Effect of indomethacin on the regulation of cerebral blood flow during respiratory alkalosis in newborn piglets

The effect of cyclooxygenase inhibition by indomethacin on regional cerebral blood flow (CBF) during hypocapnia induced by hyperventilation and during hypercapnia induced by CO2 inhalation was examined. CBF was measured in 27 anesthetized, ventilated piglets (2-8 d) using microspheres in control and indomethacin treated animals (5 mg/kg) after hyperventilation or inhalation of 6% CO2. In the control group (n = 6), CBF decreased significantly (p less than 0.05) to all regions of the brain after hyperventilation with a 32% decrease in the cerebral cortex. In the indomethacin-treated group (n = 6), blood flow significantly decreased by 35 to 49% in all regions of the brain, except the cerebral white matter, during normocapnia with no further decrease in flow during subsequent hypocapnia. Although CBF increased significantly after indomethacin treatment during hypercapnia the response was markedly attenuated with blood flow to the cerebral gray matter, hippocampus and pons rising only 42, 25, and 42% in contrast to 108, 75, and 225% in the control group. Since indomethacin decreased resting CBF, unilateral sympathetic nerve stimulation at 15 Hz was used to test the specificity of indomethacin on hypocapnic vasoconstriction (n = 5). Unilateral sympathetic nerve stimulation caused a further statistically significant decrease in CBF on the stimulated side after hyperventilation with indomethacin (12%), which was comparable to that which occurred during normocapnia (16%). The data demonstrate that indomethacin attenuates the cerebrovascular sensitivity to both increases and decreases in CO2/H+ and implicate a possible role for vasoactive prostanoids in mediating the response of CBF to fluctuations in CO2 in newborn piglets.     

Retinal, choroidal and total ocular blood flow response to hypercarbia during spontaneous breathing and mechanical ventilation

The effect of hypercarbia on ocular blood flow was studied in the newborn piglet with the isotope-labeled microsphere method. Blood flow measurements were made during spontaneous breathing and during paralyzation (pancuronium) and mechanical ventilation. Retinal blood flow increased from 0.40 +/- 0.07 (mean +/- SEM) ml/min/g at baseline levels to 0.91 +/- 0.17 ml/min/g at a PaCO2 level of 11.0 kPa during spontaneous ventilation. A similar response was observed during paralyzation and mechanical ventilation (0.89 +/- 0.15 ml/min/g at a PaCO2 of 11.1 kPa). For choroidal blood flow, however, the increase caused by hypercarbia during spontaneous ventilation (16.14 +/- 3.69 to 29.15 +/- 3.22 ml/min/g) was significantly reduced when the animals were paralyzed and mechanically ventilated (15.99 +/- 2.99 to 23.51 +/- 3.41 ml/min/g). Since choroidal blood flow accounts for 60-80% of oxygen delivery to the retina, paralyzation and mechanical ventilation may significantly reduce oxygen delivery to the retina during hypercarbia.     

Administration of indomethacin for the prevention of periventricular-intraventricular hemorrhage in high-risk neonates

One hundred twenty-two preterm infants were enrolled in a placebo-controlled, double-blind trial using intravenous indomethacin for the prevention of periventricular-intraventricular hemorrhage (PVH-IVH). Before random assignment, data on the infants were stratified according to low-weight (500 to 999 g) or high-weight (1000 to 1500 g) subgroups. Cranial sonography was used to document the absence of PVH-IVH before enrollment and the occurrence of PVH-IVH during the 7-day protocol. Indomethacin, 0.1 mg/kg, or placebo was administered before 12 hours of age and at 24, 48, and 72 hours of age. Five patients receiving indomethacin and six receiving placebo were withdrawn before completion of the study. In the remaining 111 patients, the indomethacin and placebo groups were comparable with respect to gestational ages, maternal complications, Apgar scores, ventilatory requirements, complications of prematurity, and mortality rate. PVH-IVH developed in six of 56 infants who received indomethacin and 11 of 55 infants who received placebo (P = 0.174). Analysis of the individual strata showed that the indomethacin-treated infants in the low-weight subgroup sustained a higher mortality rate (11/17 vs 3/16; P = 0.008) without a reduction in the incidence of PVH-IVH. Infants in the indomethacin-treated high-weight subgroup demonstrated a significantly lower incidence of PVH-IVH (2/39 vs 8/39; P = 0.04), but the frequency of high-grade hemorrhages was comparable for both indomethacin- and placebo-treated groups. In summary, the prophylactic administration of intravenous indomethacin for the prevention of PVH-IVH cannot be recommended for infants less than 1000 g. In preterm infants between 1000 and 1500 g birth weight, indomethacin significantly reduced the incidence of PVH-IVH.     

Effects of pentoxifylline on the cardiovascular manifestations of group B streptococcal sepsis in the piglet.

Pentoxifylline (PTXF) is a methylxanthine that modifies leukocyte function and inhibits cytokine release. To evaluate its effects on the cardiovascular manifestations of sepsis secondary to group B streptococci, 14 anesthetized, mechanically ventilated piglets were studied over a 240-min period. Animals were randomly assigned to a treatment group that received a PTXF bolus (20 mg/kg) followed by a continuous infusion of 5 mg/kg/h before and during group B streptococci (1 x 10(8) colony forming units/kg/min) administration and a control group that received saline as a placebo. Comparison of the hemodynamic measurements and arterial blood gases during the first 90 min of PTXF treatment with those of the control group resulted in the following 90 min values: systemic arterial blood pressure was significantly higher in the PTXF group (89 +/- 10 versus 56 +/- 30 mm Hg; p less than 0.005) as was cardiac output (0.18 +/- 0.04 versus 0.10 +/- 0.07 L/kg/min; p less than 0.005). Pulmonary vascular resistance remained lower in the PTXF-treated animals (135 +/- 117 versus 248 +/- 119 mm Hg/L/min/kg; p less than 0.001), and these animals were less acidotic as measured by pH (7.07 +/- 0.2 versus 7.31 +/- 0.1; p less than 0.05) and base deficit (-15 +/- 9 versus -5 +/- 2 mmol/L; p less than 0.05). Median survival time was significantly longer in the PTXF group (210 versus 90 min; p less than 0.002). These data demonstrate that PTXF can ameliorate some of the deleterious hemodynamic manifestations of group B streptococci sepsis and result in improved survival in a young animal model.     

Randomized double-blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus

A prospective randomized controlled trial was performed to compare the effects of ibuprofen with indomethacin on cerebral hemodynamics measured using near infrared spectroscopy in preterm infants during treatment for patent ductus arteriosus. Infants were randomly assigned to three intravenous doses of either indomethacin (0.20-0.25 mg/kg, 12 hourly) or ibuprofen (5-10 mg/kg, 24 hourly) and also received a dose of saline. The primary end points of the study were the effects of the first dose on cerebral blood flow (CBF) and cerebral blood volume. Fifteen infants received indomethacin and 18 received ibuprofen. The group mean (SD) values for CBF (mL x 100 g(-1) x min(-1)) before and after the first dose of indomethacin were 13.6 (4.1) and 8.3 (3.1), respectively, the change being significant (p<0.001). In contrast, no significant changes in CBF were observed with the first dose of ibuprofen, the respective before and after values being 13.3 (3.2) and 14.9 (4.7) mL x 100 g(-1) x min(-1). The median (interquartile range) value for change in cerebral blood volume (mL/100 g) after the first dose in the indomethacin group was -0.4 (-0.3 to -0.6) and in the ibuprofen group was 0.0 (0.1 to -0.1), the difference between the two groups being significant (p<0.001). Cerebral oxygen delivery changed significantly after the first dose in the indomethacin group but not in the ibuprofen group. Significant reductions in CBF, cerebral blood volume, and cerebral oxygen delivery also occurred after the 24-h dose of indomethacin, but there were no significant changes after the 48-h dose of saline in the indomethacin group or after the 24- and 48-h doses of ibuprofen. The patent ductus arteriosus closure rates after indomethacin and ibuprofen were 93 and 78%, respectively. We conclude that ibuprofen, unlike indomethacin, has no adverse effects on cerebral hemodynamics and appears to mediate patent ductus arteriosus closure.     

Alae nasi activation in preterm infants during oral feeding.

Preterm infants may demonstrate impaired ventilation during oral feeding with resultant hypoxemia and hypercarbia. This study was designed to determine whether infants activate a representative upper airway muscle, the ala nasi, in response to these ventilatory changes. Ten preterm infants (postconceptional age at study 35 +/- 4 wk, weight 2.2 +/- 0.1 kg) were studied during a control period, continuous feeding, subsequent intermittent feeding, and a period of nonnutritive sucking. Nasal airflow was measured with a pneumotachometer to quantify minute ventilation. The alae nasi electromyogram (EMGAN) was recorded with surface electrodes, and sucking pressure was detected by a catheter in the feeding nipple. End-tidal CO2 and O2 saturation were also recorded during each period. The percentage of breaths associated with EMGAN activity increased from 41 +/- 13% during the control period to 95 +/- 5% and 93 +/- 7% during continuous and intermittent sucking, respectively (p < 0.05). Eighty-seven +/- 5% of EMGAN activity occurred during inspiration. During continuous and intermittent sucking, the amplitude of EMGAN activity also increased (6.8 +/- 5.2 and 6.7 +/- 4.0 arbitrary units/breath, respectively) compared with the control period (2.4 +/- 2.8 units/breath, p < 0.05). In association with the increase in EMGAN activity, O2 saturation fell from 98 +/- 1% in the control period to 95 +/- 1% during both continuous and intermittent feeding (p < 0.05), and minute ventilation fell from 274 +/- 80 mL/min/kg during the control period to 190 +/- 81 and 208 +/- 57 mL/min/kg during continuous and intermittent feeding, respectively (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of therapeutic dose of indomethacin on the cerebral circulation of newborn pigs

The effects of treatment with 0.2 mg/kg of indomethacin on the cerebral blood flow and cerebral oxygen consumption of hypotensive, unanesthetized, newborn pigs were investigated. Hypotension was induced by hemorrhage (30 ml/kg) which reduced mean arterial pressure from 60 to 34 mm Hg. The decline in cerebral vascular resistance that occurred with hemorrhage allowed blood flow to all brain regions and cerebral oxygen consumption to continue unchanged. Treatment with 0.2 mg of indomethacin decreased plasma 6-keto-prostaglandin F1 alpha markedly and caused a modest increase in cerebral vascular resistance from 0.75 +/- 0.07 to 0.85 +/- 0.02 mm Hg X 100 g X min/ml at 40 min posttreatment. As a result, blood flow throughout the brain fell about 20%. Similarly, cerebral oxygen consumption declined from 2.88 +/- 0.13 to 2.03 +/- 0.21 ml O2/100 g X min following treatment of hypotensive piglets with 0.2 mg/kg of indomethacin. However, all piglets were conscious 40 min after treatment. We conclude that, although 0.2 mg/kg of indomethacin affects cerebral hemodynamics of hypotensive piglets, the effects are very modest in comparison to large increases in cerebral vascular resistance, decreases in cerebral blood flow and oxygen consumption, and coma that follow treatment of hypotensive piglets with 5 mg/kg of indomethacin.     

Effects of a leukotriene antagonist on the early hemodynamic manifestations of group B streptococcal sepsis in piglets

In order to evaluate the influence of leukotrienes on group B streptococcal (GBS) sepsis we studied the effect of a leukotriene antagonist, FPL 57231, on the early hemodynamic changes occurring secondary to an infusion of live GBS. Paralyzed, mechanically ventilated piglets received a continuous intravenous infusion of bacteria (5 X 10(8) org/kg/min) while systemic arterial pressure and pulmonary artery pressure were measured continuously. Cardiac output was measured by thermodilution; and plasma samples for determination of thromboxane B2 and 6-keto-PGF1 alpha were taken at preset intervals. In addition to GBS, treatment animals received a continuous infusion of FPL 57231 starting 15 min after the bacterial infusion was begun. Study animals as a whole responded to bacteria within 15 min with a marked elevation in pulmonary artery pressure from 13.6 +/- 4 to 44.6 +/- 6 mm Hg (p less than 0.001), and a decline in PaO2 (79 +/- 9 to 44 +/- 5 mm Hg) (p less than 0.001) and a cardiac output (0.27 +/- 0.07 to 0.15 +/- 0.06 liter/min/kg) (p less than 0.0001). In animals treated with FPL 57231 these changes were reversed or significantly attenuated by 60 min. In the control group pH deteriorated significantly to 7.17 +/- 0.1 compared to baseline values (p less than 0.01) by 60 min, while treatment group animals maintained a pH of 7.3 +/- 0.23. Thromboxane B2 and 6-keto PGF1 alpha were similar in both groups and did not change during the study period. In addition, survival was significantly longer in treatment (191 +/- 44 min) compared to control animals (100 +/- 32 min) (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of indomethacin upon cerebral hemodynamics of newborn pigs

Treatment of unanesthetized newborn pigs with indomethacin trihydrate (5 +/- 1 mg/kg, intravenous) decreased cerebral blood flow uniformly throughout the brain by 18-28% without changing cardiac output, arterial pressure, or arterial blood gases and pH. Breathing 10% O2, 9% CO2 with the balance N2 (hypoxia/hypercapnia) caused cerebral blood flow to increase from 102 +/- 12 to 218 +/- 19 ml/100 g . min. Intravenous administration of indomethacin during hypoxia/hypercapnia caused a uniform decrease in cerebral flow throughout the brain to levels (94 +/- 5 ml/100 g . min) indistinguishable from those when the piglet was breathing ambient air. Further, 2.5 h later, the cerebral hyperemia caused by hypoxia/hypercapnia was attenuated markedly (129 +/- 19 ml/100 g . min). Vehicle treatment did not alter resting cerebral blood flow or cerebral hyperemia in response to hypoxia/hypercapnia. Measurements of 6-keto-prostaglandin F1 alpha, thromboxane B2, and prostaglandin E2 demonstrated that intravenously administered indomethacin crossed the blood-brain barrier of newborn pigs in sufficient quantity to inhibit prostanoid release into the cerebrospinal fluid passing over the surface of the brain. The mechanism by which indomethacin reduces cerebral blood flow and attenuates cerebral hyperemia cannot be determined from the present experiments. We conclude that intravenous administration of indomethacin decreases cerebral blood flow and attenuates cerebral hyperemia induced by severe, combined hypoxia/hypercapnia in newborn pigs.     

Brain superoxide anion generation during asphyxia and reventilation in newborn pigs

Superoxide anion generation during severe asphyxia and reventilation was assessed in newborn pigs. Using closed cranial windows over the parietal cortices, superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined during asphyxia/reventilation. Asphyxia was induced by turning off the respirator and occluding the endotracheal tube. In each animal, 2.4 mM NBT dissolved in artificial cerebrospinal fluid was placed under one window and under the opposite window, NBT (2.4 mM) plus SOD (60 U/mL) dissolved in artificial cerebrospinal fluid was used. A significant increase in SOD-inhibitable NBT reduction was observed in asphyxiated piglets (14.67 +/- 4.5 pmol/mm2 x 20 min) when compared with control piglets (2.82 +/- 1.1 pmol/mm2 x 20 min). In another group in which the animals were treated with indomethacin (5 mg/kg i.v.) before asphyxia/reventilation, there was minimal SOD-inhibitable NBT reduction. Our results indicate that superoxide anion is generated on the cerebral cortex during asphyxia/reventilation via the prostaglandin endoperoxide synthase pathway.     

Newborn piglets with meconium aspiration resuscitated with room air or 100% oxygen

We investigated whether newborn piglets exposed to hypoxemia and severe meconium aspiration could be reoxygenated with room air as efficiently as with 100% O(2). Twenty-one 2- to 5-d-old piglets were randomly divided into three groups: 1) the room air group: hypoxemia, meconium aspiration, and reoxygenation with room air (n = 8); 2) the O(2) group: hypoxemia, meconium aspiration, and reoxygenation with 100% O(2) (n = 8); and 3) the control group: meconium aspiration, and reoxygenation with room air (n = 5). Hypoxemia was induced by ventilation with 8% O(2) until the mean blood pressure reached <20 mm Hg or the base excess reached <-20 mM. At this point, reoxygenation was started with either room air or 100% O(2). Three milliliters per kilogram of meconium 110 mg/mL was instilled into the trachea immediately before the start of reoxygenation. The O(2) tension in arterial blood was significantly lower in the room air group; at 5 min of reoxygenation it was 9.1 +/- 0.5 kPa versus 43.5 +/- 6 kPa in the O(2) group (p < 0.05). At 5 min of reoxygenation the tidal volume per kilogram was 12.1 +/- 0.7 mL/kg in the room air group and 13.1 +/- 0.9 mL/kg in the O(2) group (NS). There were no significant differences between the room air and the O(2) groups during 120 min of reoxygenation in mean arterial blood pressure, pulmonary arterial pressure, cardiac index, base excess, or plasma hypoxanthine. In conclusion, hypoxic newborn piglets with meconium aspiration were found to be reoxygenated as efficiently with room air as with 100% O(2).     

Effects of pancuronium bromide on cerebral blood flow changes during seizures in newborn pigs.

We investigated the effects of pancuronium bromide pretreatment on cerebral blood flow (CBF) during bicuculline-induced seizures in anesthetized piglets. Arterial blood pressure, gases, pH, cerebral electrocortical activity, and CBF (radioactive microsphere) were monitored at baseline, 10 min after administration of pancuronium (0.3 mg/kg i.v.; n = 9) or vehicle (normal saline; n = 8), and again at 5, 15, and 60 min after bicuculline (3 mg/kg i.v.). No change in CBF from baseline was observed at 10 min after either saline or pancuronium treatment, before induction of seizures. In the saline group, CBF was 36 +/- 3 mL.min-1.100 g-1 before bicuculline and increased to 166 +/- 24 and 205 +/- 35 mL.min-1.100 g-1 at 5 and 15 min, respectively, after bicuculline, returning toward baseline by 60 min. In the pancuronium group at 5 min after bicuculline, CBF increased from 45 +/- 7 to 169 +/- 26 mL.min-1.100 g-1, but fell to 88 +/- 17 mL.min-1.100 g-1 at 15 min in contrast to saline-treated piglets. Also, at 15 min of seizures, differences between groups were observed in arterial blood pressure, gases, and pH. Although these variables were in the normal range with pancuronium treatment, the saline-treated animals had increased arterial blood pressure (81 +/- 6 mm Hg) and PCO2 (6 +/- 0.4 kPa) and decreased PO2 (7 +/- 0.5 kPa) and pH (6.91 +/- 0.06). Electrocortical activity was abnormal during seizures in both groups. At 60 min, reversal to normal activity was observed in six of nine pancuronium-treated animals versus two of eight saline-treated animals. These data suggest that pancuronium limits cerebral hyperemia during prolonged seizures by attenuating increases in blood pressure as a result of elimination of skeletal muscle activity. This leads to minimal alteration of arterial PCO2, PO2, and pH during seizures.     

Changes in ovine hepatic circulation and oxygen consumption at birth

The umbilical vein provides the majority of hepatic blood flow during fetal life. After birth, liver blood flow is derived from the hepatic artery and portal vein, but ductus venosus patency can alter portal venous blood flow to the liver. To characterize changes in hepatic blood flow and oxygen metabolism in the immediate perinatal period, we studied liver and ductus venosus blood flow in seven fetal sheep before and after birth using the radionuclide-labeled microsphere method. Hepatic blood flow fell from 423 +/- 117 (mean +/- SD) mL/min/100 g liver in the fetus to 144 +/- 73 by 2 h after delivery. Although portal venous blood flow increased progressively from 2 to 10 h (137 +/- 48 to 305 +/- 140 mL/min/100 g), because of increasing ductus venosus shunt flow, total hepatic blood flow did not change. Hepatic arterial flow was 46 +/- 24 mL/min/100 g at 2 h, providing 35% of total hepatic blood flow, and did not change over the next 8 h. Hepatic oxygen delivery fell after birth from 58 +/- 25 mL/min/100 g liver in the fetus to 21 +/- 11 at 2 h and then remained constant. Hepatic oxygen consumption was 7.3 +/- 2.6 mL/min/100 g liver in the fetus and ranged from 3.2 +/- 1.5 to 4.1 +/- 1.8 mL/min/100 g liver during the 10 h after birth. Loss of the umbilical-placental circulation at birth substantially reduces hepatic blood flow. Hepatic arterial flow does not increase to compensate for decreases in total hepatic blood flow. The persistent ductus venosus shunt compromises portal venous supply to the liver.(ABSTRACT TRUNCATED AT 250 WORDS)     

Near infrared spectroscopy-measured changes in cerebral blood volume and cytochrome aa3 in newborn lambs exposed to hypoxia and hypercapnia, and ischemia: a comparison with changes in brain perfusion and O2 metabolism.

OBJECTIVES: Validation of near infrared spectroscopy (NIRS)-measured changes in cerebral blood volume (deltaCBV) and cytochrome aa3 (deltaCytaa3) as estimators of changes in brain perfusion and oxygenation in the newborn lamb during hypoxia and hypercarbia, and additional hypotension. METHODS AND MATERIALS: In 33 newborn lambs brain perfusion assessed by carotid artery blood flow (deltaQcar: ml/min)and cerebral metabolic rate of oxygen (deltaCMRO2: ml O2/min) were related to NIRS-derived deltaCBV (ml/100 g) and deltaCytaa3 (microM) during combined hypoxia and hypercarbia and additional hypotension. Combined hypoxia and hypercapnia was induced by ventilation with 6-8% of O2 and 10% of CO2 during 30 min, and additional hypotension ( < 35 mmHg for 5 min) was induced by careful withdrawal of blood. RESULTS: CBV increased during hypoxia and hypercarbia, decreased during additional hypotension and was related to deltaQcar: (0.009 ml/100 g change per ml/min Qcar: P < 0.0001). Cytaa3 increased during hypoxia and hypercarbia, decreased during subsequent additional hypotension andshowed a reverse relationship with deltaCMRO2 (-1.65 microM change per ml O2/min CMRO2: P <0.0001). Cytaa3 remained above baseline during reperfusion. CONCLUSIONS: deltaCBV estimates changes in brain perfusion, but overestimates brain perfusion during hypotension. The pattern of deltaCytaa3 suggests less oxygen utilisation by brain tissue during hypoxia and subsequent reperfusion.     

Studies of the immaturity of the ADH-dependent cAMP system in conscious newborn piglets--possible impairing effects of renal prostaglandins

In 24 conscious newborn piglets the effects of 20 micrograms/kg body weight IV 1-deamino-8-D-arginine-vasopressin (DDAVP) in group 1, 5 mg/kg PO indomethacin in group 2, and the combined effects of both drugs in group 3 were studied by measuring urinary flow rate, urinary osmolality, creatinine clearance, total urinary and nephrogenous cyclic-adenosine 3':5'-monophosphate (cAMP) excretion, medullary cAMP content, and renal prostaglandin (PG)E2 and PGF2 alpha, excretion. DDAVP alone had no significant effects on ther above parameters, whereas indomethacin alone reduced only the PG excretion significantly. When both drugs were administered simultaneously, urinary concentration increased significantly (urinary flow rate decreased from 2.4 +/- 0.4 to 1.4 +/- 0.3 ml/hr (means +/- S.E.), and urinary osmolality increased from 444 +/- 29 to 552 +/- 33 mOsm/liter). Total urinary and nephrogenous cAMP excretion increased from 590 +/- 48 to 854 +/- 78 and 302 +/- 36 to 590 +/- 81 pmoles/hr/g kidney weight, respectively, whereas PGE2 and PGF2 alpha decreased from 249 +/- 33 to 19 +/- 4 and 192 +/- 32 to 43 +/- 7 pg/hr/g kidney weight, respectively. In addition, medullary cAMP content was considerably higher in group 3 (2010 +/- 200 pmoles/g medulla) than that observed in the control (1187 +/- 137), DDAVP (1218 +/- 115), and indomethacin (1230 +/- 168) groups.     

Impact of prostaglandin and thromboxane synthesis blockade on disposition of group B streptococcus in lung and liver of intact piglet.

Group B streptococci (GBS) localizing in the lungs of infant piglets is killed in part by an oxygen radical-dependent mechanism (Bowdy BD, Marple SL, Pauly TH, Coonrod JD, Gillespie MN: Am Rev Respir Dis 141:648-653, 1990). The source of bactericidal oxygen radicals is unknown, but cyclooxygenation of arachidonic acid, an initial event in prostanoid synthesis, is accompanied by substantial oxygen radical generation. Because blockade of prostaglandin H synthase (cyclooxygenase) with indomethacin prevents GBS-induced pulmonary hypertension, we reasoned that the salutary effect of indomethacin might be associated with a reduction in the efficacy of bactericidal activity directed against GBS. To address this possibility, the distribution and viability of 111In-labeled GBS (10(8) colony forming units/kg/min i.v. for 15 min) were assessed in lungs and livers of control piglets, piglets treated with indomethacin (1 mg/kg), and piglets treated with OKY-046 (10 mg/kg), an inhibitor of thromboxane synthase that also forestalls GBS-induced pulmonary hypertension. Relative to control animals, indomethacin treatment increased pulmonary GBS uptake with no change in bacterial distribution into the liver. OKY-046 failed to influence pulmonary bacterial uptake but promoted a substantial increase in GBS depositing in the liver. In contrast to its effects on pulmonary bacterial deposition, indomethacin failed to increase lung bacterial viability relative to control animals. Indomethacin also was without effect on hepatic bacterial viability. OKY-046 failed to influence pulmonary bacterial viability but markedly augmented hepatic GBS viability to the extent that significant bacterial proliferation occurred.(ABSTRACT TRUNCATED AT 250 WORDS)     

The relation between lower limb pooling and blood flow during orthostasis in the postural orthostatic tachycardia syndrome of adolescents

OBJECTIVES: Postural orthostatic tachycardia syndrome (POTS) is characterized by symptoms of lightheadedness, fatigue, and signs of edema, acrocyanosis, and exaggerated tachycardia within 10 minutes of upright posture. Our objective was to determine how vascular properties contribute to the pathophysiology of POTS in adolescents. STUDY DESIGN: We compared 11 patients aged 13 to 18 years with 8 members of a control group, recording continuous heart rate and blood pressure and using strain-gauge plethysmography to measure forearm and calf blood flow and to estimate venous pressure while the subjects were supine. Calf blood flow and size change were measured during 70 degrees head-up tilt. RESULTS: Resting calf venous pressure was higher in the POTS group compared with the control group. Resting resistance was decreased in both the forearm (15 +/- 2 vs 30 +/- 4) and calf (27 +/- 2 vs 42 +/- 5) in the POTS group. Calf blood flow 60 seconds after tilt increased from 1.9 +/- 0.4 mL/100 mL/min to 6.6 +/- 2.3 mL/100 mL/min in the POTS group but only by half in the control group. Flow remained elevated in the POTS group but decreased to 70% baseline in the control group. Calf volume increased twice as much in the POTS group compared with the control group over a shorter time (13 vs 30 minutes). CONCLUSIONS: Lower resistance at baseline reflects a defect in arterial vasoconstriction in POTS, further exacerbated during upright posture.     

Effects of active compression-decompression cardiopulmonary resuscitation with the inspiratory threshold valve in a young porcine model of cardiac arrest

Active compression-decompression (ACD) cardiopulmonary resuscitation (CPR) with the inspiratory threshold valve (ITV) has been recently recommended by the American Heart Association for treatment of adults in cardiac arrest (class IIb: alternative, useful intervention), but this new technique has never been used in a pediatric population. Thus, this study was designed to evaluate ACD + ITV CPR in a young porcine model of cardiac arrest. After 10 min of ventricular fibrillation, and 8 min of standard CPR, ACD + ITV CPR was performed in seven 4- to 6-wk-old pigs (8-12 kg); defibrillation was attempted 8 min later. Within 2 min after initiation of ACD + ITV CPR, mean (+/- SEM) coronary perfusion pressure increased from 18 +/- 2 to 24 +/- 3 mm Hg (p = 0.018). During standard versus ACD + ITV CPR, mean left ventricular myocardial and total cerebral blood flow was 59 +/- 21 versus 126 +/- 32 mL.min(-1).100 g(-1), and 36 +/- 7 versus 60 +/- 15 mL.min(-1).100 g(-1), respectively (p = 0.028). Six of seven animals were successfully defibrillated, and survived >15 min. In conclusion, the combination of ACD + ITV CPR significantly increased both coronary perfusion pressure and vital organ blood flow after prolonged standard CPR in this young porcine model of ventricular fibrillation.     

The effect of tin (IV)-protoporphyrin-IX on bilirubin production and excretion in the rat

Tin (IV)-protoporphyrin-IX alpha (tin-heme) may have use in treating neonatal jaundice. To evaluate its effect on bilirubin metabolism, we measured bile-bilirubin excretion in adult, male Sprague-Dawley rats (350-500 g). After a 4-h baseline period, tin-heme (100 mumol/kg) or buffer was injected subcutaneously, and bile was collected for 19 h. Bile flow, bile salt excretion, and bile-bilirubin excretion (averaging 600 +/- 60 ng/100 g/min for all animals) remained stable in the control period. Tin-heme treatment did not alter bile flow or bile salt excretion, but within 2 h bilirubin output was significantly reduced. The nadir of output was 5 h after injection when it was 380 +/- 40 ng/100 g/min (p less than 0.001). Cumulative excretion over 19 h was reduced 30.8% (p less than 0.01). To determine if tin-heme interfered with hepatic uptake or excretion of bilirubin, additional animals were administered intravenous bilirubin at 30 mg/kg/h for 3 h after tin-heme injection. Neither peak bile-bilirubin (37.4 +/- 4.68, control; 38.19 +/- 3.81 micrograms/100 g/min, treated) nor cumulative excretion (87.8 +/- 4.7, control; 88.9 +/- 4.2%, treated) were altered. Biliary excretion of tin-heme was measured under various experimental conditions. When administered alone, maximal excretion was 4 h after injection (4.41 +/- 1.58 micrograms/100 g/min); by 15 h, it fell to 0.024 +/- 0.011 microgram/100 g/min; 20-h cumulative tin-heme excretion in bile was 21.8 +/- 3.1% of the administered dose. Intravenous coadministration of albumin or albumin and bilirubin reduced the peak output but did not alter cumulative excretion of tin-heme. These data indicate that tin-heme reduces endogenous bilirubin formation but does not impair hepatic uptake and excretion. Bile is a major excretory route for tin-heme.     

Lubeluzole pretreatment does not provide neuroprotection against transient global cerebral ischemia in fetal sheep near term

The aim of the present study was to test the neuroprotective effect of the novel benzothiazol compound lubeluzole on neuronal cell damage in fetal sheep arising from global cerebral ischemia. Thirteen fetal sheep were prepared at a mean gestational age of 127 +/- 1 d (term is at 147 d). Six fetuses were treated with lubeluzole (0.33 mg/kg estimated body weight) before induction of global cerebral ischemia (-90, -60, and -30 min), while the remainder (n = 7) received solvent. Cerebral ischemia was induced by occluding both carotid arteries for 30 min. Cerebral blood flow was measured by injecting radio-labeled microspheres before (-90 min), during (+3 min and +27 min), and after (+40 min, +3 h, and +72 h) cerebral ischemia. Neuronal cell damage was assessed in the cerebrum and deeper brain structures by light microscopy. Values are given as means +/- SD. In control fetuses, blood flow to the cerebrum was reduced from 100 +/- 25 mL.100 g(-1) min(-1) to less than 20 mL.100 g(-1) min(-1) during ischemia. Shortly after ischemia, hyperperfusion occurred (217 +/- 66 mL.100 g(-1)min(-1)) followed by a tendency toward hypoperfusion (72 +/- 17 mL.100 g(-1) min(-1)) later on (+3 h). Significant differences in blood flow to the various brain structures between the control and study groups could not be observed. Neuronal cell damage was concentrated in the parasagittal regions of the cerebrum. Preischemic application of lubeluzole did not have any effect on the extent of neuronal cell damage. From these results, we conclude that pretreatment with lubeluzole fails to protect the brain of fetal sheep near term from injury after transient global cerebral ischemia. However, because the observation period lasted only 3 d, a possible effect of lubeluzole on pathophysiological mechanisms inducing delayed neuronal cell death cannot be fully excluded.