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.     

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.     

Blood withdrawal and infusion via umbilical catheters: effect on cerebral perfusion and influence of ibuprofen

Withdrawal and infusion of blood via umbilical catheters can affect cerebral blood flow in preterm infants. We compared the effects on cerebral perfusion of 3 ml/kg blood withdrawal and infusion via umbilical arterial (UAC) and venous (UVC) catheters in 16 infants < or =32 weeks gestation, age <24 h, on mechanical ventilation. Near infrared spectroscopy was used to monitor changes in cerebral oxy- and deoxyhemoglobin, total cerebral hemoglobin (an index of cerebral blood volume; CBV) and HbD (an index of cerebral intravascular oxygenation). In 10 infants the study was repeated 1 h after intravenous administration of 10 mg/kg ibuprofen as prophylaxis against PDA. Withdrawal and infusion via the UVC caused significant MABP and concordant HbD and CBV changes. Smaller modifications were seen following blood withdrawal and infusion via the UAC. Ibuprofen attenuated cerebral hemodynamic changes associated with withdrawal, but not infusion, from UAC and UVC.     

Pain control: non-steroidal anti-inflammatory agents

The non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol) are the most common analgesic drugs used in neonates and infants despite limited pharmacodynamic data. Both drugs act through inhibition of cyclooxygenase enzymes. Neonatal acetaminophen clearance is reduced in premature neonates (0.7 L h(-1) x 70 kg(-1)) and increases to 5 L h(-1) x 70 kg(-1) at term (40% adult rates); adult rates are reached within the first year of life; NSAID clearance follows similar trends. Volume of distribution is increased in the neonatal period. Dosing of both drug groups is tempered by concerns about toxicity. Acetaminophen hepatotoxicity is less common in neonates than in older children and adults, possibly due to reduced oxidative enzyme activity (e.g. CYP 2E1). Data concerning NSAID adverse effects in the neonatal period are few. Renal function is reduced 20% after NSAID use for patent ductus arteriosus closure in premature neonates and there is no increased frequency of intraventricular haemorrhage. No significant difference in the change in cerebral blood volume, change in cerebral blood flow, or tissue oxygenation index was found between administration of ibuprofen or placebo in neonates. Future studies should define concentration-response relationships for these drugs that are age and pathology specific.     

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.     

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.     

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.     

Interactions of ibuprofen with influenza infection and hyperammonemia in an animal model of Reye's syndrome.

We have previously reported that a single meal of an arginine-free diet rapidly induces hyperammonemia in young ferrets and that aspirin administration in conjunction with influenza B infection and arginine-free diet results in clinical and biochemical alterations consistent with Reye's syndrome. The objective of the present study was to test whether ibuprofen administration, either alone or in combination with influenza infection and arginine-free diet, produces a similar effect. Two-mo-old ferrets were inoculated intranasally with influenza B virus, treated with therapeutic doses of ibuprofen, and fed a single meal of an arginine-free diet. Arginine-free diet caused a significant increase in plasma ammonia and a small increase in plasma aspartate aminotransferase activity. All ferrets fed an arginine-free diet recovered within 6 to 7 h after ingesting the diet. Ibuprofen treatment, either solely or in combination with influenza infection, did not produce significant change in the plasma levels of aspartate or ornithine aminotransferase activities. A combination of ibuprofen treatment, influenza infection, and arginine-free diet caused a significant increase in the mortality and plasma ammonia levels. Plasma aspartate aminotransferase and ornithine carbamyl transferase activities were elevated, and liver ornithine carbamyl transferase activity was decreased. However, other mitochondrial enzymes such as ornithine aminotransferase were not altered, whereas the activity of cytoplasmic enzymes such as arginase were decreased. These results suggest that ibuprofen administration resulted in generalized hepatopathy rather than specific mitochondrial injury and Reye's syndrome-like changes associated with aspirin in our previous model.     

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 acetazolamide on cerebral blood flow velocity and CO2 elimination in normotensive and hypotensive newborn piglets

The objectives of this study were to measure the effect of acetazolamide on cerebral circulation, pulmonary elimination of CO2, and cerebrovascular response to hypotension in newborn piglets. Eighteen anaesthetized newborn piglets were studied. A fontanelle was surgically created and the cerebral blood flow velocity (CBFV) in an intracranial artery measured by a computerized Doppler system. In 8 piglets, 30 ml/kg of blood was removed to produce hypotension before the administration of acetazolamide. Acetazolamide (50 mg/kg i.v.) given to normotensive piglets consistently produced a large increase in CBFV (median 45% by 5 min) with no change in mean arterial blood pressure or heart rate. The rise in CBFV was negatively correlated with the starting partial pressure of CO2 in arterial blood. Within 1 min of administration of acetazolamide, the end-expiratory CO2 pressure started to fall (mean fall 1.4 kPa), and the partial pressure of CO2 in the arterial blood started to rise (mean rise 2.0 kPa), despite the controlled ventilation being unchanged. Acetazolamide had no effect on CBFV in the hypotensive piglet. It seems likely that acetazolamide produces cerebral vasodilatation by inhibiting the elimination of CO2. In hypotension, there is maximal cerebral vasodilatation, and acetazolamide cannot increase CBFV further. The interference of acetazolamide with CO2 elimination could seriously limit its use in the treatment of hydrocephalus in preterm infants.     

Cerebral vasoreactivity to arterial carbon dioxide tension in preterm infants: the effect of ibuprofen.

Cerebral vasoreactivity to CO(2), calculated by linear regression of total cerebral hemoglobin, measured by near infrared spectroscopy, and corresponding PaCO(2), in infants <32 weeks' gestation, was found to be unaffected by the administration of ibuprofen, which was given on the first postnatal day as prophylaxis against patent ductus arteriosus.     

Effects of repeated indomethacin administration on cerebral oxygenation and haemodynamics in preterm infants: Combined near infrared spectrophotometry and Doppler ultrasound study

The objectives of this study were to evaluate the effect of repeated indomethacin administration on cerebral oxygenation in relation to changes in cerebral blood flow velocity (CBFV) and other relevant physiological variables. Fourteen preterm infants with patent ductus arteriosus were studied during three subsequent indomethacin bolus administrations with intervals of 12 and 24 h. Changes in concentration of oxyhaemoglobin (cO₂Hb), deoxyhaemoglobin (cHHb) and oxidized cytochrome aa₃ (cCyt.aa₃) in cerebral tissue and changes in cerebral blood volume (CBV) were measured by near infrared spectrophotometry; changes in mean CBFV in the internal carotid artery were measured by pulsed Doppler ultrasound. Simultaneously heart rate, transcutaneouspO₂ andpCO₂, arterial O₂ saturation and blood pressure were measured. All variables were continuously recorded until 60 min after indomethacin administration. Within 5 min after each indomethacin administration, significant decreases in CBFV, CBV and cO₂Hb and cCyt.aa₃ were observed which persisted for at least 60 min, while cHHb increased or did not change at all. There were no changes in the other variables recorded. These data demonstrate that indomethacin administration is accompanied by a reduction in cerebral tissue oxygenation due to decreased cerebral blood flow. Therefore, low arterial oxygen content, either caused by low arterial O₂ saturation or by low haemoglobin concentration, may be a contraindication for indomethacin treatment in preterm infants.     

Effects of hydralazine on cardiac performance in infants receiving extracorporeal membrane oxygenation

To determine the effects of afterload reduction on cardiac performance during partial cardiopulmonary bypass, we administered hydralazine to infants who were either normotensive (n = 11) or hypertensive (n = 12) 1 hour after extracorporeal membrane oxygenation (ECMO) was begun. Load-dependent and load-independent measures of cardiac performance and indexes of cerebral blood flow were measured. Infants in both groups had similar weight, heart rate, blood pressure, and inotropic support before ECMO. Shortening fraction was normal in both groups before ECMO (47 +/- 11% vs 49 +/- 10%; p greater than or equal to 0.05), decreased during ECMO (31 +/- 18% vs 39 +/- 12%; p greater than or equal to 0.05), and did not change after administration of hydralazine (31 +/- 12% vs 37 +/- 8%; p greater than or equal to 0.05). Cardiac output was normal in both groups before ECMO (176 +/- 71 vs 157 +/- 72 ml/kg per minute; p greater than or equal to 0.05), decreased during ECMO (120 +/- 80 vs 105 +/- 64 ml/kg per minute; p greater than or equal to 0.05), and did not change after hydralazine administration. Velocity of circumferential fiber shortening, an index of contractility (circumference per second), was normal in both groups before ECMO (1.96 +/- 0.57 vs 1.90 +/- 0.43 circ/sec; p greater than or equal to 0.05), decreased during ECMO (1.18 +/- 0.83 vs 1.56 +/- 0.58 circ/sec; p greater than or equal to 0.05), and did not change after hydralazine administration. The relationship between velocity of circumferential fiber shortening and wall stress was similar in both groups before ECMO, during ECMO, and after hydralazine administration. The cerebral blood flow resistance index was similar in both groups before ECMO (0.70 +/- 0.16 vs 0.70 +/- 0.20; p greater than or equal to 0.05), decreased during ECMO (0.45 +/- 0.13 vs 0.43 +/- 0.09; p greater than or equal to 0.05), and did not change after administration of hydralazine. We conclude that hydralazine does not improve cardiac performance during ECMO.     

Effects of ibuprofen and hypoxia on neutrophil apoptosis in neonates

BACKGROUND: Ibuprofen is a cyclooxygenase inhibitor that is effective in treating patent ductus arteriosus in preterm infants. However, recent trials have suggested that it may increase the risk of developing necrotizing enterocolitis and chronic lung disease. Apoptosis of neutrophils is impaired in newborns, leading to reduced clearance of activated cells and possibly contributing to the susceptibility of infants to these inflammatory diseases. OBJECTIVES: In the present studies, we investigated the hypothesis that ibuprofen reduces neonatal neutrophil apoptosis in the setting of hypoxia or lipopolysaccharide (LPS). METHODS: Neutrophils and peripheral blood mononuclear cells were isolated from adult and cord blood and cultured in the presence or absence of ibuprofen (1.5 mM), hypoxia (<5% O2), and bacterial LPS (100 ng/ml). Apoptosis was quantified by measuring binding of FITC-Annexin V using flow cytometry. Cytokine concentrations in cell supernatants were measured by ELISA. RESULTS: After 24 h, 20% of adult and 14% of neonatal neutrophils were apoptotic. Apoptosis was reduced by hypoxia in both adult and neonatal cells. Ibuprofen further reduced neutrophil apoptosis, but only when the cells were cultured in the presence of mixed leukocytes. This suggests that the effects of ibuprofen on apoptosis are dependent on soluble products secreted by peripheral blood mononuclear cells. We found that production of tumor necrosis factor (TNF)-alpha by neonatal leukocytes was significantly increased by ibuprofen, and was further increased following exposure to ibuprofen in the presence of LPS and hypoxia. In contrast, production of macrophage inflammatory protein (MIP)-1alpha was not affected by treatment with ibuprofen, and ibuprofen blocked induction of this chemokine by LPS. CONCLUSION: We conclude that the net effect of ibuprofen on neutrophils is antiapoptotic, especially in the presence of hypoxia or LPS. This effect may be mediated, in part, by increased production of TNF-alpha by peripheral blood mononuclear cells. These data suggest that treatment of infants with ibuprofen, in the presence of infection and/or tissue hypoperfusion/hypoxia, may contribute to the development of inflammatory diseases.     

Randomized trial examining cerebral haemodynamics following artificial or animal surfactant

To determine the effects of animal and artificial surfactants on cerebral haemodynamics, 20 premature babies receiving mechanical ventilation were randomized to receive Curosurf or Exosurf surfactant. Anterior cerebral artery blood flow velocity (CABFV) was measured using Doppler ultrasound before and up to 2 h after treatment. Following animal surfactant there was a rapid reduction in CABFV (median -36%, range -43% to +8%, p < 0:01), whereas artificial surfactant resulted in a slower rise which was less marked (median +20%, range -7% to +62%, p < 0:05). There were no significant changes in blood pressure. Two hours after administration, the oxygenation index (OI) improved significantly only in babies receiving animal surfactant. In this group there was a significant association between the change in CABFV at 1 min and the change in OI at 2 h ( r = 0:66, p < 0:05). Animal surfactant produces rapid improvements in ventilation which are associated with marked alterations in cerebral haemodynamics.     

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.     

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.     

Cerebral blood flow and metabolism following pancuronium bromide in newborn lambs

The purpose of this study was to evaluate cerebral blood flow and metabolism following pancuronium bromide paralysis in healthy newborn lambs. Cerebral blood flow and cerebral metabolic rate for O2 and glucose were measured along with blood pressure and blood gases before and again at 15 and 60 min following pancuronium paralysis in seven newborn lambs. Pancuronium bromide paralysis had no effect on any of these parameters either at 15 or 60 min of paralysis. Total cerebral blood flow, cerebral metabolic rate for O2, and cerebral metabolic rate for glucose were 87 +/- 6 ml/min/100 g, 258 +/- 10 mumol O2/min/100 g, and 53 +/- 10 mmol glucose/min/100 g, respectively. Neither was any change in regional cerebral blood flow noted. In spite of being connected immediately to the ventilator, however, some animals experienced a transient increase (average = 32%) in blood pressure, that was not associated with an increase in end tidal CO2. The data suggest that pancuronium paralysis in healthy awake newborn lambs does not lead to any alteration in cerebral blood flow or metabolism.     

Comparing efficacy and tolerability of ibuprofen and paracetamol in fever

The purpose of this study was to compare antipyretic activity and evaluate tolerability of ibuprofen and paracetamol suspension in the treatment of febrile children. It was designed as a double blind, parallel group, multiple dose study comparing ibuprofen (20 mg/kg/24 hours) with paracetamol (50 mg/kg/24 hours) given at six hourly intervals for a maximum of 12 doses. Children on paediatric wards between the ages of 0.2 and 12 years, with fever as defined by an axillary temperature > or = 37.5 degrees C, were included. The main outcome measures were: change in axillary temperature; palatability of medication; changes in irritability and clinical condition; overall efficacy at the end of treatment; and number and nature of adverse events. The mean temperature change from baseline at four hours was -1.8 degrees C and -1.6 degrees C in ibuprofen and paracetamol groups respectively. In both groups: median palatability score was 'no reaction'; median irritability score at end point was 'not irritable'; median score for change in clinical condition was 'improved'; and median score for overall efficacy was 'good effect'. The proportion of patients experiencing adverse events was similar in both groups, the majority of events having doubtful or no relationship to therapy and being mild in severity. In conclusion, ibuprofen suspension was as effective and well tolerated as paracetamol in treatment of fever in young children.