The renal hemodynamic effects of ibuprofen in the newborn rabbit

In early childhood, nonsteroidal anti-inflammatory drugs are mainly used to either prevent or treat premature labor of the mother and patent ductus arteriosus of the newborn infant. The most frequently used prostaglandin-synthesis inhibitor is indomethacin. Fetuses exposed to indomethacin in utero have been born with renal developmental defects, and in both the unborn child and the term and premature newborn this drug may compromise renal glomerular function. The latter has in the past also been observed when i.v. indomethacin or i.v. acetylsalicylic acid (aspirin) were administered to newborn rabbits. The present experiments were designed to evaluate whether ibuprofen has less renal side effects than indomethacin, as claimed. Three groups of anesthetized, ventilated, normoxemic neonatal rabbits were infused with increasing doses of ibuprofen (0.02, 0.2, 2.0 mg/kg body weight) and the following renal parameters were measured: urine volume, urinary sodium excretion, GFR, and renal plasma flow. Renal blood flow, filtration fraction, and the renal vascular resistance were calculated according to standard formulae. Intravenous ibuprofen caused a dose-dependent, significant reduction in urine volume, GFR, and renal blood flow with a fall in filtration fraction in the animals receiving the highest dose of ibuprofen (2 mg/kg body weight). There was a very steep rise in renal vascular resistance. Urinary sodium excretion decreased. These experiments in neonatal rabbits clearly show that acute i.v. doses of ibuprofen also have significant renal hemodynamic and functional side effects, not less than seen previously with indomethacin.     

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.     

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.     

In vivo constriction of the ductus arteriosus by nonsteroidal antiinflammatory drugs in near-term and preterm fetal rats

Herein we report age differences of in vivo constriction of the fetal ductus arteriosus by nonsteroidal antiinflammatory drugs in near-term and preterm rats. Two potent nonsteroidal antiinflammatory drugs, indomethacin and flurbiprofen, were studied in preterm (19th and 20th day) and near-term (21st day) rats, whose gestational period was 21.5 days. The time course of fetal ductus constriction was studied on the 20th (preterm fetus) and the 21st (near-term fetus) days of gestation with indomethacin (1 mg/kg, 10 mg/kg) and flurbiprofen (10 mg/kg). In addition, 5 mg/kg of indomethacin was used on the 21st day. Maximal ductal constriction was noticed 8 h after administration. Constriction of the ductus was significantly weaker on the 20th day than on the 21st day in all three studies including indomethacin 1 mg/kg, 10 mg/kg, and flurbiprofen, 10 mg/kg. Dose-response curves were studied at 4 h following administration of indomethacin on the 19th, 20th, and 21st days, and flurbiprofen on the 20th and 21st days. With both drugs, the ductus constricted more vigorously on the 21st day than on the 20th or 19th day. These studies showed a weaker constrictive response of the ductus to nonsteroidal antiinflammatory drugs in the preterm fetus than in the near-term fetus. Twenty-four h after administration of indomethacin on the 20th day, the fetal ductus was dilated, although its plasma indomethacin concentration was high and comparable with that obtained 4 h after administration. These results show that the response of the fetal ductus to indomethacin decreased further at 24 h after administration to preterm rats.     

Acetazolamide induces indomethacin and ischaemia-sensitive pial arteriolar vasodilation in the piglet

AIM: Acetazolamide (AZD) produces cerebral vasodilation. The underlying mechanism is unclear, but it is assumed to be largely due to CO2 retention and acidosis. We tested if cerebrovascular effects of AZD were similar to hypercapnia in the newborn pig. METHODS: We used the closed cranial window/intravital microscopy technique to determine pial arteriolar diameters simultaneously with laser-Doppler flowmetry (LDF) to monitor cortical blood perfusion. Anaesthetized (Na-thiopenthal +alpha-chloralose), ventilated, 1-day-old instrumented piglets (n=38) were divided into five experimental groups: time control (n=11), indomethacin, ibuprofen, Nomega-nitro-L-arginine methyl ester (L-NAME) treatments (1, 30, 15 mg/kg, i.v., n=6, 6, 4, respectively), and global ischaemia/reperfusion (I/R, 10 min induced by elevated intracranial pressure, n=11). Responses to 5-10% inhaled CO2 were recorded before and after the treatments, and then in a similar manner to AZD (10-20 mg/kg, i.v.). RESULTS: Hypercapnia and AZD produced pial arteriolar vasodilation and increases in cortical perfusion. Consistent with previous data, hypercapnia-induced changes were abolished by indomethacin, unaltered by ibuprofen and L-NAME and were significantly attenuated after I/R. AZD-induced vasodilation was also sensitive to indomethacin and I/R and was unaltered by ibuprofen or L-NAME. CONCLUSION: The mechanism of AZD-induced vasodilation appears to be similar/identical to hypercapnia, and pial arteriolar diameter changes reflect changes in cortical perfusion.     

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.     

Effect of indomethacin on cerebral blood flow velocity of premature newborns

Using the Doppler technique, the effect of therapeutic doses of indomethacin on the cerebral blood flow velocity (CBFV) of anterior cerebral arteries was studied in 13 preterm infants with patent ductus arteriosus. The first intravenous injection of indomethacin (0.2 mg/kg, group 1, n = 10) induced a significant decrease in the area under the velocity curve at 15 min (-22%), which was sustained until 120 min (-28%, p less than 0.005). In contrast, no significant change in CBFV occurred after the third dose (group 2, n = 7). In both groups, capillary blood gases, mean arterial blood pressure, and heart rate remained stable throughout the study. In 5 mechanically ventilated infants, the increase in CBFV secondary to suctioning was significantly attenuated after the first dose of indomethacin (p less than 0.02) but not after the third (p = 0.56). Thus, an initial dose of indomethacin may attenuate CBFV increases secondary to clinical manipulations in the preterm newborn.     

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.     

Near-infrared spectroscopy measurement of oxygen extraction fraction and cerebral metabolic rate of oxygen in newborn piglets

Cerebral metabolic rate of oxygen (CMRO2), the rate at which O2 is consumed in the brain by metabolic processes, is one of the most useful measures of normal brain function. The present study investigated the use of near-infrared spectroscopy (NIRS) in the noninvasive measurement of O2 extraction fraction (OEF) and CMRO2 in the newborn piglet. Indomethacin, although used successfully to effect closure of patent ductus arteriosus in the preterm infant, is known to cause transient reductions in cerebral blood flow (CBF) in both infant and adult humans and pigs. As a test of the NIRS method, the present study also examined the effect of indomethacin-induced reductions in CBF on both OEF and CMRO2. CBF, OEF, and CMRO2 were assessed in 20 newborn piglets, 0.2-3.0 d old. Ten piglets received 0.2 mg/kg of indomethacin infused over 30 min; remaining piglets received saline infusion as control. CBF, OEF, and CMRO2 measurements were performed before infusion and at 30-min intervals for a period of 90 min post-infusion. Saline infusion elicited no response in CBF, OEF, or CMRO2. Immediately after indomethacin infusion, CBF decreased 18.1% below (p < 0.05) and OEF increased 26.2% above (p < 0.05) pre-infusion values, whereas CMRO2 showed no significant changes throughout the study. Both CBF and OEF returned to baseline within 60 min after infusion of indomethacin. The proficiency of NIRS in the measurement of OEF and CMRO2 was demonstrated through the observation of transient increases in OEF, which served to maintain CMRO2 during indomethacin-induced reductions in CBF.     

Severe anaphylactic reaction to ibuprofen in a child with recurrent urticaria

An acute anaphylactic reaction after a conventional antipyretic dose of ibuprofen was diagnosed in a child with allergic rhinitis, recurrent idiopathic urticaria, and nonimmunologic cross-reactive hypersensitivity to nonsteroidal antiinflammatory drugs and acetaminophen. The patient reported several previous, mild (isolated cutaneous) hypersensitivity reactions after exposure to acetaminophen or ibuprofen. There was no evidence of an underlying inflammatory disease except as described above. Patients with chronic or recurrent idiopathic urticaria and those with atopic disease represent groups at increased risk of nonsteroidal antiinflammatory drug hypersensitivity. Mild hypersensitivity reactions to acetaminophen and/or ibuprofen may precede subsequent, more-severe adverse reactions. Risks and benefits of continued use of nonsteroidal antiinflammatory drugs in these children should be carefully considered.     

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.     

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］     

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.     

Increased constriction of the ductus arteriosus with combined administration of indomethacin and betamethasone in fetal rats

To find a better treatment for patient ductus arteriosus of preterm infants, we studied the combined effect of indomethacin and betamethasone on the fetal ductus in rats. We used a rapid whole-body freezing technique, and the ratio of the inner diameter of the ductus to the main pulmonary artery, which was 1.0 in controls, was used as an index of constriction. Indices of ductal constriction 4 h after administration of indomethacin (1 mg/kg) alone, betamethasone (1 mg/kg) alone or in combination in near-term rats were 0.56 +/- 0.05 (mean +/- SEM), 0.76 +/- 0.06, and 0.17 +/- 0.03, respectively. In preterm rats too, a marked increase in fetal ductus constriction was observed with the combined administration of these two drugs. Study of the dose effect of betamethasone revealed that maximal effects were obtained with 1 mg/kg of betamethasone combined with indomethacin in both preterm and near-term fetal rats. Increased constriction of the fetal ductus with combination treatment persisted from 1 to 8 h after administration. Administration of betamethasone 24 h before the rat was killed did not augment constriction of the fetal ductus by indomethacin administered 4 h before they were killed. Fetal ductus constriction by sulindac, another nonsteroidal antiinflammatory drug with little inhibitory effect on renal function, also was augmented by combined use with betamethasone (1 mg/kg). In conclusion, ductal constriction was markedly increased by combined administration of indomethacin and betamethasone in near-term and preterm fetal rats.     

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.     

Mechanisms of adrenomedullin-induced increase of pulmonary blood flow in fetal sheep

Mechanisms of adrenomedullin-induced increases in fetal pulmonary blood flow were examined in 19 near-term fetal sheep using four key blocker drugs: nitric oxide synthase inhibitor (N(omega)-nitro-L-arginine), calcitonin gene-related peptide (CGRP) receptor blocker, ATP-dependent potassium (K(ATP)) channel blocker (glibenclamide), and cyclooxygenase inhibitor (indomethacin). Catheters were inserted into the left pulmonary artery and superior vena cava to administer drugs and into the main pulmonary and carotid arteries to measure pressures and heart rate. An ultrasonic flow transducer was placed around the left pulmonary artery to measure flow continuously. Adrenomedullin (mean 1.06 microg/kg) was injected into the left pulmonary artery before and after infusion of N(omega)-nitro-L-arginine (mean 96.5 mg/kg, n = 6), glibenclamide (mean 11.8 mg/kg, n = 6), CGRP receptor blocker (mean 312.0 microg/kg, n = 6), and indomethacin (mean 1.7 mg/kg, n = 8). Blockade was confirmed by appropriate agonist injection. The adrenomedullin-induced response in left pulmonary artery blood flow was inhibited by N(omega)-nitro-L-arginine (inhibition rate 99%) and significantly attenuated by glibenclamide (inhibition rate 44%); however, no significant changes were found with CGRP receptor blocker or indomethacin (inhibition rate 0 and 17%, respectively). The responses of the main pulmonary and carotid arterial pressures were similarly affected by those blockers. Our data suggest that in the fetal pulmonary circulation, the adrenomedullin-induced increase in pulmonary blood flow depends largely on nitric oxide release and partly on K(ATP) channel activation, and does not involve the CGRP receptor or a cyclooxygenase-mediated mechanism.     

Effect of phenobarbital on cerebral blood flow in the newborn piglet under stress

Heart rate, cardiac output, mean arterial blood pressure (MABP), and cerebral blood flow (CBF) were measured in 12 newborn piglets (6 controls and 6 pretreated with 20 mg/kg phenobarbital), under two different stresses: pain stimulation and intravenous injection of 2.5 mg/kg phenylephrine. Phenobarbital prevented pain-induced tachycardia (p less than 0.05 versus controls) but failed to prevent hemodynamic changes induced by phenylephrine. CBF remained relatively constant throughout the study. A better correlation between cerebral vascular resistance and MABP was noted in the phenobarbital group (r = 0.58, p less than 0.01) than in the controls (r = 0.15, p = NS), suggesting that phenobarbital potentiates the vasoconstrictor effect of catecholamines.     

Ibuprofen suspension in the treatment of juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group

Ninety-two children with juvenile rheumatoid arthritis were randomly assigned to treatment in a multicenter, double-blind, 12-week trial designed to compare the efficacy and safety of a liquid formulation of ibuprofen at a dosage of 30 to 40 mg/kg/day versus those of aspirin at a dosage of 60 to 80 mg/kg/day. No significant intergroup differences in response rates or in the amount of improvement in articular indexes of disease activity were observed. More children treated with aspirin discontinued treatment early because of adverse reactions. After this trial, 84 additional patients with juvenile rheumatoid arthritis entered a 24-week, multidose (30, 40, and 50 mg/kg/day), open trial of ibuprofen suspension. Favorable response rates for the three groups were similar, and continued improvement was observed throughout the 24-week period. A dose-response relationship was observed with respect to adverse reactions of the upper gastrointestinal tract. We conclude that ibuprofen suspension is an effective nonsteroidal antiinflammatory drug and that its tolerability in children is acceptable.     

The effect of phenobarbital on cerebral blood flow in newborn infants with foetal distress

The effect of phenobarbital on cerebral blood flow (CBF) was investigated by the intravenous Xenon¹³³ clearance technique in seven term newborn infants with signs of mild to moderate hypoxic ischaemic encephalopathy, all on sustained spontaneous ventilation. Phenobarbital treatment had no significant effect on CBF 60 min after loading dosage (20mg/kg i.v.). Likewise, no significant change in mean arterial blood pressure, heart rate or transcutaneous gas tensions was observed. Though slight changes in CBF of short duration cannot be excluded, conventional dosage of phenobarbital to term newborn infants with foetal distress apparently imposes no risk of cerebrovascular damage.     

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.