Wireless multichannel electroencephalography in the newborn.

OBJECTIVES: First, to determine the feasibility of an ultra-compact wireless device (microEEG) to obtain multichannel electroencephalographic (EEG) recording in the Neonatal Intensive Care Unit (NICU). Second, to identify problem areas in order to improve wireless EEG performance. STUDY DESIGN: 28 subjects (gestational age 24-30 weeks, postnatal age <30 days) were recruited at 2 sites as part of an ongoing study of neonatal apnea and wireless EEG. Infants underwent 8-9 hour EEG recordings every 2-4 weeks using an electrode cap (ANT-Neuro) connected to the wireless EEG device (Bio-Signal Group). A 23 electrode configuration was used incorporating the International 10-20 System. The device transmitted recordings wirelessly to a laptop computer for bedside assessment. The recordings were assessed by a pediatric neurophysiologist for interpretability. RESULTS: A total of 84 EEGs were recorded from 28 neonates. 61 EEG studies were obtained in infants prior to 35 weeks corrected gestational age (CGA). NICU staff placed all electrode caps and initiated all recordings. Of these recordings 6 (10%) were uninterpretable due to artifacts and one study could not be accessed. The remaining 54 (89%) EEG recordings were acceptable for clinical review and interpretation by a pediatric neurophysiologist. Of the recordings obtained at 35 weeks corrected gestational age or later only 11 out of 23 (48%) were interpretable. CONCLUSIONS: Wireless EEG devices can provide practical, continuous, multichannel EEG monitoring in preterm neonates. Their small size and ease of use could overcome obstacles associated with EEG recording and interpretation in the NICU.

Refractory neonatal candidemia and high-dose micafungin pharmacotherapy.

OBJECTIVE: Preterm neonates with candidemia frequently have persistently positive blood cultures, despite the use of conventional antifungal therapy. Our institutional treatment protocol for invasive candidiasis incorporates lipid complex amphotericin B as initial therapy with the sequential addition of fluconazole and high-dose micafungin (10 mg kg(-1)) every 48 to 72 h, if cultures from a sterile site remain positive. Our study objectives were to compare the clinical profiles and outcomes of preterm neonates with candidemia that responded to or were refractory to conventional antifungals. We further evaluate the clinical efficacy of high-dose micafungin pharmacotherapy of refractory candidemia. STUDY DESIGN: A chart review was performed on preterm infants (n=29) with invasive candidiasis and demographic, microbiologic and outcome data abstracted. Proportions and continuous variables were compared between the groups using Fisher's exact two-tailed test and t-test. RESULT: The refractory (n=19) candidemia and early responder (n=10) groups had comparable mean (+/-s.d.) gestation, 27(+/-3.1) vs 27.8 (+/-2.7) weeks. The refractory group was administered antibiotics for a longer duration, 14.5 (+/-10.3) vs 7.1 (+/-5) days, had a preponderance of non-albicans infections, 11 (57.9%) vs 1 (10%) and were on enteral feeds > 20 ml kg(-1) day(-1) significantly less often (21 vs 70%). Mortality was significantly higher (53 vs 20%) and fungal clearance rates lower (63.1 vs 90%), with a longer duration to clearance in the group with refractory candidemia. Mean aspartate aminotransferase (AST) showed a statistically significant increase following micafungin treatment, although clinical significance remains unclear. CONCLUSION: Candidemia refractory to conventional antifungals is associated with prolonged antibiotic use, lack of enteral nutritive feeds and non-albicans infection. Despite high-dose micafungin pharmacotherapy in combination with conventional antifungals, infants with refractory candidemia had high mortality and poor fungal clearance.

Effect of ibuprofen L-lysinate on bilirubin binding to albumin as measured by saturation index and horseradish peroxidase assays.

OBJECTIVE: To demonstrate, in vitro, the influence of increasing ibuprofen (IBU) concentration on bilirubin-albumin (B-A) binding. STUDY DESIGN: The influence of IBU on B-A binding was measured by saturation index and horseradish peroxidase assays. B-A solutions were prepared at B:A ratios of 0.5, 1.0, 1.5 and 2.0 and bilirubin concentrations of 5 and 10 mg per 100 ml. Drug concentrations used were 142.5, 200 and 285 mg l(-1) for IBU and 100 and 200 mg l(-1) for acetyl salicylic acid (ASA). Similar tests were performed on premature newborn sera with bilirubin concentrations of 5 to 10 mg per 100 ml. RESULT: By the saturation index test, significant displacement of bilirubin from albumin with IBU was demonstrated only on B-A solution with high B:A ratio of 2.0 and IBU concentration of 285 mg l(-1) and was less as compared to ASA. No displacement was observed in the sera of jaundiced neonates. By the horseradish peroxidase assay using B-A solutions, free bilirubin was significantly increased at (1) increasing concentrations of bilirubin in solution and (2) increasing B:A ratios in a solution containing 5 mg per 100 ml of bilirubin. In the sera of jaundiced neonates, significantly higher free bilirubin concentrations were observed when IBU was added to serum with bilirubin concentration of 10 mg per 100 ml as compared to 5 mg per 100 ml (0.062+/-0.004 versus 0.026+/-0.005, P<0.001 by Student's t-test). CONCLUSION: Displacement of bilirubin was demonstrated only at high IBU concentration and high B:A ratio. However, free bilirubin levels were not shown to increase with increasing IBU concentration.

Neonatal facial coding system scores and spectral characteristics of infant crying during newborn circumcision.

OBJECTIVE: To determine the relations between Neonatal Facial Coding System (NFCS) scores and measures of infant crying during newborn circumcision. METHODS: Video and audio recordings were made of infant facial activity and cry sounds, respectively, during the lysis phase of circumcisions of 44 healthy term males (<3 d of age). All infants received topical analgesia before circumcision. NFCS scores were determined by blinded assistant from video recordings of facial activity. Measures of infant crying were determined via spectrum analysis of audio recordings by a blinded, independent researcher. Pearson product-moment correlations were used to examine relationship between NFCS scores and measures of crying. Principal component factor analysis detected dimensions underlying related measures of crying. Factor scores from a factor analysis were used in stepwise linear regression to predict NFCS scores. RESULTS: Higher NFCS scores correlated with lower peak fundamental frequency of crying (P<0.01) and with higher amplitudes of crying at peak fundamental frequency and dominant frequency and in overall cry sample (P<0.01). The factor analysis showed 3 significant orthogonal dimensions underlying measures of crying: Power and Velocity (amplitude and rapidity), Pitch of Crying (frequency characteristics), and Infant Arousal (turbulence and intensity) accounting for 42.3%, 17.8%, and 14.6% of variance, respectively. A regression analysis showed all 3 factor scores accounted for significant and separate portions of variance (P<0.001). The best predictor of NFCS score was Power and Velocity (P<0.002), followed by Infant Arousal (P<0.002), and Pitch of Crying (P<0.007). DISCUSSION: These data provide some of the first known evidence linking specific measures of infant crying with an independent, validated measure of pain.

PGE2/TXB2 imbalance in neonatal hypoxemic respiratory failure.

BACKGROUND: An imbalance of vaso-constrictor and -dilator mediators has been implicated in the pathogenesis of the pulmonary hypertension accompanying neonatal hypoxemic respiratory failure (NHRF). AIM: To characterize plasma PGE2, TXB2 and their ratio in normal newborns and in those with NHRF. METHODS: Twenty newborns with NHRF received inhaled PGE1 (IPGE1) by jet nebulizer in doses of 25, 50, 150 and 300 ng/kg/min followed by weaning. Blood for PGE2 and TXB2 assay using EIA was available in 8 neonates with NHRF prior to IPGE1. Umbilical cord arterial samples were also obtained at delivery from 10 normal newborns to serve as controls. RESULTS: Compared to normal newborns, those with NHRF had significantly lower PGE2/TXB2 ratios after controlling for preterm gestation (< 37 weeks) and postnatal age (p < 0.05). Notably, all subjects except one in the NHRF group had a value of < 1.0 (range 0.1-1.2) compared to a value of > 1.0 in all subjects in the Control group (range 1.1-5.2). CONCLUSIONS: Lower PGE2/TXB2 ratio in subjects with NHRF compared with controls reflects a predominance of vaso-constrictor activity in these patients as the basis of pulmonary hypertension. Plasma PGE2/TXB2 ratio may have important implications for the diagnosis and treatment of NHRF.

Systematic review: intravenous Ibuprofen in preterm newborns.

Ibuprofen, a nonsteroidal antiinflammatory drug, widely used as antipyretic, antiinflammatory, and analgesic agent and for therapy of arthritis, exerts a dose-dependent constriction of the ductus arteriosus in newborn lambs. Two intravenous preparations, namely ibuprofen lysine and ibuprofen-THAM, have been studied in preterm newborns with patent ductus arteriosus. Clinical trials have compared IV ibuprofen to placebo, or to indomethacin. Pharmacodynamic effects of this drug before and after its administration have also been evaluated. Compared with placebo, IV ibuprofen effectively closed PDA with minimal effect on renal function. One study using intravenous ibuprofen-THAM showed decreased renal function and increased risk of NEC and PPHN. Compared with indomethacin, IV ibuprofen lysine exerted similar efficacy (75% to 93% closure). However, indomethacin increased abnormal renal function and decreased mesenteric and cerebral blood flow and bio-energetics. Two clinical trials showed that ibuprofen did not reduce the incidence of intraventricular hemorrhage compared with placebo. The drug has prolonged elimination (plasma half-life = ca 23 hours), suggesting that once daily dosing is appropriate. Dose finding studies indicate that a starting dose of 10 mg/kg followed by 5 mg/kg/d for 2 more days provides optimal efficacy with the least adverse effects. Neonatal data on ibuprofen and indomethacin indicate that, on the first day of life when IVH prevention is desired, indomethacin and not ibuprofen should be used since ibuprofen has no effect on IVH risk. On or after the second day of postnatal life, when early or therapeutic PDA closure is needed, ibuprofen and not indomethacin is probably the first choice due to its better adverse event profile.

Analgesia and sedation during mechanical ventilation in neonates.

BACKGROUND: Endotracheal intubation and mechanical ventilation are major components of routine intensive care for very low birth weight newborns and sick full-term newborns. These procedures are associated with physiologic, biochemical, and clinical responses indicating pain and stress in the newborn. Most neonates receive some form of analgesia and sedation during mechanical ventilation, although there are marked variations in clinical practice. Clinical guidelines for pharmacologic analgesia and sedation in newborns based on robust scientific data are lacking, as are measures of clinical efficacy. OBJECTIVE: This article represents a preliminary attempt to develop a scientific rationale for analgesia sedation in mechanically ventilated newborns based on a systematic analysis of published clinical trials. METHODS: The current literature was reviewed with regard to the use of opioids (fentanyl, morphine, diamorphine), sedative-hypnotics (midazolam), nonsteroidal anti-inflammatory drugs (ibuprofen, indomethacin), and acetaminophen in ventilated neonates. Original meta-analyses were conducted that collated the data from randomized clinical comparisons of morphine or fentanyl with placebo, or morphine with fentanyl. RESULTS: The results of randomized trials comparing fentanyl, morphine, or midazolam with placebo, and fentanyl with morphine were inconclusive because of small sample sizes. Meta-analyses of the randomized controlled trials indicated that morphine and fentanyl can reduce behavioral and physiologic measures of pain and stress in mechanically ventilated preterm neonates but may prolong the duration of ventilation or produce other adverse effects. Randomized trials of midazolam compared with placebo reported significant adverse effects (P < 0.05) and no apparent clinical benefit; the findings of a meta-analysis suggest that there are insufficient data to justify use of IV midazolam for sedation in ventilated neonates. CONCLUSIONS: Despite ongoing research in this area, huge gaps in our knowledge remain. Well-designed and adequately powered clinical trials are needed to establish the safety, efficacy, and short- and long-term outcomes of analgesia and sedation in the mechanically ventilated newborn.

Lidocaine 4% cream compared with lidocaine 2.5% and prilocaine 2.5% or dorsal penile block for circumcision.

This study evaluated the efficacy and safety of lidocaine 4% cream (LMX4), compared with lidocaine 2.5% and prilocaine 2.5% (EMLA) or dorsal penile block (DPNB) for analgesia during circumcision. Healthy, term males (n = 54), younger than 1 week old undergoing circumcision were randomly assigned to open-label pretreatment with LMX4, EMLA, or DPNB. Heart rate (HR; beats per minute [bpm]), respiratory rate (RR; breaths/minute), and arterial oxygen saturation as measured by pulse oximetry (Sp O2; %) were monitored at baseline, and during drug application, circumcision, and recovery. Mean differences were compared using the general linear model. At the end of drug application, mean HR for infants receiving LMX4 (146 bpm; standard error of mean [SEM], 8.0 bpm) was lower than that for DPNB (176 bpm; SEM, 8.3 bpm; p < 0.05). No significant difference in mean HR was observed between treatments during circumcision. Mean RR was higher during circumcision for EMLA compared with LMX4 (p < 0.05) and DPNB (p < 0.05). At lysis, mean RR was significantly lower in DPNB than LMX4 and EMLA. The number of Sp O2 samples was too small for comparison. Three infants (one receiving LMX4 and two receiving EMLA) experienced local reactions (p = 0.54). No adverse effects were observed with DPNB. No difference in analgesic efficacy was observed between treatments according to HR. Differences in RR may reflect a varying level of analgesia. The safety profile was similar for all treatments. LMX4 is an effective analgesic for newborn circumcision.

Management of infiltration injury in neonates using duoderm hydroactive gel.

Neonates are at increased risk of injury from infiltration of intravenous fluids because of small vessel size and immature skin structure. Until recently, hyaluronidase injection was used to prevent tissue injury following the infiltration of intravenous solutions in neonates. The production of hyaluronidase injection was discontinued in 2001. The alternative, compounded hyaluronidase injection is not regulated by the U.S. Food and Drug Administration and is subject to variation in quality assurance practices. Amorphous hydrogels have been used as wound dressings for sloughy or necrotic wounds in a variety of clinical settings. Hydrogels facilitate autodebridement of the wound by rehydrating slough and enhancing the rate of autolysis. No adverse effects or increased infection rates have been associated with the use of hydrogel dressings. DuoDerm Hydroactive gel is a sterile, preservative-free, viscous, hydrating gel composed of natural hydrocolloids. We report our experience using DuoDerm Hydroactive gel for management of injury secondary to the infiltration of total parenteral nutrition solution and lipid emulsion in three neonates.

Pharmacogenomics and renal drug disposition in the newborn.

Genetic polymorphisms in the genes coding for drug metabolizing enzymes, drug transporters, and drug receptors are major determinants of an individual's response to drugs. The potential interactions of pharmacogenomics of renal drug transporters and drug receptors with renal drug disposition and the immature kidneys are briefly reviewed. Examples of gene polymorphisms seen in the RAAS (renin angiotensin system), beta-adrenergic receptors, dopamine receptors and cytochrome P450 and their potential clinical impact are discussed. The human newborn has deficient hepatic and renal drug metabolism and disposition. This immaturity in drug-handling capacity may potentially be superimposed to genetic polymorphisms determining drug metabolism and transport thereby substantially increasing interpatient variability in drug dose requirements and in drug responses in the newborn. Pharmacogenomics is a tool that can be used to individualize drug therapy in newborns to minimize adverse drug effects and to optimize efficacy.

Group B Streptococci and inducible nitric oxide synthase: modulation by nuclear factor kappa B and ibuprofen.

Group B Streptococci (GBS) neonatal infections cause a complex inflammatory process involving numerous biochemical mediators. Nitric Oxide (NO) is generated by many cell types in response to different inflammatory signals. Nuclear factor kappa B (NFkappaB) plays an important role in the inflammatory process and may induce a number of biochemical mediator genes, including the inducible nitric oxide synthase (iNOS). We tested the hypothesis that GBS induces iNOS gene expression through activation of NFkappaB. We also tested whether ibuprofen (IBU) will suppress iNOS expression by blocking NFkappaB activation. Cerebral microvascular endothelial cells isolated from newborn piglets were harvested for the determination of iNOS gene expression and activation of NFkappaB. GBS significantly induced iNOS mRNA expression (5- to 6-fold, P < .005) and iNOS protein (3- to 4-fold, P < .01) at 24 hours. DNA-NFkappaB binding activity was detected within 15 minutes of GBS treatment and reached a maximal effect at 3 hours. Treatment with IBU significantly suppressed GBS-induced iNOS mRNA expression at 24 hours, and NFkappaB activity at 3 hours, suggesting that suppression of GBS-induced iNOS mRNA expression by IBU occurs by blocking of NFkappaB activation. These data show that NFkappaB activation is an early step in the induction of iNOS gene expression by GBS and that this interaction may play a vital role in the pathogenesis of GBS neonatal infections.

Nitric oxide, prostaglandins, and impaired cerebral blood flow autoregulation in group B streptococcal neonatal meningitis.

Impaired autoregulation of cerebral blood flow (CBF) contributes to CNS damage during neonatal meningitis. We tested (i) the hypothesis that cerebrovascular autoregulation is impaired during early onset group B streptococcal (GBS) meningitis, (ii) whether this impairment is regulated by vasoactive mediators such as prostaglandins and (or) nitric oxide (NO), and (iii) whether this impairment is preventable by specific and (or) nonspecific inhibitors: dexamethasone, ibuprofen, and Nomega-nitro-L-arginine, a NO inhibitor. Sterile saline or 10(9) colony-forming units (cfu) of heat-killed GBS was injected into the cerebral ventricle of newborn piglets. CBF autoregulation was determined by altering cerebral perfusion pressure (CPP) with balloon-tipped catheters placed in the aorta. GBS produced a narrow range of CBF autoregulation due to an impairment at the upper limit of CPP. We report that in vivo in the early stages (first 2 h) of induced GBS inflammation (i) GBS impairs the upper limit of cerebrovascular autoregulation; (ii) ibuprofen, dexamethasone, and Nomega-nitro-L-arginine not only prevent this GBS-induced autoregulatory impairment but improve the range of cerebrovascular autoregulation; (iii) these autoregulatory changes do not involve circulating cerebral prostanoids; and (iv) the observed changes correlate with the induction of NO synthase gene expression. Thus, acute early onset GBS-induced impairment of the upper limit of CBF autoregulation can be correlated with increases of NO synthase production, suggesting that NO is a vasoactive mediator of CBF.

Plasma homocysteine concentrations of preterm infants.

Mild hyperhomocysteinemia in adults is associated with an increased risk of vascular disease. Although information is available about plasma homocysteine concentrations in childhood, data are entirely lacking for preterm infants despite their known abnormalities of sulfur amino acid metabolism. We measured plasma total homocysteine concentrations of 9 preterm infants (gestational age 23-31 weeks) within 48 h of birth and over the subsequent 14 days of life, and 4 term infants (gestational age 36-39 weeks) on a single occasion within 72 h of birth. As measured within 48 h of birth, average plasma homocysteine and cysteine concentrations of the preterm infants were 3.8 +/- 0.3 and 122 +/- 8 microM, both significantly less than those of the term infants (6.1 +/- 1.3 and 187 +/- 39) and of normal adults (8.2 +/- 0.5 and 232 +/- 6). Plasma homocysteine (but not cysteine) appeared to gradually increase during the first 2 weeks of life (p = 0.053). Our results indicate that hyperhomocysteinemia does not normally occur in preterm infants.

Deregulation of cyclooxygenase and nitric oxide synthase gene expression in the inflammatory cascade triggered by experimental group B streptococcal meningitis in the newborn brain and cerebral microvessels.

Group B Streptococcus (GBS) is the most common cause of neonatal sepsis and meningitis. Despite antibiotics, GBS in the newborn initiates a cascade of molecular and biological events leading to altered cerebral perfusion, blood-brain barrier disruption, cerebral edema, intracranial hypertension, neurological damage, and even death. Having previously shown that GBS infection impairs cerebral blood flow autoregulation and increases prostaglandin (PG) levels, we examined the regulation of some crucial inflammatory mediators (PGs, nitric oxide (NO), tumor necrosis factor-a) in the brain and cerebral microvessels (MVs) from newborn piglets. Cyclooxygenase (COX), the key enzyme in PG biosynthesis, exists in two isoforms, COX-1 and COX-2. Both may be directly induced by NO in a model of renal inflammation. Besides its neurotransmitter role, NO is a potent vasorelaxant whose production is catalyzed by at least three distinct nitric oxide synthases (NOS) (bNOS, ecNOS, iNOS). Western blot analyses showed that the newborn (4 day old) brain expressed lower levels of COX-1 (8-fold), COX-2 (20-fold), bNOS (12-fold), and ecNOS (5-fold) than in the 1 day old. MV showed approximately equal levels of COX-2, lower levels of COX-1 (4-fold), bNOS (5-fold), and higher levels of ecNOS (20-fold) in comparison to 4-day-old cerebral MV. A 4-day-old brain expressed lower levels of bNOS (5-fold), ecNOS (10-fold), and COX-1 (2-fold) than the 6-week-old pig. COX-2 protein was undetected in a 4-day-old pig brain, but present in great excess in MV. Purified MV showed lower ecNOS (14-fold), COX-1 (2-fold), and about equal levels of bNOS and COX-2 in comparison with MV from 6-week-old pigs. Reverse transcription polymerase chain reaction analyses confirmed these results. Treatment with noo-nitro-L-arginine (LNA), a NOS inhibitor, downregulated COX-1 expression in the newborn brain and both COX-1 and COX-2 cerebral MV expression. GBS infection (10(9) colony-forming units, 0.5 mL intracerebroventricular) of sedated newborn piglets induced the expression of tumor necrosis factor-alpha in the cerebrospinal fluid after 2 hours, upregulated bNOS expression in both brain and MVs, upregulated ecNOS in MVs, and downregulated COX-1, COX-2, and ecNOS in the brain. GBS did not trigger the expression of iNOS. Our data suggest that there is a net deficiency of NOS isoforms in the immature brain and microvasculature of the 4-day-old piglet and that the differences in expression lead to the immature control of NO and PG production, rendering newborns particularly susceptible to neurological damage because of the undeveloped nature of their response mechanisms. Moreover, the GBS-induced cascade deregulates the gene expression of interacting inflammatory mediators and may cause a net vasoconstrictor/vasodilator imbalance, leading to cerebral hypertension and edema in the early stages of infection. Pharmacological manipulations of the inflammatory cascade could lead to novel therapeutic approaches for the treatment of GBS meningitis.

Histamine release during cardiopulmonary bypass in neonates and infants.

PURPOSE: Histamine release has been previously documented in adults and children during cardiopulmonary bypass (CPB). It has not been studied in neonates nor during deep hypothermic circulatory arrest (DHCA). Histamine effects could explain many perioperative complications of congenital cardiac surgery such as dysrhythmias and massive oedema. Therefore, documentation of histamine release in the perioperative period is of clinical importance. The source of histamine can be determined by measurement of tryptase which is released with histamine from mast cells but not basophils. METHODS: Blood samples for histamine and tryptase were taken before and after specific events eg. cross-clamp removal, during anaesthesia and CPB in 14 infants and seven neonates undergoing complex congenital heart repairs and were analysed by commercial radioimmunoassays. Haemodynamic variables and pre and post-op weights were recorded to look for correlation between pathophysiological events and histamine release. RESULTS: Histamine concentration decreased at the start of bypass (0.69 to 0.38 ng.ml-1 at five minutes, (P < .005). There were no changes associated with DHCA and a small rise with reventilation (P < 0.02). Histamine concentration was lower in neonates than in infants (P < 0.05) during CPB. Plasma histamine and tryptase concentrations did not correlate, suggesting histamine release was from basophils and not from mast cells. Haemodynamic variables did not correlate with histamine concentrations. CONCLUSION: There was no major histamine release during CPB in infants and neonates. There was no relationship between histamine concentrations and clinical variables. Histamine released during CPB appears to come from basophils and may be a function of age.

Pharmacokinetics and protein binding of intravenous ibuprofen in the premature newborn infant.

The elimination, disposition and protein binding of ibuprofen (IBU) in premature infants were studied for use in the prevention of intraventricular hemorrhage and closure of patent ductus arteriosus. The kinetic profile of i.v. IBU lysine (10 mg/kg bolus) given within the first 3 h after birth was studied in 21 premature neonates (mean birthweight = 944.7 g, range: 575-1450 g; gestational age: 26.8 weeks, range: 22-31 weeks). Blood samples (0.3 ml/sample) were obtained at time 0 and at 1, 3, 6, 12, 24, 48, and 72 h post-dose for IBU by high-performance liquid chromatography (HPLC). Kinetic analyses assumed applicability of one open-compartment model and calculations from the model-independent areas under the time concentration curve (AUC). Data (mean +/- SEM) show that apparent volume of distribution (AVd) was 62.1 +/- 3.9 ml/kg, plasma t1/2 beta was 30.5 +/- 4.2 h, elimination rate constant (Kel) was 0.032 +/- 0.004 h-1, plasma clearance was 2.06 +/- 0.33 ml/kg/h and plasma concentration (Cp) at 1 h was 180.6 +/- 11.1 mg/l. Gestational age and birthweight were not related to drug elimination. In 10 neonates, IBU maintenance dose of 5 mg/kg once daily on days 2 and 3 generated mean Cp of 116.6 +/- 54.5 mg/l and 113.6 +/- 58.2 mg/l, respectively. Protein binding by ultrafiltration and capillary electrophoresis showed that the percentage bound IBU was significantly lower in full term cord plasma (94.98 +/- 0.39%, n = 26) compared to adult plasma protein (mean +/- SE = 98.73 +/- 0.31%, n = 8, p < 0.0001). Compared to data from adults and older children, IBU elimination is markedly prolonged in neonates and protein binding is slightly lower. Thus, investigational and clinical therapeutic regimens should be adjusted to account for decreased drug disposition to ensure safe and effective therapy.