Metabolism of theophylline to caffeine in human fetal liver.

Caffeine (1,3,7-trimethylxanthine) is a biotransformation product of theophylline (1,3-dimethylxanthine) in the human fetus. Liver explants, obtained from human fetuses with gestational ages of 12 to 20 weeks, were incubated with theophylline and produced caffeine and, in lesser amounts, 1,3-dimethyluric acid and 3-methylxanthine. These findings suggest that the predominant pathway in theophylline metabolism in the fetus and newborn infant is the methylation reaction producing caffeine. This may contribute to the neonate's exceedingly slower elimination of caffeine relative to theophylline. Caffeine produced from theophylline may add to the pharmacologic effects of theophylline in newborn infants with apnea.

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.

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.

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.

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.

The role of adenosine in the vascular adaptation of neonatal cerebral blood flow during hypotension.

This study investigated the potential role of adenosine in cerebral blood flow (CBF) regulation in the neonate during moderate and severe hypotension. Experiments were done in anesthetized, 1- to 3-day-old piglets. Regional CBF (determined by radiolabeled microsphere technique) and cerebral metabolic rate for O2 (CMRO2) were measured (a) during normotension and (b) during a 3-min period of moderate (58 +/- 9 mm Hg) or severe (36 +/- 7 mm Hg) hypotension produced by the inflation of a balloon catheter placed in the aortic root. Measurements of CBF and CMRO2 were performed successively after intracerebroventricular (i.c.v.) injections of vehicle (n = 17), the adenosine receptor blocker 8-phenyltheophylline (8-PT, 10 micrograms, n = 14), and the A2-receptor agonist 5'-N-(ethylcarboxamide)adenosine (NECA, 2 ng, n = 8). After i.c.v. administration of vehicle, none of the parameters studied was significantly altered by moderate hypotension, but severe hypotension decreased the total CBF (mean +/- SD) from 86 +/- 24 to 40 +/- 15 ml min-1 100 g-1 and CMRO2 from 3.2 +/- 0.8 to 1.8 +/- 1.0 ml min-1 100 g-1 (p less than 0.05). Administration of 8-PT did not alter these parameters during normotension, but significantly decreased CBF during moderate hypotension compared to postvehicle values (53 +/- 11 versus 81 +/- 12 ml min-1 100 g-1, p less than 0.05). This loss of autoregulation was completely reversed by NECA. During severe hypotension, 8-PT altered the CBF redistribution towards the brainstem.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of adenosine on total and regional cerebral blood flow of the newborn piglet.

The effect of adenosine on total and regional CBF, measured by radiolabeled microspheres, was assessed in 16 anesthetized and ventilated newborn (1-3 days old) piglets. They received a ventriculocisternal perfusion containing either CSF alone (controls, n = 5) or CSF mixed with two different concentrations of adenosine (15 min each) randomly assigned using the following doses: 0.1 microM, 10 microM, 100 microM, 1 mM (n = 4), or 10 mM (n = 6). Mean CSF adenosine concentration (by HPLC) before perfusion was 0.6 +/- 0.4 microM. Total and regional CBF were not altered by the perfusion of CSF alone. All adenosine concentrations, except at low doses, increased total and regional CBF, without altering the cerebral metabolic rate for oxygen. Brainstem blood flow was increased by a mean of 110, 145, 306, and 378% with 10 microM, 100 microM, 1 mM, and 10 mM concentrations, respectively. Except for the highest concentration, CBF response was dose dependent in each region of the brain with the following order of potency: brainstem greater than periventricular area greater than telencephalon, midbrain, total brain, and cerebellum. These data indicate that, in the newborn, adenosine is a potent vasodilator of cerebral vessels. If the newborn brain can synthesize appropriate concentrations of adenosine, this nucleoside may play a major role in regional CBF regulation during the neonatal period.

Caffeine metabolism in the newborn.

The concentrations of caffeine and metabolites in urine have been examined as a function of age to explore the remarkably slow elimination of caffeine by human infants. Urine samples were obtained from 3 adults and 10 infants aged 8 days to 8 months during therapeutic treatment with caffeine. A high-performance liquid chromatographic (HPLC) procedure involving reversed-phase partition chromatography was developed to separate caffeine and 13 of its metabolites. During the first month of life, caffeine accounted for more than 85% of the identifiable products in urine. Caffeine remained the predominant component for the first 3 months, but its percentage decreased gradually to the adult value of less than 2% by the age of 7 to 9 months. This change reflected increasing metabolite production, not decreasing urinary caffeine concentration. The adult metabolite pattern of partially demethylated xanthines and urates was attained by 7 to 9 months. The data indicate that the 4-day plasma t1/2 of caffeine characteristic of the newborn depends in large part on slow urinary excretion of unchanged drug since there is little or no metabolism. Subsequent decrease in the t1/2 to about 4 hr by the age of 8 months correlates closely with the rise in metabolite production.

Doxapram metabolism in human fetal hepatic organ culture.

The biotransformation of doxapram, a respiratory stimulant was studied with use of explants from human fetal livers (n = 15 fetuses) obtained from therapeutic abortions (gestational age, 10 to 20 weeks). Explants were cultured in Leibowitz medium and the media from cultured samples were collected before and at 3, 6, 12, and 24 hours after incubation with 2.5, 5.0, and 10 micrograms/ml doxapram. The concentrations of doxapram and its metabolites (AHR 0914, an analog of doxapram, AHR 5955 or ketodoxapram, and AHR 5904) were measured by high pressure liquid chromatography. Explant histopathology and alkaline phosphatase activity showed no direct toxic effects of the drug on liver tissue. The fastest rate of doxapram metabolism occurred during the first 3 hours of incubation (198 +/- 73.3, 438 +/- 63.3, and 538 +/- 62 ng/mg/hr liver protein at doxapram concentrations of 2.5, 5.0, and 10.0 micrograms/ml, respectively). At 3 hours of incubation, the amount of doxapram metabolized (nanogram per milligram of liver protein) was significantly higher (p less than 0.01) at doxapram concentrations of 10.0 (1616 +/- 186) and 5.0 microgram/ml (1315 +/- 190) than at 2.5 micrograms/ml (594 +/- 220). The oxidative pathway producing keto-doxapram, or AHR 5955 and AHR 5904, is more active than the de-ethylation producing the analog of doxapram AHR 0914. Data indicate substantial metabolism of doxapram by the human fetal lives.

Risk factors in retrolental fibroplasia.

Possible determinant factors that may increase the risk of the occurrence of retrolental fibroplasia (RLF) were analyzed in 80 infants born in 1975 and 1976 with birth weights between 501 and 1,500 gm and who survived. Active and/or cicatricial RLF occurred in 27 (33.8%) infants and the factors significantly associated with RLF were: gestational age (P less than .001); apnea requiring bag and mask resuscitation with oxygen (P less than .001); septicemia (P less than .005); degree of illness; blood transfusion; and mechanical ventilation. Severe cicatricial RLF developed in eight (10%) infants (grades 2 to 5). In the group of infants all of whom had apnea which required resuscitation, septicemia was also significantly associated with RLF (P less than .01). A highly significant association between RLF and severe myopia (P less than .001) was found in follow-up in all infants. Data show a resurgence and high incidence of RLF in low birth weight infants who survived. Infants with these factors should be considered to have greater risk for the occurrence of RLF and ophthalmologic examination prior to, and within three months following discharge is recommended.

Ibuprofen enhances retinal and choroidal blood flow autoregulation in newborn piglets.

The role of prostanoids in setting the range of autoregulation of retinal blood flow (RBF) and choroidal blood flow (ChBF) in the newborn was assessed. The RBF, ChBF, and arterial and cerebral sinus concentrations of PGE, PGF2 alpha, 6-keto-PGF1 alpha and TXB2 were measured over a wide range of mean systemic blood pressure (blood pressure (BP): 17-117 mm Hg) in newborn piglets treated with ibuprofen (30 mg/kg iv) or its vehicle (n = 8, in each group). Hypertension and hypotension were induced 80 min apart on each animal, by inflating balloon-tipped catheters placed at the aortic isthmus and root, respectively. Blood flow and prostanoid concentrations were measured 20 min before (basal) and during the induced changes in BP. In vehicle-treated piglets, RBF did not change with BP between 50 and 90 mm Hg (r = 0.33, P = 0.27), but changed as a function of BP beyond this range (tau = 0.52, P less than 0.01); ChBF increased with BP throughout the range studied (17-117 mm Hg; tau = 0.89, P less than 0.001). The relationship between O2 delivery to the retina and choroid and BP (tau greater than 0.43, P less than 0.01) was similar to that seen between RBF and ChBF with BP. The concentration of all prostanoids increased when BP was reduced to less than 50 mm Hg. When BP was raised to more than 90 mm Hg, prostaglandin concentrations increased, and those of TXB2 did not change. Ibuprofen treatment reduced the basal concentrations of all prostanoids to nearly undetectable levels and prevented their changes during hypotension and hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Dissociation between prostaglandin levels and blood flow to the retina and choroid in the newborn pig after nonsteroidal antiinflammatory drugs.

To assess whether prostaglandins contribute to the control of basal retinal and choroidal hemodynamics, retinal (RBF) and choroidal blood flow (ChBF) were measured by a microsphere technique in 1- to 4-day-old pigs before and after (at 20 and 60 min) administration of indomethacin (0.3 mg/kg, n = 6 or 10 mg/kg, n = 5), ibuprofen (40 mg/kg, n = 7), naproxen (20 mg/kg, n = 5) or vehicle (n = 8). In 40 other animals, PGF2 alpha, PGE2, and 6-keto-PGF1 alpha were measured in the retina and choroid at times corresponding to blood flow measurements. Mean arterial blood pressure and blood gases and pH were not altered by any of the agents. Except for the lower dose of indomethacin (0.3 mg/kg), which did not change retinal and choroidal prostaglandin concentrations, the prostaglandin levels were decreased similarly (P < 0.01) by the three drugs. However, RBF and ChBF were not changed by ibuprofen and naproxen, but decreased to the same extent after low and high doses of indomethacin. The data suggest that the effects of indomethacin on RBF and ChBF cannot be simply attributed to prostaglandin synthesis inhibition, and that prostaglandins may not play a significant role in controlling basal blood flow to the retina and choroid.

Effect of group B streptococcal meningitis on retinal and choroidal blood flow in newborn pigs.

PURPOSE: To assess the effect of group B streptococcal (GBS) meningitis on retinal blood flow (RetBF) and choroidal blood flow (ChBF) autoregulation in sedated newborn piglets (1 to 5 days of age). METHODS: Fourteen study animals injected with 0.5 ml heat-killed GBS (10(9)) were compared to 10 control animals injected with 0.5 ml saline. The site of injection for both groups was the cerebral lateral ventricles. RetBF and ChBF were measured by radioactive microspheres (141Ce, 51Cr, 113Sn, 85Sr, 95Nb, 46Sc) over a mean arterial blood pressure (MABP) range of 20 to 150 mm Hg. Hypertension and hypotension were induced 2 hours apart in random sequence on each animal by inflating balloon-tipped catheters placed at the descending aorta and the aortic root, respectively. RetBF and ChBF were measured 15 minutes before and after injection of GBS or saline (baseline) and during hypotension or hypertension. RESULTS: Fifth-order polynomial regression analyses of RetBF and ChBF (ml/100 g per minute) versus MABP showed that in control animals, blood flows were constant at MABP of 60 to 110 mm Hg for RetBF and was pressure passive above and below these ranges. However, no autoregulation was observed for ChBF throughout the MABP range. In contrast, RetBF of GBS-treated animals increased with increasing blood pressure throughout range of MABP studied, and absence of autoregulation was maintained in the choroid. Vascular resistance (mm Hg/ml per minute/100 g) increased as MABP was raised to maintain constant flow and was correlated linearly with MABP at 60 to 110 mm Hg (r = 0.6682, P = 0.0003) in RetBF of control animals but not in GBS-treated animals (r = -0.291, P = NS). Vascular resistance did not change with MABP for ChBF of control animals (r = -0.264, P = NS) but decreased as MABP was raised in GBS-treated animals (r = -0.548, P < 0.0001). GBS did not alter oxygen delivery, which varied directly with MABP in control animals (RetBF: r = 0.74, P < 0.001; ChBF: r = 0.68, P < 0.001) and in GBS-treated animals (RetBF: r = 0.55, P < 0.001; ChBF: r = 0.68, P < 0.001). CONCLUSION: Group B streptococcal meningitis significantly impairs eye blood flow autoregulation and may contribute to increased risk of retinal damage in infants with meningitis.

Congenital diaphragmatic hernia: pathophysiology and pharmacologic support.

The incidence of death from congenital diaphragmatic hernia appears to be unchanged in recent years despite advances in resuscitation, transport, and ventilatory support. Bilateral lung hypoplasia and abnormal pulmonary vascular reactivity as developmental consequences of the defect appear to play a major role in the continued high mortality rate. Recent advances in pharmacologic support have further elucidated the mechanisms of ventilatory failure in these patients and may represent means of improving survival in the future.

Influence of adenosine on cerebral blood flow during hypoxic hypoxia in the newborn piglet.

This study investigated the role of adenosine in the regulation of neonatal cerebral blood flow (CBF) during moderate (arterial PO2 = 47 +/- 9 Torr) and severe (arterial PO2 = 25 +/- 4 Torr) hypoxia. Twenty-eight anesthetized and ventilated newborn piglets were assigned to four groups: 8 were injected intravenously with the vehicle (controls, group 1); 13 received an intravenous injection of 8-phenyltheophylline (8-PT), a potent adenosine receptor blocker, either 4 mg/kg (group 2, n = 6, mean cerebrospinal fluid (CSF) levels less than 1 mg/l) or 8 mg/kg (group 3, n = 7, mean CSF levels less than 3.5 mg/l); and 7 received an intracerebroventricular injection of 10 micrograms 8-PT (group 4). During normoxia, CBF was not altered by vehicle or 8-PT injections. In group 1, 10 min of moderate and severe hypoxia increased total CBF by 112 +/- 36 and 176 +/- 28% (SE), respectively. Compared with controls, the cerebral hyperemia during moderate hypoxia was not altered in group 2, attenuated in group 3 (to 53 +/- 13%, P = NS), and completely blocked in group 4 (P less than 0.01). CBF increase secondary to severe hypoxia was attenuated only in group 4 (74 +/- 29%, P less than 0.05). CSF concentrations of adenosine and adenosine metabolites measured by high-performance liquid chromatography increased during hypoxia. Arterial O2 content was inversely correlated (P less than 0.005) to maximal CSF levels of adenosine (r = 0.73), inosine (r = 0.87), and hypoxanthine (r = 0.80).(ABSTRACT TRUNCATED AT 250 WORDS)

Abolition of ventilatory response to caffeine in chemodenervated lambs.

In this study we have evaluated the role of the peripheral chemoreceptors in the ventilatory response to caffeine at a dose currently used in human infants for treatment of central apneas (10 mg/kg). Twelve lambs were studied; six had carotid body denervation (CBD) and six had a sham denervation (intact). The denervation was done the 2nd wk of life, and the study of the response to caffeine infusion was carried out at a mean age of 82 days. The awake and nonsedated animals received 10 mg/kg of caffeine, and caffeine blood levels were, respectively, 8.8 and 9.0 mg/l in the intact and in the CBD lambs. The intact lambs responded to caffeine by a significant immediate increase in minute ventilation (VE) of 46% from 274 to 400 ml X min-1 X kg-1 (P less than 0.001), 1 min after caffeine infusion. This response rapidly faded, but VE was still increased at 2 h, 314 ml X min-1 X kg-1. The increase in ventilation was brought about by a change in mean inspiratory flow (VT/TI), which increased from 9.9 to 14.0 ml X s-1 X kg-1 within 1 min (P less than 0.01); VT/TI was still increased at 11.2 ml X s-1 X kg-1 2 h later. In contrast, for the CBD lambs there was no response to caffeine infusion as measured by VE or VT/TI. We conclude that bolus caffeine infusion produces a rapid response in VE followed by a fall in VE that remained above base line until at least 2 h postinfusion, and the intact chemoreceptor function appears as an essential mediator for these increases in ventilation, since the peripheral chemodenervation has completely abolished the VE response to this particular dose of caffeine.

Dose effect of caffeine on control of breathing and respiratory response to CO2 in cats.

The dose effect of caffeine (10-70 mg/kg iv) on pulmonary ventilation (VE), mean inspiratory flow (VT/TI), and tracheal pressure generated 0.3 and 0.5 s (P0.3 and P0.5, respectively) after the onset of inspiration against airway occluded at end expiration was studied in cats anesthetized with pentobarbital sodium (35 mg/kg ip) breathing various gas mixtures. With air and 50% O2 (balance N2), increasing doses of caffeine caused a progressive increase in VE that was associated with a reduction in end-tidal PCO2. When the latter was maintained at control (precaffeine) level by inhalation of CO2, the increase in VE was, at all caffeine levels, about three times that under nonisocapnic conditions. Both under isocapnic and nonisocapnic conditions the greatest incremental changes of VE were observed after administration of the first 10-mg/kg aliquot of caffeine, i.e., the current acceptable clinical dose. In all instances, the changes in VE were proportionally the same as the corresponding changes in VT/TI, P0.3, and P0.5, suggesting that caffeine did not appreciably alter either the shape of the inspiratory driving pressure waveform or the impedance of the respiratory system but simply acted by increasing the amplitude of the neuromuscular inspiratory output. An additive interaction between caffeine and end-tidal PCO2 was observed in the VE, VT/TI, and P0.3 responses at levels of CO2 at or below the eucapnic range.

Protein binding and bilirubin displacing properties of bumetanide and furosemide.

We evaluated the protein binding and comparative bilirubin displacing properties of bumetanide and furosemide in pooled adult and cord serum by ultrafiltration (UF), difference spectra (DS), and Sephadex Gel-25 (SG-25) filtration. By UF, bumetanide was found to be highly protein bound (96.7 per cent), similar to published data on furosemide (97.2 per cent). SG-25 filtration and DS showed an equal shift to the left of the free bilirubin curve when bumetanide and furosemide were added to serum, in adult and cord, at equimolar concentrations and both shifted the free bilirubin curve equally. Bilirubin displacement was greater (P less than 0.001) in cord than in adult serum with both drugs. When "presumed therapeutic" plasma concentration of furosemide (1-2 mg/liter) and bumetanide (0.5 mg/liter) were compared, it was noted that bumetanide displaced significantly less (P less than 0.001) bilirubin from albumin in cord blood than furosemide. Hence, bumetanide displaces less bilirubin at "presumed therapeutic" plasma concentrations than furosemide, suggesting that it might be more prudent to use bumetanide in sick neonates with hyperbilirubinemia. Data also provide evidence that bilirubin displacement by both diuretics is greater in neonatal serum albumin than in the adult.

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.