Morphine kinetics after diamorphine infusion in premature neonates.

1. The pharmacokinetics of morphine were studied in 26 newborn premature neonates (26-38 weeks gestational age) who were given a loading dose of 50 micrograms kg-1 of diamorphine followed by an intravenous infusion of 15 micrograms kg-1 h-1 of diamorphine. Plasma concentrations of morphine were measured during the infusion at steady-state and for 24 h after the cessation of the diamorphine infusion. 2. The mean steady-state plasma morphine concentration (+/- s.d.) for a diamorphine infusion rate of 15 micrograms kg-1 h-1 was 62.5 +/- 22.8 ng ml-1. 3. Morphine clearance was 3.6 +/- 0.9 ml min-1 kg-1, the elimination half-life was 8.9 +/- 3.3 h and the volume of distribution was 2.7 +/- 1.01 kg-1. 4. Morphine elimination kinetics were described by a mono-exponential function. 5. There was a direct relationship between the gestational age of the patients and the clearance (r2 = 0.31, P = 0.003) and half-life (r2 = 0.35, P = 0.01) of morphine, but no relationship was found between gestational age and volume of distribution. 6. The results suggest that the currently used dosing regimen of diamorphine achieves a safe and effective morphine concentration in the premature newborn but that the loading dose could be modified to achieve a more rapid onset of analgesia.     

Morphine metabolism in neonates and infants.

The metabolism of morphine was studied in seven fullterm neonates and five infants receiving a continuous infusion of morphine. All the patients had detectable plasma concentrations of morphine 3-glucuronide (M3G) and 10 had detectable concentrations of morphine 6-glucuronide (M6G). The mean plasma clearance of morphine was 20.1 ml min-1 kg-1 in neonates and 23.4 ml min-1 kg-1 in the group as a whole. The M3G/morphine ratio (7.3) was higher than that previously reported for preterm neonates (5.0) but lower than that reported for children (23.9).     

Morphine glucuronidation in human fetal and adult liver

Summary The glucuronyltransferase activity towards morphine was measured in microsomes isolated from liver specimens obtained from human fetuses and cancer patients. All the fetal livers investigated had measurable UDP-glucuronyltransferase activity towards morphine. There was no correlation between the gestational age (15 to 27 weeks) and the glucuronidation rate. The mean value of the enzymatic activities was higher in fetal livers obtained by hysterotomy (0.20 nmoles×min⁻¹×mg⁻¹) than in livers obtained after induced abortion (0.11 nmoles×min⁻¹×mg⁻¹). The average rate of glucuronidation in microsomes from adult liver (mean 1.15 nmoles×min^t-1×mg⁻¹) was 6 to 10 times higher than in the fetal liver microsomes. Together with previous investigations on human adult and fetal liver glucuronidation, the present results support the theory of heterogeneity of human UDP-glucuronyltransferase.     

Urinary metabolites of doxapram in premature neonates.

1. Urine samples from 20 premature neonates who received doxapram by i.v. infusion were analysed for drug metabolites by g.l.c-mass spectrometry. 2. In addition to doxapram, all urines contained at least one metabolite, but the known metabolite, 3-ketodoxapram, was detected in only 50% of the samples, and in some instances only in trace amounts. 3. Significant inter-individual differences in the metabolic pathways of doxapram were observed. 4. A total of six metabolites of doxapram were isolated three of which have not been observed previously in human or in dog. 5. Appropriate structures for the new metabolites have been deduced from their mass spectral fragmentation pathways, and are 1-ethyl-4-[2-(N-formyl-N-(2-hydroxy-ethyl)amino)ethyl]-3,3-diphenyl-2- pyrrolidinone (VII), 1-ethyl-4-[2-(4-morpholin-2-onyl)ethyl]-3,3-diphenyl-2-pyrro lidinone (IX) and 4-ethenyl-1-ethyl-3,3-diphenyl-2-pyrrolidinone (X).     

Pharmacokinetics of dexamethasone in premature neonates

Objective: Dexamethasone is frequently used in premature neonates with bronchopulmonary dysplasia, however little is known about its disposition in this population. Methods: We evaluated the pharmacokinetics of dexamethasone in 9 premature neonates with a mean gestational age of 27.3 weeks and a postnatal age of 21.8 days. Results: There was a strong relationship between clearance (4.96 ml·min^–1·kg^–1) and gestational age (r=0.884). Pharmacokinetic parameters were grouped based on a gestational age of less than 27 weeks (Group I) and greater than 27 weeks (Group II). Mean clearance in group I and group II was 1.69 and 7.57 ml·min^–1·kg^–1, respectively. Mean distribution volume in group I and II was 1.26 and 2.19 l·kg^–1, respectively. No significant relationships were noted between the disposition of dexamethasone and ventilator requirements or adverse effects. Conclusion: The pharmacokinetics of dexamethasone in premature neonates was related to gestational age.     

Patent ductus arteriosus in premature neonates

Persistent patency of the ductus arteriosus is a major cause of morbidity and mortality in premature infants. In infants born prior to 28 weeks of gestation, a haemodynamically significant patent ductus arteriosus (PDA) can cause cardiovascular instability, exacerbate respiratory distress syndrome, prolong the need for assisted ventilation and increase the risk of bronchopulmonary dysplasia, intraventricular haemorrhage, renal dysfunction, cerebral palsy and mortality. We review the pathophysiology, clinical features and assessment of haemodynamic significance, and provide a rigorous appraisal of the quality of evidence to support current medical and surgical management of PDA of prematurity. Cyclo-oxygenase inhibitors such as indomethacin and ibuprofen remain the mainstay of medical therapy for PDA, and can be used both for prophylaxis as well as for rescue therapy to achieve PDA closure. Surgical ligation is also effective and is used in infants who do not respond to medical management. Although both medical and surgical treatment have proven efficacy in closing the ductus, both modalities are associated with significant adverse effects. Because the ductus does undergo spontaneous closure in some premature infants, improved and early identification of infants most likely to develop a symptomatic PDA could help in directing treatment to the at-risk infants and allow others to receive expectant management.     

Urinary metabolites of doxapram in premature neonates

1. Urine samples from 20 premature neonates who received doxapram by i.v. infusion were analysed for drug metabolites by g.l.c-mass spectrometry.

2. In addition to doxapram, all urines contained at least one metabolite, but the known metabolite, 3-ketodoxapram, was detected in only 50% of the samples, and in some instances only in trace amounts.

3. Significant inter-individual differences in the metabolic pathways of doxapram were observed.

4. A total of six metabolites of doxapram were isolated three of which have not been observed previously in human or in dog.

5. Appropriate structures for the new metabolites have been deduced from their mass spectral fragmentation pathways, and are 1-ethyl-4-[2-(N-formyl-N-(-2-hydroxy-ethyl)amino)ethyl]-3,3-diphenyl-2-pyrrolidinone (VII), 1-ehtyl-4-[2-(4-morpholin-2-only)ethyl]-3,3-diphenyl-2-pyrrolidinone (IX) and 4-ethyl-1-ethyl-3,3-diphenyl-2-pyrrolidinone (X).     

Population pharmacokinetics of caffeine in premature neonates

Objective: To determine population pharmacokinetic parameters of caffeine in premature neonates. Methods: This population analysis was done using 145 serum concentration measurements gathered from 75 hospitalized patients during their routine clinical care. The data were analysed by use of NONMEM (mixed effects modelling) according to a one-compartment open model with either zero or first-order absorption and first-order elimination. The effect of a variety of developmental, demographic and clinical factors (gender, birth weight, current weight, gestational age, postnatal age, postconceptional age and concurrent treatment with phenobarbital and parenteral nutrition) on clearance and volume of distribution was investigated. Forward selection and backward elimination regression identified significant covariates. Results: The final pharmacostatistical model with influential covariates were as follows: clearance (ml · h⁻¹) =5.81 · current weight (kg) + 1.22 · postnatal age (weeks), multiplied by 0.757 if gestational age ≤ 28 weeks and 0.836 if the current primary source of patients' nutrition is parenteral nutrition, and volume of distribution (ml) = 911 · current weight (kg). The interindividual variability in clearance and the residual variability, expressed as coefficients of variation, were 14.87% and 18.44%, respectively. Due to the lack of information on the data set we were unable to characterize the interindividual variability for volume of distribution. Conclusion: In this study, which involved on average only two serum concentrations of caffeine per patient, the use of NONMEM gave us significant and consistent information about the pharmacokinetic profile of caffeine when compared with available bibliographic information. Additionally, parenteral nutrition and low gestational age (≤ 28 weeks) may even come to be considered as risk factors, and their presence may serve as an indicator of the need for periodic monitoring of caffeine concentrations in premature infants. Received: 27 July 1996 / Accepted in revised form: 26 November 1996     

The pharmacokinetics and physiological effects of buprenorphine infusion in premature neonates.

1. The pharmacokinetics and physiological effects of buprenorphine were studied in 12 newborn premature neonates (27 to 32 weeks gestational age) who were given a loading dose of 3.0 micrograms kg-1 of buprenorphine followed by an intravenous infusion of 0.72 micrograms kg-1 h-1 of buprenorphine. Plasma concentrations of buprenorphine were measured during the infusion, at steady-state and for 24 h after the cessation of the buprenorphine infusion. 2. The mean steady-state plasma buprenorphine concentration (+/- s.d.) for an infusion rate of 0.72 micrograms kg-1 h-1 was 4.3 +/- 2.6 ng ml-1. 3. Buprenorphine clearance was 0.23 +/- 0.07 l h-1 kg-1, the elimination half-life was 20 +/- 8 h and the volume of distribution was 6.2 +/- 2.11 l kg-1. 4. Small but significant falls were noted in systolic blood pressure at 6 h and heart rate at 1, 6 and 12 h after the administration of buprenorphine, but these did not appear to cause any clinical deterioration. 5. Four of the 12 subjects studied required an increase in the infusion rate of buprenorphine to achieve adequate sedation. 6. The results suggest that this dosing regimen of buprenorphine is safe but may not be as effective as other opioids in producing sedation and analgesia in premature newborns.     

The kinetic profile of gentamicin in premature neonates

The kinetic profile of gentamicin in premature infants has been studied to enable the development of optimized dosage schedules for neonatal intensive-care units and to stress the relationship between the pharmacokinetic parameters and several demographic, developmental and clinical factors which might be associated with changes in gentamicin disposition. Sixty-eight newborn patients of 24- to 34-weeks gestational age and 600-3,100 g current weight in their first week of life, undergoing routine therapeutic drug monitoring of their gentamicin serum levels, were included in this retrospective analysis. Gentamicin pharmacokinetic parameters were determined through non-linear regression by using a single-compartment open model. By regression analysis the current weight (g) was shown to be the strongest co-variate, and both gentamicin clearance (L h(-1)) and volume of distribution (L) had to be normalized. Additionally, gentamicin clearance depended on gestational age with a cut-off at 30 weeks, which allowed the division of the overall population into two subsets (< 30 weeks and between 30-34 weeks of gestational age). The younger neonates (<30 weeks of gestational age) showed a lower gentamicin clearance (0.0288 vs 0.0340 L h(-1) kg(-1)), a slightly higher volume of distribution (0.464 vs 0.435 L kg(-1)), and a longer half-life (11.17 vs 8.88 h) compared with the older subgroup (30-34 weeks of gestational age). On the basis of the pharmacokinetic parameters obtained, we suggest loading doses of 3.7 and 3.5 mg kg(-1) for the two subgroups of neonates (<30 weeks and 30-34 weeks of gestational age), respectively. The appropriate maintenance doses in accordance with the characteristics of the patients should be 2.8 mgkg(-1)/24h and 2.6 mg kg(-1)/18 h for neonates < 30 weeks and between 30-34 weeks of gestational age, respectively. Finally, when compared with previous studies, the information obtained on the pharmacokinetics and determinants of the pharmacokinetic variability of gentamicin in neonates was shown to be consistent.     

Morphine metabolite pharmacokinetics during venoarterial extra corporeal membrane oxygenation in neonates

OBJECTIVE: To examine morphine metabolite serum concentrations in neonates undergoing venoarterial extra corporeal membrane oxygenation (ECMO) and to quantify clearance differences between these neonates and those subjected to noncardiac major surgery. PATIENTS AND METHODS: This was an observational study in level III referral centre. Fourteen neonates (< 7 days old) undergoing ECMO were included. Morphine and concomitant medications were given by protocol, adapted to the clinical conditions of the neonates. Pharmacokinetic findings were compared with those from a previous study in infants after noncardiac major surgery. Nonlinear mixed-effect modelling was used. Parameter estimates were standardised to a 70 kg person using allometric modeling RESULTS: Morphine-3-glucuronide (M3G) was the predominant metabolite. Formation clearance to M3G at the start of ECMO on day 1 was lower than those in postoperative children, but matured more rapidly. After 10 days formation clearances of M3G in neonates on ECMO equalled those of postoperative children. Higher ECMO flows were associated with reduced formation clearances. Elimination clearances of M3G, but not morphine-6-glucuronide (M6G), were lower in the ECMO neonates; this was attributable to reduced renal clearance. These elimination clearances were correlated positively with ECMO flow and negatively with dopamine dose. Haemofiltration cleared M3G and M6G, but not morphine. CONCLUSION: Formation clearance to M3G, the predominant metabolite, is reduced during the first 10 days of ECMO. Elimination clearance of M3G and M6G is related to creatinine clearance. ECMO flow had a small effect on metabolite clearance. Higher flows were associated with decreased formation clearances, possibly reflecting illness severity. Dopamine dose reflected decreased renal clearance.     

Population pharmacokinetics of ibuprofen enantiomers in very premature neonates

The objective of the present study was to evaluate the pharmacokinetic parameters for both S- and R-ibuprofen enantiomers in very premature neonates (gestational age strictly inferior to 28 weeks) and possible relationships between the pharmacokinetic parameters and various covariates. Newborns were randomized to receive ibuprofen or placebo for the prophylactic treatment of patent ductus arteriosus (PDA) at an initial dose of 10 mg/kg ibuprofen within 6 hours after birth, followed by two 5-mg/kg doses at 24-hour intervals (n = 52). If a PDA was still present afterwards, a curative course of ibuprofen using the same dosage regimen was administered (n = 10). A sparse sampling strategy was used because only 2 samples were collected after the third prophylactic injection and 1 after the third curative injection. A model including the chiral transformation of R- to S-ibuprofen was fitted to the concentration-time data using a population approach (NONMEM). R- and S-ibuprofen t(1/2) were about 10 hours and 25.5 hours, respectively. After prophylactic treatment, the mean clearance of R-ibuprofen (CLR = 12.7 mL/h) was about 2.5-fold higher than for S-ibuprofen (CLS = 5.0 mL/h). In addition, clearance of R- and S-ibuprofen increased significantly with gestational age. The mean estimation of R-ibuprofen clearance was found to be higher than for S-ibuprofen, and the clearance of both enantiomers increased with gestational age. This should be considered to assess pharmacokinetic-pharmacodynamic relationships of ibuprofen in premature neonates and subsequently to understand and refine the use of ibuprofen in managing PDA either as a prophylactic or curative treatment.     

Clinical evaluation of ceftizoxime in neonates and premature infants

Ceftizoxime (CZX) was evaluated for absorption and excretion as well as for therapeutic effectiveness in neonates and premature infants. The following results were obtained. 1. Serum CZX concentrations were determined in 8 neonates or premature infants who were not more than 6 days old. Serum concentrations of the drug were examined in 6 neonates and/or premature infants after intravenous administration of about 20 mg/kg body weight. Average concentration at 1/2, 2, 4 and 6 hours after administration were 52.3, 36.4, 26.7 and 16.7 micrograms/ml, respectively. Serum concentrations in the other 2 infants who were given 29.7 and 25.1 mg/kg, were as high as 71 and 94 micrograms/ml at 1/2 hour and 22.1 and 39 micrograms/ml at 6 hours, respectively. Serum half-lives in 5 of the 6 mature neonates ranged from 2.36 to 3.34 hours, with averaged 2.75 hours, but was exceptionally long, 7.92 hours, in the other one. Half-lives in the 2 premature infants were 4.14 and 4.90 hours. 2. The therapeutic effectiveness on bacterial infection was evaluated for 10 newborn infants. Intravenous doses of 16.9 to 24.6 mg/kg were given in b.i.d. or t.i.d. regimen to 4 cases with pneumonia and 2 with septicemia, urinary tract infection and fetal infection each. To 1 infant with septicemia complicated with cephalohematoma, higher doses ranged from 21.8 to 49.8 mg/kg were given t.i.d. or q.i.d. Therapeutic efficacies were assessed as "Excellent" in 3, "Good" in 6, and "Poor" in 1, with an efficacy rate of 90.0%. Eradication of bacteria was complete in 2 infants each with Escherichia coli-induced septicemia or urinary tract infection. 3. For prophylactic use, the drug was given to 8 newborn infants in intravenous doses of 17.5 to 29.1 mg/kg b.i.d. or t.i.d. and no infection occurred in 7 cases. 4. No adverse reactions were obtained. Slight and transient increases in platelet count, GOT and GPT in 1 case and eosinophilia in another were observed. 5. These results suggested that CZX in an intravenous dose of 20 mg/kg b.i.d. or t.i.d. regimen in newborn infants up to 7 days of age would be effective and safe for the treatment of neonatal bacterial infections.     

Fundamental study of piperacillin sodium in term and premature neonates

Piperacillin sodium (PIPC) is a semisynthetic penicillin displaying high antibacterial activities against Gram-positive and Gram-negative bacteria including Pseudomonas sp., Proteus sp., etc. It acts bactericidally and is stable against beta-lactamases. The usefulness of PIPC in the treatment of infections in mature and premature neonates was investigated and the following results were obtained. The pharmacokinetics (half-life, distribution volume, total body clearance) of PIPC after 50 mg/kg intravenous drip infusion in 10 cases of neonates were examined. Relationship between T1/2 and hours after birth was clearly determined. Adverse effects and abnormality in laboratory test values were not observed. It is considered from the above results that PIPC may be an useful antibacterial agent for the treatment of infections in neonates.     

Effect of phenobarbital administration on theophylline clearance in premature neonates

The effect of phenobarbital administration on theophylline clearance was studied in 24 premature neonates. Aminophylline was administered according to a standard protocol of 6 mg/kg loading dose followed by a maintenance dose of 2.5-5 mg/kg/12 h. Of the 24 neonates studied, 12 received a mean phenobarbital dose of 26.34 mg/kg/d (ranging from 2 mg every 24 h to 25 mg every 12 h) and the mean phenobarbital concentration was 56.12 micrograms/ml (range 22-112 micrograms/ml). The remaining 12 patients did not require phenobarbital therapy but did receive aminophylline alone. The two groups were closely matched for gestational age, 5-min Apgar scores, and sex (p greater than 0.2). Steady-state theophylline clearance was determined at least once a week for four or more separate weeks. The study lasted a minimum of 8 wk and if more than one theophylline clearance was determined in any given week, the mean of these clearances was used. Both groups demonstrated an increase in mean theophylline clearance over time (from 15.75 and 16.67 ml/h/kg to 30.33 and 35.42 ml/h/kg for the aminophylline and aminophylline plus phenobarbital groups, respectively). The mean slope, an indicator of the average change in theophylline clearance, was 2.19 for the aminophylline group and 3.27 for the aminophylline plus phenobarbital group (p greater than 0.2), indicating that the theophylline clearance for neonates receiving phenobarbital was not significantly different from that for neonates receiving aminophylline alone. Based on this information, aminophylline does not need to be adjusted solely based on concomitant phenobarbital administration; however, theophylline concentrations should be monitored since theophylline clearance can change rapidly and unpredictably in neonates.     

Response to inhaled nitric oxide in premature and term neonates

Inhaled nitric oxide (iNO) has emerged as a promising therapeutic agent in the treatment of persistent pulmonary hypertension of the newborn. Several theories exist regarding causes of both response and nonresponse to iNO. Clinical trials differentiate disease entities (primary vs secondary persistent pulmonary hypertension associated with meconium aspiration syndrome, pneumonia or congenital diaphragmatic hernia) and their specific response rates. iNO combined with high-frequency ventilation appears to be superior to inhalation of nitric oxide (NO) during conventional ventilation. Little is known regarding the role of the degree of lung expansion and its modification -- no matter what mode of ventilation is applied. Gestational age plays an important role in relation to the potential adverse effects of NO. Of particular concern in the premature neonate is the effect of NO on bleeding time and the inhibition of platelet aggregation. Those potentially hazardous effects need to be carefully weighed against early intervention with iNO at a comparably low oxygenation index in order to prevent the vicious cycle of hypoxaemia and subsequent increased right-to-left shunting. Further studies are required to determine the optimal timing, mode of delivery and mode of ventilation used with iNO therapy in order to optimise the response of premature and term neonates.