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1.  Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance 
What is already known about this subject
Effects of size, renal function, age (postnatal age, gestational age and postmenstrual age) as predictors of vancomycin clearance in premature neonates are established, but the relative contribution of each component remains poorly quantified, largely because these variables are closely correlated.
We have quantified the covariates contributing to vancomycin clearance population parameter variability in order to establish the major covariates required for dosing predictions. Size, standardized using allometric models, was the primary covariate used in our analysis.
What this study adds
Size explained 49.8%, postmenstrual age 18.2% and renal function 14.1% of clearance variability.
Descriptors of the relationship between age and clearance in premature neonates vary.
The use of a variable slope sigmoidal model to describe the relationship between clearance and postmenstrual age predicted an adult clearance of 3.79 l h−1 70 kg−1 (95% confidence interval 2.76, 4.98) from premature neonatal data.
To identify and quantify factors describing the variability of vancomycin clearance in premature neonates.
Population pharmacokinetics were estimated (NONMEM) in 214 neonates [postmenstrual age (PMA) 30.4 weeks, range 24–34 weeks; postnatal age 11.9 days, range 1–27 days; weight 1.30 kg, range 0.42–2.6 kg] using therapeutic drug monitoring data. Covariate analysis included weight, PMA, serum creatinine, use of inotropes or ibuprofen, positive blood culture and respiratory support. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data (604 observations).
The population estimate for volume of distribution (V) was 39 l 70 kg−1 (coefficient of variation 19.4%). Clearance (CL) increased from 0.897 l h−1 70 kg−1 at 24 weeks PMA to 2.02 l h−1 70 kg−1 by 34 weeks PMA. The between-subject variability for CL was 18.6% and the between-occasion variability was 12.2%. The use of ibuprofen reduced clearance, but this effect was attributable to reduced renal function. Overall, 82% of the variability of CL was predictable. Size explained 49.8%, PMA 18.2% and renal function 14.1%. The use of a variable slope sigmoidal model to describe the relationship between clearance and PMA predicted an adult clearance of 3.79 l h−1 70 kg−1 (95% confidence interval 2.76, 4.98).
Size, renal function and PMA are the major contributors to clearance variability in premature neonates. The small (18%) unexplained variability in clearance suggests target concentration intervention is unnecessary if size, age and renal function are used to predict the dose. Extrapolation to an adult clearance from neonatal data is possible using allometric size models and a function describing clearance maturation.
PMCID: PMC2000709  PMID: 16869817
allometry; drug interactions; pharmacokinetics; premature infants; vancomycin
2.  Morphine, morphine-6-glucuronide and morphine-3-glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions  
1The pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) were studied in 19 ventilated newborn infants(24–41 weeks gestation) who were given a loading dose of 50 μg kg−1 or 200 μg kg−1 of diamorphine followed by an intravenous infusion of 15 μg kg−1 h−1 of diamorphine. Plasma concentrations of morphine, M3G and M6G were measured during the accrual to steady-state and at steady state of the diamorphine infusion.
2Following both the 50 μg kg−1 or 200 μg kg−1 loading doses the mean steady-state plasma concentration (±s.d.) of morphine, M3G and M6G were 86±52 ng ml−1, 703±400 ng ml−1 and 48±28 ng ml−1 respectively and morphine clearance was found to be 4.6±3.2 ml min−1 kg−1.
3M3G formation clearance was estimated to be 2.5±1.8 ml min−1 kg−1, and the formation clearance of M6G was estimated to be 0.46±0.32 ml min−1 kg−1.
4M3G metabolite clearance was 0.46±0.60 ml min−1 kg−1, the elimination half-life was 11.1±11.3 h and the volume of distribution was 0.55±1.13 l kg−1. M6G metabolite clearance was 0.71±0.36 ml min−1 kg−1, the elimination half-life was 18.2±13.6 h and the volume of distribution was 1.03±0.88 l kg−1.
5No significant effect of the loading dose (50 μg kg−1 or 200 μg kg−1) on the plasma morphine or metabolite concentrations or their derived pharmacokinetic parameters was found.
6We were unable to identify correlations between gestational age of the infants and any of the determined pharmacokinetic parameters.
7M3G:morphine and M6G:morphine steady-state plasma concentration ratios were 11.0±10.8 and 0.8±0.8, respectively.
8The metabolism of morphine in neonates, in terms of the respective contributions of each glucuronide pathway, was similar to that in adults.
PMCID: PMC2042627  PMID: 8799518
diamorphine; morphine; morphine-6-glucuronide; morphine-3glucuronide; pharmacokinetics; metabolism; premature newborn; intravenous infusion; dose regimen
3.  Effect of closed endotracheal suction in high-frequency ventilated premature infants measured with electrical impedance tomography 
Intensive Care Medicine  2009;35(12):2130-2134.
To determine the global and regional changes in lung volume during and after closed endotracheal tube (ETT) suction in high-frequency ventilated preterm infants with respiratory distress syndrome (RDS).
Prospective observational clinical study.
Neonatal intensive care unit.
Eleven non-muscle relaxed preterm infants with RDS ventilated with open lung high-frequency ventilation (HFV).
Closed ETT suction.
Measurements and results
Changes in global and regional lung volume were measured with electrical impedance tomography. ETT suction resulted in an acute loss of lung volume followed by spontaneous recovery with a median residual loss of 3.3% of the maximum volume loss. The median stabilization time was 8 s. At the regional level, the lung volume changes during and after ETT suction were heterogeneous in nature.
Closed ETT suction causes an acute, transient and heterogeneous loss of lung volume in premature infants with RDS treated with open lung HFV.
PMCID: PMC2779442  PMID: 19774364
Endotracheal suction; Premature infant; High-frequency ventilation; Electrical impedance tomography
4.  Pharmacokinetics of morphine infusion in premature neonates. 
Archives of Disease in Childhood  1993;69(1 Spec No):55-58.
Morphine pharmacokinetics were studied in 17 premature neonates (26-34 weeks' gestation) after intravenous infusion during the first 24 hours of life. Infants received either standard dose morphine that comprised of a 100 micrograms/kg/hour loading infusion for 2 hours followed by a maintenance infusion of 12.5 micrograms/kg/hour, or a high dose of 200 micrograms/kg/hour for 2 hours followed by 50 micrograms/kg/hour. Mean plasma concentrations of morphine (SD) after 2 and 24 hours were 99 (12.9) and 96.4 (3.2) ng/ml, and 184.2 (37.7) and 319 (71.2) ng/ml for the standard and high dose regimens, respectively. Morphine-3-glucuronide plasma concentrations achieved about 20% and 80% of morphine values at 2 and 24 hours respectively. Morphine-6-glucuronide could not be detected at 2 hours, but attained 20-25% of morphine plasma concentrations by 24 hours. The population mean morphine clearance was 2.4 ml/min/kg, the elimination half life was 8.75 hours and the volume of distribution was 1.82 1/kg. High plasma concentrations of morphine appeared to be well tolerated. Although mean arterial blood pressure decreased during the first six hours of treatment, this was not statistically significant; two infants experienced transient muscle rigidity, but no evidence of seizures was noted. There appears to be no clinical advantage in using the high dose regimen.
PMCID: PMC1029400  PMID: 8346956
5.  Neonatal Procedural Pain and Preterm Infant Cortisol Response to Novelty at 8 Months 
Pediatrics  2004;114(1):e77-e84.
Objectives. Stress systems may be altered in the long term in preterm infants for multiple reasons, including early exposure to procedural pain in neonatal intensive care. This question has received little attention beyond hospital discharge. Stress responses (cortisol) to visual novelty in preterm infants who were born at extremely low gestational age (ELGA; ≤28 weeks), very low gestational age (VLGA; 29–32 weeks), and term were compared at 8 months of age corrected for prematurity (corrected chronological age [CCA]). In addition, among the preterm infants, we evaluated whether cortisol levels at 8 months were related to neonatal exposure to procedural pain and morphine in the neonatal intensive care unit.
Methods. Seventy-six infants, 54 preterm (≤32 weeks' GA at birth) and 22 term-born infants who were seen at 8 months CCA composed the study sample, after excluding those with major sensory, motor, or cognitive impairment. Salivary cortisol was measured before (basal) and 20 minutes after introduction of novel toys (post 1) and after developmental assessment (post 2).
Results. Salivary cortisol was significantly higher in ELGA infants at 8 months, compared with the VLGA and term groups before and after introduction of visual novelty. Term-born and VLGA infants showed a slight decrease in cortisol when playing with novel toys, whereas the ELGA group showed higher basal and sustained levels of cortisol. After controlling for early illness severity and duration of supplemental oxygen, higher basal cortisol levels in preterm infants at 8 months' CCA were associated with higher number of neonatal skin-breaking procedures. In contrast, cortisol responses to novelty were predicted equally well by neonatal pain or GA at birth. No relationship between morphine dosing and cortisol response was demonstrated in these infants.
Conclusions. ELGA preterm infants show a different pattern of cortisol levels before and after positive stimulation of visual novelty than more maturely born, VLGA preterm and term-born infants. Exposure to high numbers of skin-breaking procedures may contribute to “resetting” basal arousal systems in preterm infants.
PMCID: PMC1351380  PMID: 15231977
6.  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.
PMCID: PMC1368489  PMID: 1888639
7.  Evaluation of a morphine maturation model for the prediction of morphine clearance in children: how accurate is the predictive performance of the model? 
Recently, a maturation model that incorporates a sigmoidal Emax type model has been proposed for the estimation of morphine clearance in paediatric patients. The primary objective of this report is to evaluate the predictive performance of the morphine maturation model for the prediction of morphine clearance in children of different ages. The secondary objective of this report is to evaluate the predictive performance of exponent 0.75 on bodyweight in the absence of the sigmoidal part of the morphine maturation model.
In order to evaluate the predictive performance of the morphine maturation model, the clearance values of morphine for individual children (preterm neonates to 5-year-old children; n = 147) were obtained from the literature. The predicted clearance of morphine in an individual child, obtained from the maturation model as well as from the fixed exponent 0.75 was compared with the observed clearance in that individual child.
The morphine maturation model's predictive power in neonates, infants and younger children is poor and the inclusion of the sigmoidal part in the model only helps in reducing the substantial error introduced in the prediction due to the application of exponent 0.75 on bodyweight. Furthermore, the real benefit of the sigmoidal Emax part of the model disappears by 1 year of age.
The morphine maturation model has a poor predictive power of morphine clearance in preterm and term neonates, infants and very young children and may not be of any practical value for the prediction of morphine clearance in this age group.
PMCID: PMC3018029  PMID: 21143504
allometric scaling; clearance; maturation model; paediatric population
8.  Internalizing behaviours in school-age children born very preterm are predicted by neonatal pain and morphine exposure 
Greater neonatal pain is associated with higher internalizing behaviours in very preterm infants at 18 months corrected age, but it is unknown whether this relationship persists to school age. Moreover, it is unclear whether morphine ameliorates or exacerbates the potential influence of neonatal pain/stress on internalizing behaviours. We examined whether neonatal pain-related stress is associated with internalizing behaviours at age 7 years in children born very preterm, and whether morphine affects this relationship.
101 children born very preterm (≤ 32 weeks gestation) were seen at mean age 7.7 years. A parent completed the Parenting Stress Index and Child Behavior Checklist questionnaires. Neonatal pain-related stress (the number of skin-breaking procedures adjusted for clinical factors associated with prematurity) was examined in relation to internalizing behaviour, separately in subjects mechanically ventilated and exposed to both pain and morphine (n = 57) and those never mechanically ventilated, exposed to pain but not morphine (n = 44).
In the non-ventilated group, higher skin-breaking procedures (p = 0.037) and parenting stress (p = 0.004) were related to greater internalizing behaviours. In the ventilated group, greater morphine exposure (p = 0.004) was associated with higher child internalizing scores.
In very preterm children who undergo mechanical ventilation, judicious use of morphine is important, since morphine may mitigate the negative effects of neonatal pain on nociception but adversely affect internalizing behaviours at school age. Management of procedural pain needs to be addressed in very preterm infants in the NICU, to prevent long-term effects on child behaviour.
PMCID: PMC4016156  PMID: 24318537
9.  Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates 
AIMS—To compare the safety and effectiveness of morphine and diamorphine for the sedation of ventilated preterm neonates in a double blind, randomised trial.
METHODS—Eighty eight babies were allocated to receive either morphine (n = 44) or diamorphine (n = 44) by bolus infusion (200 or 120mcg/kg, respectively, over two hours), followed by maintenance infusion (25 or 15 mcg/kg/h, respectively) during the initial phase of their respiratory disease. Serial monitoring of physiological, behavioural, and biochemical variables over the first 24 hours of the infusions was performed. Longer term outcomes were also monitored.
RESULTS—Morphine, but not diamorphine, was associated with a mean (SEM) decrease in mean arterial blood pressure of 2.2 (1.0) mm Hg (p = 0.05) over the initial loading infusion. Physiological (blood pressure variability) and behavioural measures of sedation (clinical assessment and sedation scoring) indicated that the two drug regimens were equally effective after 24 hours, but the sedative effects of diamorphine were evident more quickly than those of morphine. Both regimens significantly reduced plasma adrenaline concentrations over the first 24 hours of the infusions. No significant differences in mortality, ventilator days, chronic lung disease or intracranial lesions were noted.
CONCLUSIONS—Both drug regimens reduce the stress response to ventilation in preterm neonates. However, diamorphine's more rapid onset of sedation and morphine's hypotensive tendency suggest that diamorphine is preferable for the sedation of mechanically ventilated preterm neonates.

PMCID: PMC1720807  PMID: 9797622
10.  Opioids and clonidine modulate cytokine production and opioid receptor expression in neonatal immune cells 
Opioids and clonidine, used in for sedation, analgesia and control of opioid withdrawal in neonates, directly or indirectly activate opioid receptors expressed in immune cells. Therefore, our objective is to study how clinically relevant concentrations of different opioids and clonidine change cytokine levels in cultured whole blood from preterm and full-term infants.
Study design
Using blood from preterm (≤ 30 weeks gestational age, n=7) and full-term (≥37 weeks GA, n=19) infants, we investigated the changes in cytokine profile (IL-1β, IL-6, IL-8, IL-10, IL-12p70, and TNF-α), cyclic adenosine monophosphate (cAMP) levels and μ-, δ-, and κ- opioid receptor (OPR) gene and protein expression following in-vitro exposure to morphine, methadone, fentanyl, or clonidine at increasing concentrations ranging from 0 to 1 mM.
Following LPS activation, IL-10 levels were 146-fold greater in cultured blood from full-term than from preterm infants. Morphine and methadone, but not fentanyl, at >10-5M decreased all tested cytokines except IL-8. In contrast, clonidine at <10-9M increased IL-6, while at >10-5M increased IL-1β and decreased TNF-α levels. All cytokine changes followed the same patterns in preterm and full-term infant cultured blood and matched increases in cAMP levels. All three μ-, δ- and κ-OPR genes were expressed in mononuclear cells from preterm and full-term infants. Morphine, methadone and clonidine, but not fentanyl, at >10-5M decreased the expression of μ-OPR, but not δ- or κ-OPRs.
Generalized cytokine suppression along with downregulation of μ-OPR expression observed in neonatal mononuclear cells exposed to morphine and methadone at clinically relevant concentrations contrast with the modest effects observed with fentanyl and clonidine. Therefore, we speculate that fentanyl and clonidine may be safer therapeutic choices for sedation and control of opioid withdrawal and pain in neonates.
PMCID: PMC3640758  PMID: 23047422
morphine; methadone; fentanyl; clonidine; inflammation; preterm infant; full-term infant
11.  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).
PMCID: PMC1381474  PMID: 1467140
12.  Increased Clearance of Morphine in Sickle Cell Disease: Implications for Pain Management 
Acute vaso-occlusive painful episodes associated with sickle cell disease (SCD) are frequently treated with morphine. Many SCD individuals require relatively higher doses of morphine to achieve optimal analgesia. We studied pharmacokinetics of morphine in SCD to explore if altered disposition could be a factor for increased requirement of morphine in this population. The study subjects were in steady state of health to avoid the effect of hemodynamic changes associated with vaso-occlusion on morphine disposition. The plasma concentrations of morphine and its major metabolites were measured at timed intervals in 21 SCD subjects after they received a single 0.1 mg/ Kg infusion of morphine sulfate. USCPACK software was used to fit candidate pharmacokinetic models. Non-compartmental pharmacokinetic parameters for morphine were calculated. Morphine clearance was 2.4 – 3.6 L/h, half-life was 0.3 – 0.7 hours, AUC0−∞ was 27.7 – 42.5 ng*h/mL, and volume of distribution was 0.96 – 3.38 L/kg. Clearance of morphine in the study population was 3 – 10 folds higher than published estimates in the non-SCD population, with correspondingly lower AUC and half-life. Volume of distribution was similar. This observation suggests that due to increased clearance SCD individuals may require higher dose and frequency of morphine to achieve comparable plasma levels.
PMCID: PMC3086992  PMID: 21277838
Sickle cell disease; morphine; pharmacokinetics; clearance; pain management
13.  Endotracheal Suctioning in Preterm Infants Using Four-Handed versus Routine Care 
To evaluate the effect of four-handed care on preterm infants’ physiologic and behavioral responses to and recovery from endotracheal suctioning versus routine endotracheal (ETT) suctioning.
Randomized crossover design with infants as their own controls.
Single-family-room newborn intensive care unit in an academic health center.
Ten intubated infants on conventional ventilation with inline suctioning who were fewer than 37 weeks gestation at birth, and less than one week of age.
Each infant was observed twice on a single day. One observation involved routine ETT suctioning and one involved four-handed care. Physiologic and behavioral response data were collected.
No differences were noted when comparing baseline heart rate (HR) or oxygen saturation (SpO2) data to those obtained during and after suctioning while in the routine care condition. In the four-handed care condition, mean SpO2 increased from preobservation 95.49 to during observation saturation 97.75 (p = .001). Salivary cortisol levels did not differ between groups at baseline or postsuctioning. No significant difference in behavior state was observed between the two conditions. More stress and defense behaviors occurred postsuctioning when infants received routine care as opposed to four-handed care (p = .001) and more self-regulatory behaviors were exhibited by infants during (p = .019) and after suctioning (p = .016) when receiving four-handed care. No statistical difference was found in the number of monitor call-backs postsuctioning.
Four-handed care during suctioning was associated with a decrease in stress and defense behaviors and an increase in self-regulatory behaviors.
PMCID: PMC3565562  PMID: 23316894
Endotracheal suctioning; preterm infants; developmental care
14.  Pre-Emptive Morphine Analgesia Attenuates the Long-Term Consequences of Neonatal Inflammation in Male and Female Rats 
Pediatric research  2008;64(6):625-630.
Despite mounting evidence on the importance of pain management in preterm infants, clinical use of analgesics in this population is limited. Our previous studies have shown that neonatal inflammation results in long-term alterations in adult somatosensory thresholds, characterized by decreased baseline nociceptive sensitivity, and enhanced hyperalgesia following a subsequent inflammatory insult. The present studies were conducted to determine if pre-emptive morphine attenuates these negative consequences. At P0, pups received an injection of morphine sulfate (MS) before an intraplantar injection of 1% carrageenan (CGN). Control pups received either saline (SAL) followed by intraplantar CGN, MS followed by intraplantar SAL, or SAL followed by intraplantar SAL. Pre-emptive morphine significantly attenuated neonatal injury-induced hypoalgesia in adolescence and adulthood. Similarly, morphine pre-treated animals displayed significantly less hyperalgesia and recovered faster from a subsequent inflammatory insult compared to controls. Neonatal morphine had no significant effect on morphine analgesia in adulthood. Interestingly, neonatally injured animals that did not receive morphine displayed a significant rightward shift in the morphine dose response curve in the absence of peripheral inflammation. Together, these results demonstrate that pre-emptive morphine significantly attenuates the long-term behavioral impact of neonatal inflammatory injury.
PMCID: PMC2638169  PMID: 18679159
morphine; pain; premature infant; opioid analgesia; neonate
15.  The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine 
To investigate the pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) in healthy volunteers after the administration of morphine by subcutaneous bolus injection (s.c.b.) and subcutaneous infusion (s.c.i.) over 4 h, and to compare the results with the intravenous bolus (i.v.) administration of morphine.
Six healthy volunteers each received 5 mg morphine sulphate by i.v., s.c.b. and short s.c.i. over 4 h, on three separate occasions, in random order, each separated by at least 1 week. Plasma samples were assayed for morphine, M6G and M3G.
After i.v. morphine, the concentrations of morphine, M6G and M3G and their pharmacokinetic parameters were similar to those we have observed previously, in other healthy volunteers (when standardized to nmol l−1, for a 10 mg dose to a 70 kg subject). After s.c.b. morphine, similar results were obtained except that the median tmax values for morphine and M3G were significantly longer than after i.v. morphine (P < 0.001 and P < 0.05, respectively), with a trend to a longer tmax for M6G (P = 0.09). The appearance half-lives after s.c.b. morphine for M6G and M3G were also significantly longer than after i.v. morphine (P = 0.03 and P < 0.05, respectively). Comparison of log-transformed AUC values indicated that i.v. and s.c.b. administration of morphine were bioequivalent with respect to morphine, M6G and M3G. In comparison with i.v. morphine, morphine by s.c.i. was associated with significantly longer median tmax values for morphine (P < 0.001), M6G (P < 0.001) and M3G (P < 0.05), and the mean standardized Cmax values significantly lower than after both i.v. and s.c.b. morphine (morphine P < 0.001, M6G P < 0.001 and M3G P < 0.01 for each comparison). Comparison of log-transformed AUC values after i.v. and s.c.i. morphine indicated that the two routes were not bioequivalent for morphine (log-transformed AUC ratio 0.78, 90% CI 0.66–0.93), M6G (0.72, 90% CI 0.63–0.82), or M3G (0.65, 90% CI 0.54–0.78). A small stability study indicated no evidence of adsorptive losses from morphine infused over 4 h using the infusion devices from the study.
Although bioequivalence was demonstrated between the s.c.b. and i.v. routes of morphine administration, the bioavailabilities of morphine, M6G and M3G after s.c.i. were significantly lower than after i.v. administration. However, despite this, the study demonstrates that the subcutaneous route is an effective method for the parenteral administration of morphine.
PMCID: PMC2014910  PMID: 10718775
infusion; morphine-3-glucuronide (M3G); morphine-6-glucuronide (M6G); morphine; pharmacokinetics; subcutaneous
16.  Population pharmacokinetic analysis of vancomycin in neonates. A new proposal of initial dosage guideline 
To determine the population pharmacokinetic parameters of vancomycin in neonatal patients with a wide range of gestational age and birth weight, and subsequently to design an initial dosing schedule for vancomycin in neonates.
Using nonlinear mixed-effects modelling (NONMEM VI), the pharmacokinetics of vancomycin were investigated in 70 neonates with postmenstrual age and body weight ranging 25.1–48.1 weeks and 0.7–3.7 kg, respectively. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data. Nine demographic characteristics and 21 co-administered drugs were evaluated as covariates of clearance (CL) and distribution volume (Vd) of vancomycin.
Weight-normalized clearance of vancomycin was influenced by postmenstrual age (PMA) and co-administration of amoxicillin-clavulanic acid. Weight-normalized volume of distribution was influenced by co-administration of spironolactone. CL and Vd of the typical individual in this study population (PMA = 34.6 weeks, weight = 1.7 kg) were estimated to be 0.066 l h−1 kg−1 (95% CI 0.059, 0.073 l h−1 kg−1) and 0.572 l kg−1 (95% CI 0.505, 0.639 l kg−1), respectively. This model was used to predict a priori serum vancomycin concentrations in a validation group (n= 41), which were compared with observed concentrations to determine the predictive performance of the model. The 95% confidence interval of mean prediction error included zero for both peak and trough vancomycin concentrations.
Postmenstrual age, co-administration of amoxicillin-clavulanic acid and spironolactone have a significant effect on the weight-normalized CL and Vd. An initial dosage guideline for vancomycin is proposed for preterm and full-term neonates, whereas the population pharmacokinetic model can be used for dosage individualization of vancomycin.
PMCID: PMC2997311  PMID: 21039765
amoxicillin-clavulanic acid; neonates; NONMEM; postmenstrual age; spironolactone; vancomycin
17.  Pharmacokinetics of single dose intravenous propacetamol in neonates: effect of gestational age 
Aim: To investigate the pharmacokinetics and pharmacodynamics of single dose propacetamol in preterm and term infants on the first day of life.
Methods: Neonates were stratified by gestational age. Preterm (< 37 weeks) and term (37–41 weeks) infants received a single dose of propacetamol in the first 24 hours of life when they had minor, painful procedures or as additional treatment in infants receiving opioids. Blood samples were taken from an arterial line, and pain was evaluated by a multidimensional pain scale. Results were reported as mean (SD). Student's t and Wilcoxon tests were used to compare the groups.
Results: Thirty neonates were included, 10 of which were term infants. Serum half life was 277 (143) minutes in the preterm infants and 172 (59) minutes in the term infants (p < 0.05). Clearance was 0.116 (0.08) litre/kg/h in the preterm infants and 0.170 (0.06) litre/kg/h in the term infants (p < 0.05). Gestational age correlated with serum half life (r = -0.46). No effect of sex or administration of prenatal steroids was found on the pharmacokinetics of paracetamol. In neonates who only received propacetamol (n = 15), the level of analgesia seemed to be associated with the therapeutic (> 5 mg/l) level.
Conclusions: A correlation was found between gestational age and the serum half life of propacetamol. The maturational trend of clearance and half life in preterm and term neonates is in line with data on the pharmacokinetics of propacetamol beyond the newborn period.
PMCID: PMC1721651  PMID: 14711849
18.  Characteristics of Distribution of Morphine and Metabolites in Cerebrospinal Fluid and Plasma with Chronic Intrathecal Morphine Infusion in Humans 
Anesthesia and analgesia  2012;115(4):797-804.
Despite widespread use of chronic intrathecal (IT) infusions of morphine, there is little systematic human work evaluating the steady-state morphine concentrations or cerebrospinal (CSF) chemistry after long-term IT morphine delivery. We sought to address these issues in patients receiving chronic IT morphine infusion.
Pain patients with implanted catheters and pumps (range: 127–2165 days), receiving a stable dosing (> 1 week) of IT morphine by infusion, were entered into the study. The following sequence was performed: 1) estimation of pain score; 2) radiograph localization of catheter tip; 3) Percutaneous sampling of lumbar CSF at the L4-5 or L5-S1 space. CSF/plasma samples were assayed for chemistry, and morphine and its 3/6 glucuronide metabolites (M3G, M6G) by liquid chromatography mass spectrometry.
Nineteen patients were enrolled. CSF samples were obtained from 16 subjects. Three patients were not included in the primary analysis because one catheter was epidural, one catheter was fractured and one had a granuloma at the catheter tip. Of the 13 sampled patients, the range of daily doses, rates and concentrations were 1.6–25 mg/d and 0.1–1 ml/d, 5–50 mg/mL, respectively. The principal observations were: i) morphine, M3G and M6G were present in the CSF and plasma and showed a significant regression slope when plotted versus daily dose; ii) in contrast, the regression slope of the group ratio Morphine: M3G: M6G plotted versus daily dose in CSF or plasma was not different from zero; iii) plotting “normalized” CSF analyte concentration (e.g., concentration at site/daily IT morphine dose) against the segmental distance of the sampling site from the catheter tip revealed a significant decline in concentration of morphine, but not of conjugates as a function of distance from the catheter tip; iv) plotting CSF protein, glucose, red and white cell counts versus daily morphine dose or morphine concentration at the sampling site revealed no significant regression; and v) patients with a catheter failure or a granuloma showed reduced concentrations of morphine in their CSF.
Chronic infusion of morphine shows high concentrations which correlate with the infusion dose and the proximity of the sampling site to the infusion site with no effects on CSF chemistry.
PMCID: PMC3456964  PMID: 22822192
19.  Morphine metabolism in children. 
1. The metabolism of morphine was studied in 12 children and nine premature neonates on a continuous infusion of morphine (10-360 micrograms kg-1 h-1). 2. The mean plasma clearance of morphine was significantly higher in children than neonates (25.7 and 4.7 ml min-1 kg-1, respectively) (P less than 0.01). 3. All the neonates and children had detectable concentrations of morphine-3-glucuronide (M3G) in plasma. All the children and five neonates had detectable concentrations of morphine-6-glucuronide (M6G) in plasma or urine. 4. The M3G/morphine ratios in plasma and urine, and M6G/morphine ratios in urine were significantly higher in children than neonates (P less than 0.01), suggesting that morphine glucuronidation capacity is enhanced after the neonatal period. 5. There was no difference in the M3G/M6G ratio in children and neonates, indicating a parallel development of both glucuronidation pathways.
PMCID: PMC1380022  PMID: 2590614
20.  Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU 
Pain  2005;113(3):293-300.
Data from animal models indicate that neonatal stress or pain can permanently alter subsequent behavioral and/or physiological reactivity to stressors. However, cumulative effects of pain related to acute procedures in the neonatal intensive care unit (NICU) on later stress and/or pain reactivity has received limited attention. The objective of this study is to examine relationships between prior neonatal pain exposure (number of skin breaking procedures), and subsequent stress and pain reactivity in preterm infants in the NICU. Eighty-seven preterm infants were studied at 32 (±1 weeks) postconceptional age (PCA). Infants who received analgesia or sedation in the 72 h prior to each study, or any postnatal dexamethasone, were excluded. Outcomes were infant responses to two different stressors studied on separate days in a repeated measures randomized crossover design: (1) plasma cortisol to stress of a fixed series of nursing procedures; (2) behavioral (Neonatal Facial Coding System; NFCS) and cardiac reactivity to pain of blood collection. Among infants born ≤ 28 weeks gestational age (GA), but not 29–32 weeks GA, higher cumulative neonatal procedural pain exposure was related to lower cortisol response to stress and to lower facial (but not autonomic) reactivity to pain, at 32 weeks PCA, independent of early illness severity and morphine exposure since birth. Repeated neonatal procedural pain exposure among neurodevelopmentally immature preterm infants was associated with down-regulation of the hypothalamic–pituitary–adrenal axis, which was not counteracted with morphine. Differential effects of early pain on development of behavioral, physiologic and hormonal systems warrant further investigation.
PMCID: PMC1447527  PMID: 15661436
Preterm infant; Pain; Morphine; Cortisol; Stress; Facial reactivity; Autonomic
21.  Morphine sulphation in children. 
The metabolism of morphine was studied in nine children and seven preterm neonates receiving a continuous infusion of morphine. All the neonates and three children had detectable concentrations of morphine-3-sulphate (M3S) in urine. None of the neonates or the children had detectable concentrations of morphine-6-sulphate (M6S) in urine. None of the children had detectable concentrations of M3S in plasma. The M3S/morphine ratios were significantly higher in neonates than children (P less than 0.01), suggesting that morphine sulphation decreases after the neonatal period. The amount of M3S formed, even in neonates, is low suggesting that this is a minor metabolic pathway.
PMCID: PMC1368313  PMID: 2288836
22.  Long-term Effects of Neonatal Stress on Adult Conditioned Place Preference (CPP) and Hippocampal Neurogenesis 
Behavioural brain research  2011;227(1):7-11.
Critically ill preterm infants are often exposed to stressors that may affect neurodevelopment and behavior. We reported that exposure of neonatal mice to stressors or morphine produced impairment of adult morphine-rewarded conditioned place preference (CPP) and altered hippocampal gene expression. We now further this line of inquiry by examining both short- and long-term effects of neonatal stress and morphine treatment. Neonatal C57BL/6 mice were treated twice daily from postnatal day (P) 5 to P9 using different combinations of factors. Subsets received saline or morphine injections (2 mg/kg s.c.) or were exposed to our neonatal stress protocol (maternal separation 8 h/d ×5d + gavage feedings ± hypoxia/hyperoxia). Short-term measures examined on P9 were neuronal fluorojade B and bromodeoxyuridine staining, along with urine corticosterone concentrations. Long-term measures examined in adult mice (>P60) included CPP learning to cocaine reward (± the kappa opioid receptor (KOR) agonist U50,488 injection), and adult hippocampal neurogenesis (PCNA immunolabeling). Neonatal stress (but not morphine) decreased the cocaine-CPP response and this effect was reversed by KOR stimulation. Both neonatal stress or morphine treatment increased hippocampal neurogenesis in adult mice. We conclude that reduced learning and increased hippocampal neurogenesis are both indicators that neonatal stress desensitized mice and reduced their arousal and stress responsiveness during adult CPP testing. Reconciled with other findings, these data collectively support the stress inoculation hypothesis whereby early life stressors prepare animals to tolerate future stress.
PMCID: PMC3494415  PMID: 22061798
kappa opioid receptor; morphine; dynorphin; neonatal stress; stress inoculation hypothesis
23.  Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm 
PLoS ONE  2013;8(10):e76702.
Altered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age.
42 right-handed children born very preterm (24–32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling.
After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes.
In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.
PMCID: PMC3800011  PMID: 24204657
24.  Effects of neonatal stress and morphine on murine hippocampal gene expression 
Pediatric research  2011;69(4):285-292.
Critically ill preterm infants experience multiple stressors while hospitalized. Morphine is commonly prescribed to ameliorate their pain and stress. We hypothesized that neonatal stress will have a dose-dependent effect on hippocampal gene expression, and these effects will be altered by morphine treatment. Male C57BL/6 mice were exposed to 5 treatment conditions between postnatal day 5 and 9: 1) Control, 2) mild stress + saline, 3) mild stress + morphine, 4) severe stress + saline and 5) severe stress + morphine. Hippocampal RNA was extracted and analyzed using Affymetrix Mouse Gene 1.0 ST Arrays. Single gene analysis and gene set analysis were used to compare groups with validation by qPCR. Stress resulted in enrichment of genes sets related to fear response, oxygen carrying capacity and NMDA receptor synthesis. Morphine downregulated gene sets related to immune function. Stress plus morphine resulted in enrichment of mitochondrial electron transport gene sets, and down-regulation of gene sets related to brain development and growth. We conclude that neonatal stress alone influences hippocampal gene expression, morphine alters a subset of stress-related changes in gene expression and influences other gene sets. Stress plus morphine show interaction effects not present with either stimulus alone. These changes may alter neurodevelopment.
PMCID: PMC3085998  PMID: 21178816
25.  Inter-individual variation in morphine clearance in children 
The aim of the study was to determine the extent of inter-individual variation in clearance of intravenous morphine in children and to establish which factors are responsible for this variation.
A systematic literature review was performed to identify papers describing the clearance of morphine in children. The following databases were searched: Medline, Embase, International Pharmaceutical Abstracts, CINAHL, and Cochrane library. From the papers, the range in plasma clearance and the coefficient of variation (CV) in plasma clearance were determined.
Twenty-eight studies were identified. After quality assessment, 20 studies were included. Only 10 studies gave clearance values for individual patients. The majority of the studies were in critically ill patients. Inter-individual variability of morphine clearance was observed in all age groups, but greatest in critically ill neonates (both preterm and term) and infants. In critically ill patients, the CV was 16–9 7 % in preterm neonates, 24–87 % in term neonates, 35 and 134 % in infants, 39 and 55 % in children, and 74 % in adolescents. The CV was 37 and 44 % respectively in non-critically ill neonates and infants. The mean clearance was higher in children (32 and 52 ml min-1 kg-1) than in neonates (2 to 16 ml min-1 kg-1).
Large inter-individual variation was seen in morphine clearance values in critically ill neonates and infants.
Electronic supplementary material
The online version of this article (doi:10.1007/s00228-015-1843-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4430598  PMID: 25845657
Morphine; Pharmacokinetics; Clearance; Children; Variation

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