Selective inhibitors differentially affect cyclooxygenase-dependent pial arteriolar responses in newborn pigs

Cyclooxygenase (COX)-derived prostanoids play an important role in the cerebrovascular control of newborns. In humans and in the widely accepted model of piglets, both the COX-1 and the COX-2 isoforms are expressed in cerebral arteries. However, the involvement of these isoforms in cerebrovascular control is unknown. Therefore we tested if specific inhibitors of COX-1 and/or COX-2 would differentially affect pial arteriolar responses to COX-dependent stimuli in piglets. Anesthetized, ventilated piglets (n = 35) were equipped with a closed cranial window, and changes in pial arteriolar diameters (baseline approximately 100 microm) to hypercapnia (ventilation with 5-10% CO(2), 21% O(2), balance N(2)), arterial hypotension (40 mm Hg MABP achieved by blood withdrawal), and Ach (Ach, 10-100 microM) were determined via intravital microscopy. Arteriolar responses were repeatedly tested 15 min after IV administration of selective COX-1 and COX-2 inhibitors SC-560 and NS-398 (1-1 mg/kg), and nonselective inhibitors indomethacin (0.3-1 mg/kg), acetaminophen (30 mg/kg), and ibuprofen (30 mg/kg). Hypercapnia resulted in concentration-dependent, reversible, (approximately 20-40%) increases in pial arteriolar diameters that were unaffected by NS-398, SC-560, acetaminophen and ibuprofen. In contrast, 0.3 mg/kg indomethacin significantly reduced, 1 mg/kg virtually abolished the vasodilation. Arterial hypotension elicited (approximately 15-20%) vasodilation that was similarly reduced by NS-398 and indomethacin but was unaltered by SC-560. Ach dose-dependently constricted pial arterioles. This response was similarly attenuated by NS-398, indomethacin, and ibuprofen, but left intact by SC-560. We conclude that the assessed COX-dependent vascular reactions appear to depend largely on COX-2 activity. However, hypercapnia-induced vasodilation was found indomethacin-sensitive instead of a COX-dependent response in the piglet.     

Ischemia alters cerebral vascular responses to hypercapnia and acetylcholine in piglets

Effects of ischemia (20 min) on cerebral cortical prostanoid synthesis and microvascular responses to hypercapnia and topical acetylcholine were examined in anesthetized newborn pigs. Pial arteriolar dilation in response to hypercapnia (10% CO2 ventilation, 10 min) was absent 2 h after ischemia and reversed toward constriction by 24 h postischemia. In sham control piglets, hypercapnia increased cortical periarachnoid fluid prostanoid concentrations. After ischemia, hypercapnia did not affect prostanoid concentrations on the brain surface. Acetylcholine (10(-3) M)-induced pial arteriolar constriction was reversed toward dilation 24 h after cerebral ischemia. Further, acetylcholine-induced prostanoid synthesis was markedly attenuated after ischemia. We conclude that cerebral ischemia-reperfusion alters cerebral prostanoid synthesis and microvascular control in newborn pigs. These abnormalities persist for at least 24 h.     

Cerebrovascular reactivity remains intact after cortical depolarization in newborn piglets.

Cerebrovascular reactivity is severely affected by ischemia, and changes in vascular responses have been reported after cortical spreading depression and head trauma as well. Cortical depolarization (CD) occurs during ischemia, cortical spreading depression, and head trauma, but its effects on cerebrovascular reactivity are unclear. We tested the hypothesis that CD induced by KCl diminishes the vascular responsiveness to various vasodilatory stimuli in piglets. Responses of pial arterioles were determined by changes in vascular diameter by use of a closed cranial window and intravital microscopy. Baseline arteriolar diameters were 105 +/- 3 microm (mean +/- SEM, n = 27). CD was elicited by topical administration of 1 mol/L KCl for 3 min. Vascular responses were measured before and 1 h after CD. KCl elicited CD and constricted arterioles by 54 +/- 4% (n = 27). N-methyl-D-aspartate induced dose-dependent vasodilation that was unaffected by CD; the percent changes were 9 +/- 1 versus 8 +/- 1 (before and after CD) at 10(-5) mol/L, 19 +/- 2 versus 18 +/- 3 at 5 x 10(-5) mol/L, and 29 +/- 2 versus 26 +/- 3 at 10(-4) mol/L (n = 9). Hypercapnic vasodilation was not diminished by CD; the percent changes were 15 +/- 2 versus 16 +/- 4 at 5%, and 27 +/- 5 versus 27 +/- 6 at 10% inspired CO2 (n = 8). Aprikalim and forskolin caused dilation that was also resistant to prior CD; the percent change values were 21 +/- 4 versus 18 +/- 3 and 16 +/- 2 versus 16 +/- 4 at 10(-6) mol/L, 36 +/- 5 versus 34 +/- 5 and 34 +/- 7 versus 37 +/- 7 at 10(-5) mol/L (n = 8), respectively. Finally, calcitonin gene-related peptide-induced vasodilation was unaffected by CD; percent changes were 15 +/- 3 versus 16 +/- 2 at 10(-7) mol/L and 26 +/- 4 versus 22 +/- 3 at 10(-6) mol/L (n = 8). The intact vascular responses after CD suggest that this component is not responsible for decreased cerebrovascular reactivity after ischemia, head trauma, or cortical spreading depression.     

Comparison of ibuprofen and indomethacin therapy for patent ductus arteriosus in preterm infants

BACKGROUND: Patent ductus arteriosus (PDA) is commonly found in very low-birthweight (VLBW) infants. The presence of respiratory distress syndrome (RDS) is also associated with increased frequency of significant PDA. Intravenous indomethacin has been used to treat and to prevent PDA in premature infants since 1976. However, concern remains regarding the safety of indomethacin, which affects renal, gastrointestinal and cerebral perfusion. Intravenous ibuprofen has recently been used to treat and to prevent PDA premature infants with PDA without reducing cerebral blood flow or affecting intestinal or renal hemodynamics. The aim of the present study is to compare intravenous ibuprofen and indomethacin with regard to efficacy and safety for the early treatment of PDA in preterm infants. METHODS: A total of 63 preterm infants with RDS who had a birthweight of < or =1500 g and gestational age of < or =32 weeks, were enrolled in the present study. All patients were treated with nasal continuous positive airway pressure with additional oxygen supply in inspired air>30%, or with mechanical ventilation. The patients' serum platelet counts were>100,000/uL, and serum creatinine values were <1.5 mg/dL. There were no 3-4 grade intraventricular hemorrhages before randomization, and all patients were aged 2-7 days and had echo-cardio-graphic evidence of significant PDA. Patients were randomized into two groups: the first group of neonates (group A, n = 32) received intravenous ibuprofen lysine 10 mg/kg, followed by 5 mg/kg after 24 and 48 h; the second group (group B, n = 31) received intravenous indomethacin 0.2 mg/kg every 12 h for three doses. RESULTS: Patent ductus arteriosus closed in 27 patients from the ibuprofen group (84.4%) and in 25 patients from the indomethacin group (80.6%). PDA reopened in three patients from the ibuprofen group (9.4%) and in three patients from the indomethacin group (9.7%). One patient in the ibuprofen group and two patients in the indomethacin group required ductal ligation. Serum creatinine and blood urea nitrogen (BUN) concentrations were lower in the ibuprofen group than in the indomethacin group. Urine output and creatinine clearance values were higher in the ibuprofen group than in the indomethacin group. CONCLUSIONS: Ibuprofen therapy is as efficacious as indomethacin for the treatment of PDA in preterm infants. Infants treated with ibuprofen have higher creatinine clearance and urine output and lower serum creatinine and BUN values than infants treated with indomethacin.     

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.     

Cerebrovasodilatory contribution of endogenous carbon monoxide during seizures in newborn pigs

Carbon monoxide (CO) and the excitatory amino acid glutamate both dilate cerebral arterioles in newborn pigs. The key enzyme in CO synthesis is heme oxygenase, which is highly expressed in neurons with glutamatergic receptor activity as well as cerebral microvessels. During seizures the extracellular level of glutamate is increased, which results in excessive depolarization of neurons. We hypothesized that CO is a mediator of excitatory amino acid-induced dilation of the cerebral microvasculature during seizures. Three groups of piglets were examined: 1) i.v. normal saline (sham control), 2) topical chromium mesoporphyrin (Cr-MP, 15 x 10(-6) M), and 3) i.v. tin-protoporphyrin (Sn-PP, 4 mg/kg). Synthetic metalloporphyrins (Cr-MP and Sn-PP) are heme oxygenase inhibitors, thereby reducing CO synthesis. Implanted closed cranial windows were used to monitor changes in pial arteriolar diameters. Seizures were induced by administration of i.v. bicuculline. Changes in pial arteriolar diameters were monitored during 30 min of status epilepticus. The percent increase in pial arteriolar dilation in the saline group during seizures was 68 +/- 3%. In the metalloporphyrin groups, the pial arteriolar dilation was markedly reduced (35 +/- 3% and 13 +/- 1%, for Cr-MP and Sn-PP, respectively; p < 0.05, compared with the saline group). We conclude that metalloporphyrins by inhibition of heme oxygenase and prevention of CO synthesis attenuate pial arteriolar dilation during seizures. Therefore, CO appears to be involved in cerebral vasodilation caused by glutamatergic seizures.     

口服消炎痛和布洛芬治疗早产儿动脉导管未闭的比较

目的：静脉注射消炎痛是早产儿动脉导管未闭的常规治疗方法,但治疗过程中常出现一些副作用,如少尿、消化道出血、脑血流灌注减少。近年来,静脉注射布洛芬已用于治疗早产儿动脉导管未闭。布洛芬治疗不会减少脑血流灌注,也不会影响胃肠道和肾脏的血流动力学。伊朗目前尚无消炎痛和布洛芬的静脉制剂供应。该研究旨在比较这两种药的口服制剂治疗早产儿动脉导管未闭的疗效和安全性。方法：36例胎龄小于34周经超声心动图确诊患有动脉导管未闭的早产儿被随机分为两组,每组18人。一组给予消炎痛口服,每次0.2 mg/kg,24 h给药 1 次,共3次。另一组给予布洛芬口服,共 3 次,间隔时间为24 h,首剂为 10 mg/kg,随后两次各 5 mg/kg。用药后观察导管闭合率、副作用、并发症及临床过程。结果：用药后布洛芬组18例患儿动脉导管都闭合（100％）,而消炎痛组18例中有15例患儿动脉导管闭合（83.3%）（P＞0.05）。两组疗效差异统计学无显著性意义。治疗前后两组的血清尿素氮和肌酐含量差异也无显著性意义。消炎痛组发生了3例（16.6%）坏死性小肠结肠炎,布洛芬组则无,差异有显著性意义 (P＜0.05)。治疗1个月后两组成活率均为 94%（17／18）。消炎痛组1例死于坏死性小肠结肠炎,布洛芬组1例死于败血症。结论：口服布洛芬治疗早产儿动脉导管未闭和口服消炎痛治疗一样有效,而且坏死性小肠结肠炎的发生率较口服消炎痛治疗低。［中国当代儿科杂志,2007,9（5）：399-403］     

Effects of indomethacin and ibuprofen on mesenteric and renal blood flow in preterm infants with patent ductus arteriosus

OBJECTIVE: To evaluate the effect of intravenous ibuprofen and indomethacin for treatment of patent ductus arteriosus (PDA) on mesenteric and renal blood flow velocity in preterm infants. STUDY DESIGN: Seventeen mechanically ventilated preterm infants (<33 weeks' gestation) with PDA received either 0.2 mg/kg indomethacin (n = 8) or 10 mg/kg ibuprofen (n = 9), infused over 15 minutes. Mesenteric and renal blood flow velocity were measured by using Doppler ultrasonography. RESULTS: Indomethacin caused a significant reduction in mesenteric and renal blood flow velocity 30 minutes after drug administration; mesenteric and renal blood flow velocity did not return to the pretreatment values by 120 minutes. Ibuprofen did not alter blood flow 30 minutes after treatment, and blood flow increased 120 minutes after treatment. Mesenteric and renal blood flow velocity changes were significantly different between the 2 treatment groups. CONCLUSIONS: Compared with indomethacin, ibuprofen did not significantly reduce mesenteric and renal blood flow velocity.     

Differences in the effects in the newborn piglet of various nonsteroidal antiinflammatory drugs on cerebral blood flow but not on cerebrovascular prostaglandins

To characterize the role of prostaglandins (PG) in the regulation of basal cerebral blood flow (CBF) in the newborn, we determined the effects of four nonsteroidal antiinflammatory drugs, indomethacin (3 mg/kg, n = 8 and 10 mg/kg, n = 5), aspirin (65 mg/kg, n = 6), ibuprofen (30 mg/kg, n = 8), and naproxen (15 mg/kg, n = 6), on CBF, cerebral metabolism, and cerebrovascular PG in conscious 1- to 3-d-old piglets. Drugs and vehicle (n = 8) were injected i.v., and measurements were made 5 min before and 20 and 60 min after injections. Neither the vehicle nor any of the nonsteroidal antiinflammatory drugs exerted significant effects on mean arterial blood pressure and on blood gases and pH. All four drugs, with the exception of indomethacin at the lower dose (3 mg/kg), decreased PG to nearly undetectable levels within 20 min; the low dose of indomethacin caused a small decrease (18-32%) in PG at 60 min. However, the effects of these agents on CBF were diverse. CBF increased after the administration of aspirin, decreased to almost the same extent after both low and high doses of indomethacin, and did not change after the administration of ibuprofen and naproxen. Cerebral metabolic rate for oxygen was increased by aspirin but was unaltered by the other drugs. The data suggest that PG may not play a critical role in the regulation of basal CBF in the newborn animal and that certain nonsteroidal antiinflammatory drugs may have additional actions unrelated to the inhibition of PG synthesis.     

Effect of the cyclo-oxygenase blocker ibuprofen on cerebral blood volume and cerebral blood flow during normocarbia and hypercarbia in newborn piglets

Indomethacin modifies baseline cerebral haemodynamics and metabolism, as well as vasomotor adaptive responses. However, the significance of arachidonic acid metabolites in the regulation of cerebral circulation remains unclear. A study was made of the effect of inhibition of the cyclo-oxygenase pathway on baseline cerebral haemodynamics and CO2-induced vasodilation using the more specific cyclo-oxygenase blocker ibuprofen in a neonatal pig model. Two methods were used: radiolabelled microspheres to measure cerebral blood flow and near infrared spectroscopy to calculate absolute changes in cerebral blood volume. The relationship between CO2-induced changes in these two haemodynamic parameters was evaluated. Fifteen newborn piglets <7 d old received an i.v. infusion of either ibuprofen (30 mg/kg) (IB group, n = 8) or saline (control group, n = 7). Cerebral blood flow and absolute changes in cerebral blood volume were measured while the piglets were breathing room air at baseline and 30 min after infusion of ibuprofen or saline, and 15 min and 30 min after inducing hypercarbia. Global and regional cerebral blood flow (ml/hg/min) and absolute changes in cerebral blood volume (ml/hg) did not vary between baseline and 30 min after infusion of ibuprofen or saline. During hypercarbia, global and regional cerebral blood flow and absolute changes in cerebral blood volume increased significantly in both the ibuprofen and control groups (p < 0.01). The mean percentage increases in blood flow and blood volume at each measurement were almost identical, with approximately 90% of the increase in both parameters occurring after 15 min of hypercarbia, then reaching a plateau. However, we found no agreement between cerebral blood flow changes and absolute changes in cerebral blood volume. We conclude that ibuprofen did not alter either baseline cerebral circulation or physiological CO2-induced vasodilation in newborn pigs. We speculate that hypercarbic cerebral vasodilation could be caused either by mediators other than the cyclo-oxygenase metabolites of arachidonic acid or by a direct effect on vessel walls.     

Pressure ventilation increases brain vascular prostacyclin production in newborn pigs

Using awake, chronically catheterized newborn pigs, we measured cerebral blood flow (CBF), net cerebral vascular 6-keto-prostaglandin F1 alpha production, and cerebral metabolic rate of oxygen (CMRO2) during hypercapnia and during hypercapnia at increased mean airway pressure (Paw), both before and after treatment with indomethacin. CBF nearly doubled during hypercapnia. The hypercapnia-induced cerebral hyperemia was maintained when Paw was increased from 3 +/- 2 to 16 +/- 4 cm H2O during hypercapnia. Sagittal sinus pressure increased in proportion to the increase in Paw, and cardiac output was unchanged. Net cerebral production of 6-keto-prostaglandin F1 alpha increased from 9 +/- 1 to 15 +/- 1 ng/min/100 g tissue during hypercapnia and increased dramatically to 57 +/- 1 ng/min/100 g when hypercapnia was coupled with an increase in Paw. CMRO2 was not changed by either hypercapnia or increased Paw. After indomethacin, CBF decreased and cerebral vasodilation to hypercapnia did not occur. After indomethacin, adding increased Paw during hypercapnia dropped CBF below baseline, adversely affecting CMRO2. These results suggest that cerebral hypercapnia hyperemia requires brain prostanoid production and that when Paw is increased during hypercapnia, the contribution of prostanoids to maintaining CBF is increased. Increasing ventilation pressure during hypercapnia in piglets pretreated with indomethacin compromises CBF sufficiently to reduce CMRO2.     

Ibuprofen versus continuous indomethacin in premature neonates with patent ductus arteriosus: is the difference in the mode of administration?

Ibuprofen has been proposed as a preferential alternative to indomethacin in treating patent ductus arteriosus (PDA), because it is purported to have less renal, mesenteric, and cerebral vasoconstrictive effects. However, short and long-term safety concerns regarding ibuprofen remain. Continuous slow infusion of indomethacin also eliminates peripheral vasoconstriction and may thus offer similar benefits to ibuprofen without safety concerns. In this study, our objective was to show that treating a PDA with continuous indomethacin is similar to ibuprofen in its effect on urine output, renal function, and blood flow velocities in the renal, superior mesenteric, and anterior cerebral arteries. Sixty four prematures with PDA were randomly, prospectively assigned to either treatment. PDA closure rates were similar (74 versus 59%; p = 0.123). Nine indomethacin-treated babies (29%) versus twelve ibuprofen babies (38%) underwent repeated therapy (p = 0.656). Two indomethacin and four ibuprofen infants required surgical ligation (p = 0.672). Serum creatinine, oliguria, estimated glomerular filtration rate, and fractional excretion of sodium were similar in both groups, as were blood flow velocity parameters in the vessels studied. There were no differences in necrotizing enterocolitis, BPD, intraventricular hemorrhage, and/or retinopathy of prematurity. In conclusion, PDA treatment with either continuous indomethacin infusion or ibuprofen was equally devoid of adverse renal effects and/or peripheral vasoconstrictive effects.     

Oxygen free radicals and the cerebral arteriolar response to group B streptococci.

We used a cranial window preparation to observe the effects of direct application of group B streptococci to the surface of the brain in the adult rat. Continuous exposure to group B streptococci at concentrations of 10(3) and 10(5) organisms/mL caused progressive dilation of surface (pial) cerebral arterioles that became statistically significant (p less than 0.05) after 2.5 h. These results were reproduced with heat-killed organisms at the same concentration, but not with a bacteria-free filtrate of the growth medium. In separate studies, we found that infusion of alkaline cerebrospinal fluid (pH = 7.8) into the window did not reverse vasodilation, suggesting that it was not due to progressive cerebrospinal fluid acidosis. A solution of nitroblue tetrazolium infused into the window at the end of a 3-h exposure to the organism was promptly reduced, suggesting the presence of oxygen free radicals. Treatment with i.v. polyethylene glycol-superoxide dismutase and polyethylene glycol-catalase in doses of 10,000 and 20,000 U/kg, respectively, was itself without effect on pial arterioles, but treatment with these compounds before exposure to group B streptococci eliminated the vasodilation. These data support a role for oxygen free radicals in the pathogenesis of pial arteriolar dysfunction induced by exposure to group B streptococci.     

The nitric oxide donor molsidomine prevents ischemia/reperfusion injury of the adult rat small intestine

It is suggested that gastrointestinal mucosal blood flow depends on a balanced release of vasoactive substances from the endothelium. The present study investigated the effects of molsidomine on the small intestine after ischemia-reperfusion (I/R) injury in four groups of 10 rats each composed: (1) SO, sham operation; (2) untreated I/R; (3) ML, I/R plus molsidomine pretreatment; (4) L-NAME, I/R plus N-omega-nitro-L-arginine methyl ester pretreatment. Intestinal ischemia for 45 min and reperfusion for 60 min were applied. Ileum specimens were obtained to determine the tissue level of malondialdehyde (MDA) and histologic changes. Mean MDA levels in the SO, untreated I/R, ML, and L-NAME groups were 95.60 +/- 2.59, 136.90 +/- 4.35, 121.10 +/- 3.38, and 137.40 +/- 4.42 nmol/g wet tissue, respectively. Although the MDA level in the ML group was higher than in the SO group ( P < 0.0001), it was significantly lower compared to the untreated I/R and L-NAME groups ( P < 0.0001, P < 0.0001). Mucosal injury scores (MIS) in groups 1-4 were 0.2 +/- 0.42, 3.9 +/- 0.73, 1.5 +/- 0.70, and 4.1 +/- 0.56, respectively. In group 3 the MIS was significantly lower than in groups 2 and 4 ( P < 0.0001, P < 0.0001). Molsidomine plays a role in attenuating reperfusion injury of the small intestine by depression of tissue MDA levels and MIS and regulates post-ischemic intestinal perfusion while restoring the intestinal microcirculatory blood flow and histologic injury.     

Postasphyxial increases in prostanoids in cerebrospinal fluid of piglets

The dilator stimuli that contribute to postasphyxial increases in cerebral blood flow in the neonate are unclear. To assess the possible role of cyclooxygenase products in these responses, we measured pial arteriolar diameter in six piglets and determined levels of prostaglandin (PG) E2 and 6-keto-PG F1 alpha (hydrolysis product of PGI2) in cerebrospinal fluid (CSF) bathing the parietal cortex during control conditions, after 4-10 min of complete respiratory arrest (asphyxia), and after 5-12 min of reventilation. Pial arterioles are important resistance vessels in the cerebral circulation. Baseline pial arteriolar diameter was 220 +/- 40 micron (mean +/- SEM) and increased to a maximum of 252 +/- 49 and 267 +/- 56 micron after asphyxia and reventilation, respectively. During control conditions, CSF PGE2 (n = 6) and 6-keto-PGF1 alpha (n = 4) levels were 1947 +/- 310 and 794 +/- 147 pg/ml, respectively. During asphyxia, CSF levels of PGE2 did not increase, whereas 6-keto-PGF1 alpha increased modestly. During reventilation, CSF PGE2 increased to 3576 +/- 499 pg/ml, and 6-keto-PGF1 alpha increased to 2846 +/- 123 pg/ml. In other experiments, we determined that these CSF levels of PGE2 and PGI2 (as 6-keto-PGF1 alpha) were within the vasodilator range for pial arterioles. We conclude that postasphyxial increases in pial arteriolar diameter are associated with a rise in CSF levels of dilator prostanoids.     

Increasing ventilation pressure increases cortical subarachnoid cerebrospinal fluid prostanoids in newborn pigs

This study examines the responses of pial arterioles and venules to increased mean airway pressure (P aw-) in newborn pigs. We further characterized the changes in cortical subarachnoid cerebrospinal fluid prostanoids with increased P aw-, both before and after cyclooxygenase inhibition with indomethacin. Eight chloralose anesthetized newborn pigs were equipped with closed cranial windows and ventilated with a conventional infant pressure-cycled respirator. Increasing P aw- from 3.2 +/- 0.3 cm water to 14.3 +/- 0.6 cm water did not change pial arteriole or venule diameters. Cerebrospinal fluid prostanoids (6-keto-PGF1 alpha, TxB2, PGE2, and PGF2 alpha), however, were increased reversibly (3- to 5-fold) by increasing P aw-. After indomethacin (5 mg/kg, intravenous) pial arterioles constricted approximately 15% with increased P aw-. These results suggest that increasing ventilation pressure increases brain prostanoid production. Prostanoids appear to inhibit vasoconstriction and may be important in maintaining cerebral blood flow during the stress of mechanical ventilation.     

Dexamethasone pretreatment attenuates cerebral vasodilative responses to hypercapnia and augments vasoconstrictive responses to hyperventilation in newborn pigs

In the perinatal period, glucocorticoids are frequently administered to enhance pulmonary maturity or prevent chronic lung disease of prematurity. Recently, it has been suggested that the perinatal exposure to glucocorticoids can be associated with unfavorable neurologic development. We studied the hypothesis that 24-h pretreatment with glucocorticoid might modify cerebrovascular responses to high and low partial arterial CO(2) tension in newborn animals in vivo. A closed cranial window was implanted over the left parietal cortex of 20 anesthetized ventilated newborn (<3 d old) pigs. The actual experiments were carried out in 15 pigs: eight pretreated with a total dose of 6 mg/kg of dexamethasone and seven controls. Five pigs were used for preliminary experiments as described in the text. Pial arteriolar diameters were measured during 1) baseline conditions (normocapnia), 2) hypercapnia induced by ventilating the animals with a gas mixture containing 10% CO(2), or 3) hyperventilation with resultant hypocapnia. Under these conditions, the concentrations of 6-keto-PGF(1alpha) in the CSF were measured in five experimental animals and six controls. In summary, the dexamethasone pretreatment 1) attenuated the hypercapnia-induced dilator responses of pial arterioles and prevented the hypercapnia-associated fall in mean arterial blood pressure; 2) caused moderate, although not statistically significant, diminution in 6-keto-PGF(1alpha) levels in the CSF during baseline; 3) blocked hypercapnia-induced elevation of 6-keto-PGF(1alpha); and 4) enhanced vasoconstrictive arteriolar responses to hyperventilation. We speculate that in the clinical setting, the dexamethasone effects may compromise the adjustments of global or regional cerebral blood flow to changing physiologic states in neonates.     

Total serum bilirubin levels during cyclooxygenase inhibitor treatment for patent ductus arteriosus in preterm infants

Aim: To determine whether ibuprofen use in VLBW infants is associated with increased serum bilirubin levels and impaired neurodevelopmental outcome at 2 years of age compared to indomethacin.
Methods: We retrospectively evaluated bilirubin data and outcome parameters of 178 VLBW infants treated with COX inhibitors for a haemodynamically relevant patent ductus arteriosus (PDA) between 1998 and 2003 in a single institution. In our department ibuprofen replaced indomethacin for PDA treatment in 2001, while clinical and echocardiagraphic criteria for the indication of PDA invention have remained unchanged.
Results: Ibuprofen and indomethacin therapy groups did not differ in their baseline clinical profile. Peak serum bilirubin concentration was 10.2 mg/dL in the ibuprofen group and 8.6 mg/dL in the indomethacin group (p < 0.01), while phototherapy duration did not differ. At 2 years of age neurodevelopmental outcome was similar in both groups. In a single case analysis, four cases of adverse neurodevelopmental outcome despite inconspicuous clinical course were identified in the ibuprofen group.
Conclusion: In VLBW infants with PDA, ibuprofen treatment was associated with higher bilirubin levels than indomethacin.     

Preservation of cerebrovascular tone and reactivity by sodium channel inhibition in experimental prolonged asphyxia in piglets

Sodium channels using cAMP as a second messenger play a role in the regulation of cerebral circulation and metabolism. Cerebrospinal fluid (CSF) cAMP levels have been shown to correlate with the degree and duration of hypoxic injury and outcome and to be an indicator of cerebral vascular reactivity. We hypothesize that sodium channel inhibition either before or at termination of experimental asphyxia will attenuate cerebrovascular alterations and maintain CSF cAMP levels. Three groups of piglets with closed cranial windows were studied: asphyxia or group 1 (n = 5) and two treatment groups. Pigs were treated with 50 mg/kg of sodium channel blocker before asphyxia (group 2, n = 6) and after the termination of asphyxia and start of reventilation (group 3, n = 6). Asphyxia was sustained over 60 min by ventilating piglets with 10% O2 gas mixture and decreasing minute ventilation followed by 60 min of reventilation with room air. Every 10 min, pial arterial diameters were measured, and CSF samples were collected for cAMP determination. Vascular reactivity to topically applied isoproterenol (10(-4) M) was evaluated 60 min after recovery. During asphyxia, cAMP levels in group 2 peaked and declined at a later time with mean values remaining significantly higher than those of groups 1 and 3. During reventilation, CSF cAMP concentrations were highest in group 3 and lowest in group 1. Pial arteriolar dilation occurred during asphyxia in all three groups but to a lesser degree in the pretreated group compared with groups 1 and 3. Pial arteriolar reactivity to isoproterenol postasphyxia was preserved in both groups 2 and 3. In summary, in newborn pigs, pretreatment with sodium channel blocker resulted in higher CSF cAMP levels and a lesser degree of pial arteriolar dilation during prolonged asphyxia. Pretreatment or treatment at reventilation restored vascular tone and reactivity.     

Increased constriction of the ductus arteriosus with combined administration of indomethacin and L-NAME in fetal rats

We studied age-related changes and the caliber of the ductus arteriosus (DA) after two-pathway inhibition of prostaglandin E(2) and nitric oxide (NO) by the combined administration of indomethacin, a cyclooxygenase inhibitor, and N(G)-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, in fetal rats. Pregnant rats from day 18 to 21 of gestation were used. They were administered indomethacin orally (3 mg/kg) 3 h before cesarean section, and then L-NAME (50 mg/kg) was injected intraperitoneally 3 h before the rats were killed. Using rapid-freezing and shaving methods, the caliber of the DA in fetal rats was measured. Compared with the indomethacin alone group, indomethacin plus L-NAME further constricted the DA after indomethacin and L-NAME were simultaneously administered 3 h before the rats were sacrificed. The extent of the final DA constriction was almost equal to the addition of each effect of indomethacin and L-NAME. We concluded that the magnitude of DA constriction following indomethacin plus L-NAME was due to the additive effects of these agents, suggesting a possible method to treat patent DA in premature infants.