Rama Bhat

Pharmacokinetics of a single dose of morphine in preterm infants during the first week of life

We studied morphine pharmacokinetics after a single intravenous dose of 0.1 mg/kg in 20 newborn infants, who were born at 26 to 40 weeks of gestation and were less than 5 days of age. In the 10 infants whose gestational age was less than or equal to 30 weeks, the mean (+/- SD) distribution half-life was 50 +/- 35 minutes, elimination half-life was 10 +/- 3.7 hours, and clearance was 3.39 +/- 3.28 ml/kg/min; the corresponding values for the three term infants were 19 +/- 8 minutes, 6.7 +/- 4.6 hours, and 15.5 +/- 10 ml/kg/min, respectively. The data suggested a trend of decreasing values for distribution and elimination half-lives with increasing gestation, but a considerable degree of variation was seen. The morphine clearance rate increased as a function of gestational age at a rate of 0.9 ml/kg/min per week of gestation. Between 18% and 22% of the drug was found to be protein bound. Four hours after the dose, the drug level remained greater than or equal to 12 ng/ml in 8 of 10 infants born at greater than or equal to 31 weeks of gestation. In 8 of 10 infants born at less than or equal to 30 weeks of gestation, similar levels were maintained at 8 hours after the initial dose. We conclude that (1) there is a marked degree of variation in morphine pharmacokinetics during the neonatal period, (2) nearly 80% of the intravenously infused drug remains free, which might explain the high sensitivity to morphine in this age group, and (3) during the first week of age, adequate blood levels can be maintained by administration of morphine at 4- to 6-hour intervals in term infants and at less frequent intervals in very premature infants (less than or equal to 30 weeks of gestation).

Morphine metabolism in acutely ill preterm newborn infants

To examine the manner in which morphine is metabolized in acutely ill premature infants, we measured the levels of morphine, morphine-3- and -6-glucuronides, and codeine in timed urine specimens and paired plasma specimens at 4 hours and 24 hours after a single dose of morphine in 16 preterm infants (less than 32 weeks of gestational age). A large amount of unmetabolized morphine was found in the urine in 13 (81.2%) of the 16 infants at 4 hours; in 12 of them, morphine was excreted even at 24 hours. Urinary morphine levels varied greatly; the coefficient of variation was 130% at 4 hours and 118% at 24 hours. Codeine was not found in any of the infants. In 10 (62.5%) of the 16 infants, at least one metabolite was found in either plasma or urine. Plasma and urinary levels of morphine conjugates also varied greatly among these 10 infants (coefficient of variation: 109% to 317%). All six infants (37.5%) who had no metabolites excreted large amounts of unmetabolized morphine in the urine for up to 24 hours. Birth weight, gestational age, postnatal age, systemic blood pressure, and other clinical or physiologic variables did not differ significantly between the 10 infants who had morphine conjugates and the six who did not. We conclude that (1) nearly two thirds of acutely ill preterm infants born at less than 32 weeks of gestational age conjugate morphine; (2) irrespective of their ability to produce morphine conjugates, preterm infants excrete large amounts of morphine unmetabolized, as late as 24 hours after a single dose; (3) morphine handling patterns are highly variable among premature infants, and no obvious factors account for the variability; and (4) such variability in morphine handling in general, and the production of the highly potent morphine-6-glucuronide in particular, could explain the variance in morphine pharmacokinetic measures and in the clinical responses to morphine during the newborn period.

Octreotide therapy for chylothorax in infants and children: A brief review.

Objectives: We review physiology and pharmacology relating to the use of octreotide for chylothorax in infants and children. We review the published experience of octreotide dosing in this context. Data Source: Systematic review of the literature, including PubMed (English-only journals), citations from relevant articles, major textbooks, and personal files. Conclusions: Octreotide has been used as a successful therapeutic adjunct in a small number of neonatal cases and a larger number of pediatric cases. No consensus has been reached as to the optimal route of administration, dose, duration of therapy, or strategy for discontinuation of therapy. We suggest using higher doses (80–100 &mgr;g/kg/day) and initiating therapy early rather than using a low initial dose with upward titration. Duration of therapy required to elicit a significant response may vary between patients.

Cell death and lung cell histology in meconium aspirated newborn rabbit lung.

Abstract Meconium aspiration syndrome (MAS) is a major cause of newborn mortality and morbidity. In this study we investigated the inflammatory responses and morphological changes in the newborn lung to debris-free meconium instillation. We developed a model for studies of MAS using 2-week-old rabbit pups. Cell death was assessed by DNA staining and detection of DNA fragmentation by in situ end labeling. Cell death was seen in association with an increase of inflammatory cytokines levels, studied by ELISA. Necrotic cells were detected by staining of lavage cells with ethidium bromide and 4′,6′-diamino-2′-phenylidon. Meconium instillation resulted selectively in loss of airway and alveolar epithelial cells followed by cell death, which increased with time. Necrotic cells looked smaller and damaged with maximal counts at 24 h after instillation. Conclusion Meconium instillation into lungs caused massive cell death, possibly by apoptosis, and necrosis that may have been activated by the inflammatory cytokine production.

Effect of single dose surfactant on pulmonary function.

Sequential changes in pulmonary mechanics in response to single dose exogenous surfactant instillation were studied in 15 preterm neonates who had hyaline membrane disease (HMD). The infants were part of a larger double-blind national study. Birth weight ranged from 0.88 to 1.55 kg, and gestational age was between 27 to 32 wk. There were six infants in the surfactant group and nine in the placebo group. Pulmonary mechanics were studied before and at 2, 24, 60, and 96 h after surfactant or sham instillation using a pneumotachometer and an esophageal balloon catheter. The variables studied were dynamic compliance (Cdyn), pulmonary resistance, work of breathing, tidal volume, and minute ventilation. Infants in the surfactant group showed an immediate and significant (p less than .05) improvement in gas exchange ratio, decreased mean airway pressure (9.7 +/- 0.9 to 7.9 +/- 0.4 cm H2O) and airway resistance (133 +/- 6.3 to 92 +/- 14.9 cm H2O/L.sec) (p less than .05). Changes in Cdyn were noted only at 24 h after surfactant instillation. In the control group, gradual improvement occurred after the initial deterioration. The findings suggest that the immediate improvement in oxygenation after surfactant instillation is the result of factors other than changes in lung compliance, such as improved ventilation/perfusion and better capillary stability with decreased leakage of fluid into alveoli.

Parent decision making for life support for extremely premature infants: from the prenatal through end-of-life period.

ABSTRACT Most deaths of extremely premature infants occur in the perinatal period. Yet, little is known about how parents make life support decisions in such a short period of time. In the paper, how parents make life support decisions for extremely premature infants from the prenatal period through death from the perspectives of parents, nurses, and physicians is described. Five cases, comprised of five mothers, four neonatologists, three nurses, and one neonatal nurse practitioner, are drawn from a larger collective case study. Prenatal, postnatal and end-of-life interviews were conducted, and medical record data were obtained. In an analysis by two research team members, mothers were found to exhibit these characteristics: desire for and actual involvement in life support decisions, weighing pain, suffering and hope in decision making, and wanting everything done for their infants. All mothers received decision making help and support from partners and family, but relationships with providers were also important. Finally, external resources impacted parental decision making in several of the cases. By understanding what factors contribute to parents’ decision making, providers may be better equipped to prepare and assist parents when making life support decisions for their extremely premature infants.

High-performance liquid chromatographic determination of morphine, morphine-3-glucuronide, morphine-6-glucuronide and codeine in biological samples using multi-wavelength forward optical detection.

An isocratic high-performance liquid chromatographic method has been developed for the determination of morphine, morphine-3-glucuronide, morphine-6-glucuronide and codeine in plasma, urine and cerebrospinal fluid. The use of an efficient solid-phase extraction procedure together with a forward optical scanning detector allows a detection limit of 500 pg/ml. The method was evaluated by examination of biological samples taken from newborn infants following the intravenous administration of morphine sulfate.

Simultaneous tissue pH and transcutaneous carbon dioxide monitoring in critically ill neonates.

Clinical usefulness and factors affecting transcutaneous CO2 (PtcCO2) monitoring were studied in 22 critically ill neonates. In 10 of 22 infants, both tissue pH (pHt) and PtcCO2were monitored simultaneously using Roche pHt and CO2 electrodes. Arterial blood gases were obtained from umbilical artery catheter. The effect of variations in blood pressure, oxygenation, arterial pH (pHa) pHt, and medications on PtcCO2 were studied.There was a linear correlation between pHt and pHa (n = 108, r = 0.85, slope 1.08), PtcCO2 and PaCO2 (n = 188, r = 0.85, slope 1.49). The pHt changes correlated better with PtcCO2 than with arterial CO2 (r = 0.78, slope 1.35).The major factors affecting the PtcCO2 relationship were (a) hypoxia and (b) acidosis. When PaO2 < 40 torr, PtcCO2 correlated poorly to PaCO2 (n = 23, r = 0.48, slope 0.72) whereas, during normoxia (PaO2 > 40 torr), it correlated well, r = 0.85, slope 1.51 similarly. When pHt was > 7.30, PtcCO2 correlated better with PaCO2 (r = 0.88, slope 1.37) than during tissue acidosis (r = 0.71, slope 1.51). Mean blood pressure down to 30 mm Hg and administration of dopamine and tolazoline did not affect the PtcCO2 to PaCO2 relationship (n = 69, r = 0.86, slope 1.6).Clinically, both continuous pHt and PtcCO2 were found to be very useful in the management of critically ill neonates.

Inhibition of Meconium-Induced Cytokine Expression and Cell Apoptosis by Pretreatment With Captopril

OBJECTIVE. To study whether pretreatment of newborn lungs by captopril inhibits meconium-induced lung injury and inflammatory cytokine expression. DESIGN. Four groups of 2-week-old rabbit pups were used for the study: group 1, saline instilled rabbits; group 2, captopril-pretreated rabbits; group 3, meconium-instilled rabbits; and group 4, captopril-pretreated and then meconium-instilled rabbits. Each group was studied at different time points: 0, 2, 4, 8, and 24 hours after instillation of meconium. Experiments were done at the University of Illinois and Michael Reese Hospital at Chicago. After treatment and instillation of meconium, the right lung was fixed with formalin, and 2-μm slices were obtained for immunohistochemistry. The left lung was used for obtaining of lung lavage and measurement of total proteins (for enzyme-linked immunosorbent assay) and mRNA (for reverse transcription-polymerase chain reaction) purification. RESULTS. We found that meconium induces inflammatory cytokine expression and apoptotic lung cell death. In situ end labeling revealed a dramatic DNA fragmentation in the meconium group, which supports the presence of apoptosis. Using enzyme-linked immunosorbent assay, we demonstrated increase of interleukin 6 and interleukin 8 cytokines in meconium-instilled lungs, which were significantly decreased in captopril-pretreated lungs. Captopril pretreatment also decreased meconium-induced cell death and angiotensinogen expression. We believe this effect is explained by the ability of captopril to decrease processing of ANGEN to angiotensinogen (ANG) I and finally to ANG II. It suggests that captopril inhibits ANG II-induced lung cell apoptosis. CONCLUSION. Our results demonstrate that captopril pretreatment significantly inhibits meconium-induced lung cell death, cytokine, and ANGEN expression in newborn lungs.

Treatment of patent ductus arteriosus after exogenous surfactant in baboons with hyaline membrane disease.

ABSTRACT: The effect of early treatment of patent ductus arteriosus (PDA) on the acute course of hyaline membrane disease was tested in a primate model, after intratracheal administration of 100 mg/kg exogenous bovine surfactant phospholipids at mean ages between 2.3-2.4 h. Twentytwo premature baboons were divided into four groups: seven animals were controls (group A); five were treated with surfactant but PDA was not intervened (group B); in five surfactant treatment was followed by three doses of 0.2 mg/kg intravenous indomethacin beginning at a mean age of 5.5 h (group C); and in five surfactant treatment was followed by a surgical ligation of PDA between 5-5.5 h of age. After surfactant instillation in groups B, C, and D, a prompt and sustained improvement was noted in a/APO2, mean airway pressure, ventilator efficiency index and pulmonary compliance. However, no consistent differences were found in the respiratory variables within the surfactant treated groups during the 72-h experiment: the respiratory course in the animals treated for PDA (groups C and D) was generally similar to the animals in which PDA was not treated (group B). In animals treated with surfactant and indomethacin (group C) the mean aortic blood pressure was maintained more optimally as compared to the other three groups. These findings suggest that although a significant early ductal shunting does occur after exogenous surfactant therapy in this animal model, the expected pulmonary deterioration does not occur, and an early abrupt interruption of PDA does not seem to provide additional advantage to the immediate course of hyaline membrane disease.