operations performed might possibly have been avoided if induction had not been a part of the protocol. In the group of 41 patients managed expectantly but delivered after 16 hours of PROM prior to 33 weeks' gestation, 21.9% were clinically believed to have amnionitis but only 12 neonate had documented sepsis. The implications of these results are discussed.

Acute inflammation enhances substance P-induced plasma protein extravasation in the rat knee joint.

Acute inflammation of the rat knee joint was induced by intra-articular injection of 2% carrageenan. Intra-articular perfusion of the inflamed joint with substance P (SP) exacerbated the inflammatory condition as assessed by the degree of plasma protein extravasation into the synovial cavity. Protein extravasation induced by SP was enhanced and more persistent in the inflamed rat knee compared to normal animals. The time course of the response in the inflamed rat knee was related to SP concentration whilst the persistency of the response was positively correlated with the initial level of joint inflammation.

Time course of substance P-induced protein extravasation in the rat knee joint measured by micro-turbidimetry.

Intra-articular perfusion of the rat knee joint with substance P (SP) resulted in protein extravasation into the synovial cavity. This response was tested over a range of SP concentrations from 100 pM to 100 microM. The response was dose dependent from 10 nM to 10 microM, with each dose producing a steady rise of the protein content in the fluid aspirated from the synovial cavity for 12-16 min and then fell sharply again over an equivalent period despite continuing perfusion with SP. Concentrations below 10 nM gave rise to very brief increases in protein extravasation whose magnitude differed little over the range of 100 pM to 10 nM but differed significantly from control (saline) perfusion.

Long-term perspective on premature infant outcome and contemporary intervention issues.

Despite improvements in survival rates for low birthweight (LBW) infants, the prevalence among survivors of major neurodevelopmental impairment seems relatively stable. Cerebral palsy, the most common major impairment, can usually be ruled out by 18 months corrected age. Minor impairments such as learning disabilities cannot be ruled out until much later. The efficacy of interventional services in this population was addressed by a national randomized trial. The intervention produced large treatment effects for heavier LBW infants and moderate effects for lighter infants. Five years later, modest residual effects were found for heavier LBW infants, but not for the lighter, suggesting that 0 to 3 services alone are not sufficient to prevent scholastic disadvantage in this population.

Early-onset intraventricular hemorrhage in preterm neonates: incidence of neurodevelopmental handicap.

The neurodevelopmental outcome of very low birth weight infants experiencing early-onset intraventricular hemorrhage (IVH) occurring within the first 6 postnatal hours was compared with that of their peers without early-onset IVH at 3 years corrected age. The 440 surviving preterm infants (birth weight 600 to 1,250 g) who had been enrolled in a multicenter, prospectively randomized, controlled trial evaluating the efficacy of postnatal indomethacin to prevent IVH were evaluated with the Stanford-Binet Intelligence Scale and neurological examinations at 3 years corrected age. All study infants had echoencephalography between 5 and 11 hours of life, and testing is reported for all children residing in English monolingual households at 3 years corrected age (i.e., from the obstetric due date). Fifty five of the 73 (75%) infants with IVH within the first 5 to 11 hours survived to 3 years of age, compared with 385 of the 432 (89%) children without early-onset hemorrhage who were alive at 3 years corrected age (P<.001). Eleven of the 29 (38%) English monolingual children with early-onset IVH had Stanford-Binet intelligence quotient scores of less than 70, compared with 47 of the 249 (19%) children without early IVH (P = .03). Similarly, 7 of 28 (25%) early IVH children were found to have cerebral palsy, compared with 20 of 241 (8%) children without early IVH (P = .01). These data suggest that infants who experience the early onset of IVH are at high risk for both cognitive and motor handicaps at 3 years corrected age.

Beagle puppy model of intraventricular hemorrhage. Effect of indomethacin on cerebral blood flow.

The newborn beagle puppy has been demonstrated to provide a good model for neonatal intraventricular hemorrhage (IVH). A study was designed to determine if indomethacin can prevent IVH and if indomethacin would produce changes in cerebral blood flow (CBF). Newborn beagle puppies were randomized by computer into two groups: one was pretreated with indomethacin, a known inhibitor of prostaglandin synthetase, and the other was saline. The dogs in both groups were then assigned either to undergo hemorrhagic hypotension/volume reexpansion insult or to receive no insult. Twenty percent of all pups receiving indomethacin and undergoing the insult experienced IVH, compared to 71% of the pups undergoing insult that had been pretreated with saline. Significant alterations in the blood pressure responses to the hemorrhagic hypotension/volume reexpansion insult were noted in the former group compared to the saline-pretreated pups subjected to insult. Finally, employing carbon-14 autoradiography for the determination of CBF, it was demonstrated that indomethacin decreases resting CBF of the newborn beagle pups and, in indomethacin-pretreated animals subjected to insult, prevents the increases in CBF seen in the saline-pretreated traumatized pups.

Beagle puppy model of intraventricular hemorrhage. Effect of indomethacin on local cerebral glucose utilization.

The newborn beagle puppy has been demonstrated to provide a good model for neonatal intraventricular hemorrhage (IVH). A study was designed to determine if indomethacin can prevent IVH, and if indomethacin would produce changes in local cerebral glucose utilization (LCGU). By computerized random design, newborn beagle puppies were pretreated with either indomethacin (a known inhibitor of prostaglandin synthetase) or saline, and then assigned either to receive a hemorrhagic hypotension/volume reexpansion insult or to receive no insult. Pretreatment with indomethacin produced a marked drop in the incidence of IVH as well as significant alterations in the blood pressure responses to the hemorrhagic hypotension/volume reexpansion insult. Carbon-14 autoradiography was used to determine LCGU: no alterations were demonstrated in cerebral metabolism in uninjured pups pretreated with indomethacin compared to saline-pretreated animals. In addition, although the hemorrhagic hypotension/volume reexpansion insult produced marked alterations in LCGU in both groups of traumatized pups, indomethacin prevented the changes in LCGU in the germinal matrix and white matter that were found in the saline-pretreated animals.

Posthemorrhagic hydrocephalus. Low incidence in very low birth weight neonates with intraventricular hemorrhage.

In addition to seizures and long-term neurodevelopmental handicaps, infants with intraventricular hemorrhage (IVH) are at risk for posthemorrhagic hydrocephalus (PHH), and the incidence of this problem in preterm infants with known IVH has been reported to vary from 25% to 74%. Over a 46-month period, 438 neonates of 1250-gm birth weight or less were admitted to this Newborn Special Care Unit, and 269 survived the first 36 postnatal hours. Of these, 265 patients underwent computerized tomography and/or cranial ultrasound scanning for evaluation of germinal matrix and/or intraventricular hemorrhage (GMH/IVH): 133 infants were found to have experienced GMH/IVH, and 27 of these died within the 1st postnatal week. Of the 95 survivors with GMH/IVH, 43 were known to have GMH only; the other 52 experienced IVH and were therefore at risk for PHH. Patients with GMH/IVH underwent repeat investigations for the development of ventriculomegaly and possible PHH. Only five patients with IVH developed PHH, defined as ventriculomegaly, elevated intracranial pressure, and increasing occipitofrontal head circumference. Serial cranial ultrasound studies of 95 other consecutively admitted patients in this birth-weight range revealed an equal incidence (45%) of low intracranial pressure ventriculomegaly in both the hemorrhage and non-hemorrhage groups, but none of them required shunting for hydrocephalus. One infant with congenital aqueductal stenosis was also identified.

Intraventricular hemorrhage in a term neonate secondary to a third ventricular AVM. Case report.

An initially healthy infant born of an uncomplicated full-term gestation was brought for evaluation of the acute onset of vomiting, irritability, lethargy, and opisthotonus at 14 days of age. Computerized tomography demonstrated an intraventricular hemorrhage. Arteriography defined an angioma on the roof of the third ventricle which was successfully removed via the transcallosal interfornicial approach on the 34th day of life. Other than an easily controlled seizure disorder, the postoperative course was uneventful. At 8 months of age the child is developing normally. Arteriovenous malformations should be considered in the differential diagnosis of intraventricular hemorrhage in full-term neonates without predisposing trauma or bleeding diathesis. High-speed digital subtraction arteriography may be used to screen for this diagnosis. The transcallosal interfornicial exposure offers a satisfactory approach for excising third ventricular angiomas in young infants.

Neurodevelopmental assessment of very low birth weight neonates: effect of germinal matrix and intraventricular hemorrhage.

During a recent 36-month interval, all neonates of less than or equal to 1250 gram birth weight who were admitted to our Newborn Special Care Unit and survived the first 36 postnatal hours underwent either computed tomography or echoencephalography or both for the assessment of neonatal germinal matrix hemorrhage and intraventricular hemorrhage. Seventy of the 164 long-term surviving infants experienced neonatal germinal matrix and/or intraventricular hemorrhage (GMH/IVH Group), whereas 94 infants had studies that were negative (Non-hemorrhage Group). Serial neurodevelopmental assessments were performed on 142 (87%) of the 164 long-term surviving infants; these assessments included the Bayley Scales of Infant Development at 3, 6, 12, and 18 months (corrected age) and the Stanford-Binet and Peabody Picture Vocabulary examinations at 30 months (corrected age). At 30 months (corrected age), the incidence of major neurologic abnormalities was extremely low in both the GMH/IVH and the Non-hemorrhage groups. In addition, although there were few survivors of the more severe grades of intraventricular hemorrhage, we could detect no difference between the developmental scores of the GMH/IVH and the Non-hemorrhage Group infants.

Prediction of the development of low birth weight preterm infants by a new neonatal medical index.

A new neonatal medical index (NMI) was used to predict the mental and motor development of low birth weight, preterm infants up to 3-years-old. The NMI is a summary score of only a few clinically salient items that are readily available on brief chart review. The sample consisted of 512 of 608 infants randomly assigned to the control group of the eight-site Infant Health and Development Program and on whom the complete set of developmental outcome measures was available. The developmental tests administered were the Bayley Scales at 12 and 24 months and the Stanford-Binet at 3 years. The findings indicated the NMI was predictive of later cognitive and motor development, and in infants born weighing less than 1500 g, the effects of neonatal medical complications continued to adversely influence these children's development to at least 3 years of age. In the heavier babies the developmental effects of sociodemographic factors predominated by 24 months and beyond.

Eimeria from bats of the world: two new species from Myotis spp. (Chiroptera: Vespertilionidae).

Between 1986 and 1995, 548 fecal samples were collected from 41 species of bats (Molossidae, Mormoopidae, Phyllostomidae, Thyropteridae, and Vespertilionidae) from New Mexico, California, Baja California Sur (Mexico), and Bolivia. Of these, the feces of 28 (5%) bats, including Antrozous pallidus, Myotis ciliolabrum, Myotis lucifugus, and Myotis yumanensis (Vespertilionidae), contained oocysts representing at least 3 species of Eimeria. A new species of eimerian from M. lucifugus (3/27, 11%) and M. yumanensis (8/70, 11%) is described. Sporulated oocysts are ellipsoidal, 22.3 x 14.8 (18-25 x 13-16) microns with micropyle (approximately 2 microns) and polar granules (1-4), but an oocyst residuum is absent. The oocyst wall is slightly rough exteriorly and has 2 layers (total < or = 1 micron thick). Football-shaped sporocysts are 8.1 x 6.6 (8-11 x 5-7) microns, each with a Stieda body and granular sporocyst residuum present. A new eimerian from M. yumanensis (4/70, 6%) and M. ciliolabrum (1/12, 8%) also is described. Sporulated oocysts are spheroidal to subspheroidal, 15.0 x 14.1 (14-16 x 14-16) microns, with micropyle and oocyst residuum absent; a polar granule is present. The wall is smooth and has 2 layers (total < 1 micron thick). Sporocysts are football-shaped, 7.1 x 5.9 (6-9 x 5-7) microns, each with a Stieda body and sporocyst residuum. The sporulated oocysts of a third morphotype, found in A. pallidus (12/85, 14%), were indistinguishable from those of Eimeria arizonensis, a species typically found in murid rodents. The currently recognized species of bat Eimeria are listed, and a dichotomous key is provided.

Eimeria from bats of Bolivia: two new species from vespertilionid bats.

Between 1985 and 1987, fecal samples were collected from 71 bats representing 14 species (Desmodontidae, Molossidae, Noctilionidae, Phyllostomidae, Vespertilionidae) from 8 localities in 3 states (Beni, Pando, Santa Cruz) in Bolivia, South America. Of these, 2 black myotid bats (Vespertilionidae), Myotis nigricans, and 1 tent-making bat (Phyllostomidae), Uroderma magnirostrum, had oocysts in their feces that represent undescribed species of Eimeria. The new species from M. nigricans (2/4, 50%) has sporulated oocysts that are subspheroidal, 18.9 x 16.9 (17-23 x 14-20) microm, without a micropyle; oocyst residuum of 6-8 spheroidal globules and 1 highly refractile polar granule are present. The oocyst wall has 2 layers (approximately 1.3 microm thick), with a rough outer layer. Ovoidal sporocysts are 10.1 x 7.4 (7-14 x 5-10) microm, with a Stieda body, substieda body, and a sporocyst residuum. The new eimerian species from U. magnirostrum (1/2, 50%) has sporulated oocysts that are subspheroidal to ellipsoidal, 23.8 x 20.8 (20-26 x 19-24) microm, without micropyle or oocyst residuum, but 1-3 polar granules are present. The oocyst wall has 2 layers (approximately 1.5 microm thick), with a rough, mammilated outer layer. Ovoidal sporocysts are 11.6 x 8.6 (10-12 x 7-10) microm, with a Stieda body, substieda body and a sporocyst residuum.

Six new Eimeria species from vespertilionid bats of North America.

Twenty species of bats (Molossidae, Vespertilionidae) were collected from California, New Mexico, Oregon, South Carolina, Utah, and Baja California Norte (Mexico), and 29 of 404 (7%) animals, including Antrozous pallidus, Eptesicus fuscus, Myotis auriculus, Myotis californicus, Myotis ciliolabrum, Myotis evotis, Myotis lucifugus, Myotis thysanodes, Myotis vivesi, Myotis volans, Myotis yumanensis, and Nycticeius humeralis were infected with Eimeria spp., which represent 6 new species. Sporulated oocysts of a new species from A. pallidus are subspheroidal, 24.8 x 21.6 (22-27 x 19-24) microm with a polar granule and a large globular residuum. The oocyst wall is sculptured, with 2 layers, approximately 1.5 thick. Ovoidal sporocysts are 11.5 x 7.8 (9-13 x 7-10) microm, with Stieda body and residuum of many large granules. Sporulated oocysts of a new species from M. californicus are subspheroidal, 20.7 x 18.2 (19-23 x 16-20) microm, with 1-7 tiny polar granules, but without oocyst residuum. The oocyst wall is rough, with 2 layers, approximately 1.4 thick. Ovoidal sporocysts are 11.2 x 7.3 (10-12 x 7-8) microm, with Stieda body and a globular residuum. Sporulated oocysts of a second new species from M. californicus are subspheroidal, 23.1 x 20.7 (20-26 x 19-23) microm, with residuum and 1 polar granule, but a micropyle is absent. The oocyst wall is rough with 2 layers, approximately 1.5 thick. Ovoidal sporocysts are 12.5 x 7.2 (11-14 x 7-8) microm, with a Stieda body and residuum. Sporulated oocysts of a new species from M. ciliolabrum are subspheroidal, 24.9 x 20.1 (18-27 x 17-23) microm, with 1-2 polar granules, but without micropyle and residuum. The oocyst wall is rough with 2 layers, approximately 1.5 thick. Ellipsoidal sporocysts are 12.5 x 9.0 (8-14 x 7-10) microm, with Stieda and substieda bodies and residuum. Sporulated oocysts of a new species from M. evotis are subspheroidal, 21.3 x 18.6 (20-24 x 15-20) microm, with a prominent polar granule, but without micropyle and residuum. The oocyst wall is smooth with 2 layers, approximately 1.0 thick. Ovoidal sporocysts are 12.2 x 8.0 (11-13 x 7.5-9) microm, with Stieda and substieda bodies and residuum. Sporulated oocysts of the new species from N. humeralis are subspheroidal, 22.4 x 18 (21-24 x 17-20) microm, with 1-3 polar granules, but residuum and micropyle are absent. The oocyst wall is lightly sculptured with 2 layers, approximately 1.4 thick. Ovoidal sporocysts are 10.9 x 7.7 (9-12 x 6-8) microm, with Stieda body and residuum. Sporulated oocysts of E. pilarensis Scott and Duszynski, 1997 and those of at least 12 other morphological forms were seen in the other infected bats; these latter forms were seen in too few numbers to be adequately described as new species.