Nirmala S. Desai

Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial

BACKGROUND Opioid analgesia is commonly used during neonatal intensive care. We undertook the Neurologic Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial to investigate whether pre-emptive morphine analgesia decreases the rate of a composite primary outcome of neonatal death, severe intraventricular haemorrhage (IVH), and periventricular leucomalacia (PVL) in preterm neonates. METHODS Ventilated preterm neonates (n=898) from 16 centres were randomly assigned masked placebo (n=449) or morphine (n=449) infusions. After a loading dose (100 microg/kg), morphine infusions (23-26 weeks of gestation 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); 30-32 weeks 30 microg kg(-1) h(-1)) were continued as long as clinically justified (maximum 14 days). Open-label morphine could be given on clinical judgment (placebo group 242/443 [54.6%], morphine group 202/446 [45.3%]). Analyses were by intention to treat. FINDINGS Baseline variables were similar in the randomised groups. The placebo and morphine groups had similar rates of the composite outcome (105/408 [26%] vs 115/419 [27%]), neonatal death (47/449 [11%] vs 58/449 [13%]), severe IVH (46/429 [11%] vs 55/411 [13%]), and PVL (34/367 [9%] vs 27/367 [7%]). For neonates who were not given open-label morphine, rates of the composite outcome (53/225 [24%] vs 27/179 [15%], p=0.0338) and severe IVH (19/219 [9%] vs 6/189 [3%], p=0.0209) were higher in the morphine group than the placebo group. Placebo-group neonates receiving open-label morphine had worse rates of the composite outcome than those not receiving open-label morphine (78/228 [34%] vs 27/179 [15%], p<0.0001). Morphine-group neonates receiving open-label morphine were more likely to develop severe IVH (36/190 [19%] vs 19/219 [9%], p=0.0024). INTERPRETATION Pre-emptive morphine infusions did not reduce the frequency of severe IVH, PVL, or death in ventilated preterm neonates, but intermittent boluses of open-label morphine were associated with an increased rate of the composite outcome. The morphine doses used in this study decrease clinical signs of pain but can cause significant adverse effects in ventilated preterm neonates.

Morphine pharmacokinetics and pharmacodynamics in preterm and term neonates: secondary results from the NEOPAIN trial

BACKGROUND Relationships between plasma morphine concentrations and neonatal responses to endotracheal tube (ETT) suctioning are unknown in preterm neonates. METHODS Ventilated preterm neonates (n=898) from 16 centres were randomly assigned to placebo (n=449) or morphine (n=449). After an i.v. loading dose (100 microg kg(-1)), morphine infusions [23-26 weeks postmenstrual age (PMA) 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); and 30-32 weeks 30 microg kg(-1) h(-1)] were established for a maximum of 14 days. Open-label morphine (20-100 microg kg(-1)) was given for pain or agitation. Morphine assay and neonatal response to ETT suctioning was measured at 20-28 and 70-76 h after starting the drug infusion and at 10-14 h after discontinuation of the study drug. The concentration-effect response was investigated using non-linear mixed effects models. RESULTS A total of 5119 data points (1598 measured morphine concentrations and 3521 effect measures) were available from 875 neonates for analysis. Clearance was 50% that of the mature value at 54.2 weeks PMA (CLmat(50)) and increased from 2.05 litre h(-1) 70 kg(-1) at 24 weeks PMA to 6.04 litre h(-1) 70 kg(-1) at 32 weeks PMA. The volume of distribution in preterm neonates was 190 litre 70 kg(-1) (CV 51%) and did not change with age. There was no relationship between morphine concentrations (range 0-440 microg litre(-1)) and heart rate changes associated with ETT suctioning or with the Premature Infant Pain Profile. CONCLUSIONS A sigmoid curve describing maturation of morphine clearance is moved to the right in preterm neonates and volume of distribution is increased compared with term neonates. Morphine does not alter the neonatal response to ETT suctioning.

Active transport of cimetidine into human milk

Most xenobiotics are transferred from blood into breast milk by passive diffusion. However, an active transport mechanism has been speculated for cimetidine, and the purpose of this study was to characterize cimetidine transfer into human milk. Twelve healthy lactating volunteers received single oral doses of 100, 600, and 1200 mg cimetidine in a randomized, crossover design on 3 different days. Blood and milk specimens were collected and assayed for cimetidine. In vitro measurements, including skim to whole milk concentration ratio, milk pH, and free fractions in serum and milk were used for a diffusion model prediction of milk to serum concentration ratio of cimetidine; the mean milk/serum ratio (±SD) was 1.05 ± 0.18. The observed milk/serum ratio (5.77 ± 1.24) was 5.5 times higher than the milk/serum ratio predicted by diffusion. The observed milk/serum ratio for the three dosing regimens were not significantly different from one another. Time of peak concentration (tmax) in milk (3.3 ± 0.7 hours) displayed a delay compared with serum tmax (1.7 ± 0.6 hours). Oral clearance for 1200 mg cimetidine dose (0.47 ± 0.11 L/hr/kg) was significantly lower compared with oral clearance values for 100 and 600 mg cimetidine doses (0.59 ± 0.11 and 0.57 ± 0.13 L/hr/kg, respectively). The maternal dose of cimetidine ingested by a suckling infant based on body weight was estimated to be 6.7%, which appears to be safe under normal conditions. This study provides the first definitive evidence of an active transport system for drug transfer into human milk, which may have broader consequences for the suckling infant.

Active transport of nitrofurantoin into human milk.

Study Objective. To determine the extent to which nitrofurantoin is transferred into human milk.

Neonatal Research and the Validity of Informed Consent Obtained in the Perinatal Period

BACKGROUND: Consent for participation in clinical research is considered valid if it is informed, understood, and voluntary. In the case of minors, parents give permission for their child to participate in research studies after being presented with all information needed to make an informed decision. Although informed consent is a vital component of clinical research, there is little information evaluating its validity in neonatal intensive-care populations. The objective of this project was to determine the validity of informed consent obtained from parents of infants enrolled in the multicenter randomized research study, neurologic outcomes and pre-emptive analgesia in the neonate (NEOPAIN).DESIGN/METHODS: Parents of infants who survived to discharge and had signed consent for their newborn to participate in the NEOPAIN study at the University of Kentucky were asked 20 open-ended questions to determine their level of understanding about the NEOPAIN study. The NEOPAIN consent form, which had been approved by the University of Kentucky Medical Institutional Review Board (IRB), was used to formulate these questions. Questions addressed the timing of consent, parental understanding of the purpose, benefits, and risks of the study, the voluntary nature of the project, and their willingness to enroll in future studies if the opportunity presented. Answers were scored on a Likert scale, with 1 for no understanding and 5 for complete understanding.RESULTS: Five of 64 parents (7.8%) had no recollection of the NEOPAIN study or of signing consent. Of those who remembered the study, only 67.8% understood the purpose of the study, with a higher proportion of the mothers than fathers knowing the purpose of the study (73.3% vs 57.1%), (p=0.029). Of those who understood the purpose of the study 95% were able to verbalize the benefits, but only 5% understood any potential risks. No parents reported feeling pressured or coerced to sign consent for the project and all parents reported they would enroll their child in additional studies if asked.CONCLUSIONS: Valid consent in the antenatal/perinatal population is difficult, if not impossible, to obtain. To maximize validity of consent in the antenatal/perinatal population every effort should be made to include mothers in the consent process. Additional attention during the consent process should be given to possible risks of the study.

Changes in Neurotrophin Levels in Umbilical Cord Blood From Infants With Different Gestational Ages and Clinical Conditions

Apoptotic neuronal loss may be responsible for altered brain development associated with prematurity and perinatal insults. Neurotrophins play crucial roles in protecting neurons from entering or progressing along an apoptotic pathway. The present study examined levels of neurotrophins in human umbilical cord blood from infants at different gestational ages and clinical conditions. We collected 60 samples of cord blood and categorized them accordingly into three gestational age groups: group A (24–28 wk), group B (29–35 wk), and group C (≥36 wk). Neurotrophin levels were determined by using brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) ELISA. Clinical data were obtained by medical chart analysis. The BDNF levels were 884 ± 386, 1421 ± 616, and 2190 ± 356 pg/mL in group A, group B, and group C, respectively. Significant differences were found between groups A and B (p = 0.038), groups A and C (p = 0.0001), and groups B and C (p = 0.001). Infants with severe intraventricular hemorrhage had significantly lower cord blood BDNF levels (925 ± 513 pg/mL) compared with their normal counterparts (1650 ± 674 pg/mL;p = 0.021). NT3 levels did not show significant change either across gestational ages or with the presence of intraventricular hemorrhage. Cord blood levels of BDNF may reflect the degree of neural maturity in premature infants. Interestingly, when a complete course of antenatal steroids was given, BDNF and NT3 cord blood levels were higher than when no steroid was given. Increased neurotrophins levels may also mediate improved neurodevelopmental outcome in infants who received antenatal steroids.

Clinical and Biochemical Variation and Family Studies in the Multiple Acyl-CoA Dehydrogenation Disorders

ABSTRACT: We report clinical and biochemical studies in patients with multiple acyl-CoA dehydrogenation disorders (MAD) and their parents. A severely affected (MAD:S) patient presented with neonatal acidosis leading to death and excreted a wide range of straight- and branched-chain acyl CoA derivatives. Two patients with mild variants of the same disorder (MAD:M) presented with neurologic abnormalities, acidotic coma, and/or poor growth; they primarily excreted ethylmalonate and variable amounts of adipate. Fibroblasts from the MAD:S patient demonstrated severely defective radiolabeled substrate oxidation, while the MAD:M cells had milder oxidative defects. Fibroblasts from two other MAD:M and six other MAD:S patients demonstrated analogous defects in substrate oxidation. As a group, MAD:S cells deficient in electron transfer flavoprotein:ubiquinone oxidoreductase had significantly lower residual oxidative activities than did MAD:S cells deficient in electron transfer flavoprotein. Fibroblasts from the parents of four MAD:S patients oxidized radiolabeled substrates significantly less effectively than did normal infant controls but were indistinguishable from normal adult cells. We found relatively higher residual oxidative activities in maternal than in paternal cells. Amniocytes from a fetus at risk for MAD:S catabolized labeled substrates normally; the infant has been clinically and biochemically normal up to 30 months of age.

Hydromorphone transfer into breast milk after intranasal administration.

Study Objectives. To determine the distribution of hydromorphone into breast milk and the potential exposure of the suckling infant, and whether the distribution of hydromorphone into milk can be predicted accurately by a passive diffusion model.

Brain-Derived Neurotrophic Factor in Infants <32 Weeks Gestational Age: Correlation With Antenatal Factors and Postnatal Outcomes

Neurotrophins (NTs) play important roles in brain growth and development. Cord blood (CB) brain-derived neurotrophic factor (BDNF) concentrations increase with gestational age but data regarding postnatal changes are limited. We measured BDNF concentrations after birth in 33 preterm infants <32-wk gestation. Serum was collected at birth (CB), at day 2, between day 6 and 10 (D6), at day 30 (D30), and at day 60 (D60). BDNF concentrations fell on D2 (p = 0.03), recovered by D6 (p = 0.10), and continued to rise thereafter at D30 (p = 0.06) and D60 (p = 0.01) compared with CB. CB BDNF concentrations positively correlated with duration of rupture of membranes (r = 0.43, p = 0.04). Antenatal steroids (ANS, p = 0.02), postnatal steroids (PNS, p = 0.04), and retinopathy of prematurity (ROP, p = 0.02) were identified as significant factors in multivariate analyses. The median (25–75th interquartile range) CB BDNF concentrations were higher in infants who received a complete course ANS compared with those who received a partial course [1461 (553–2064) versus 281 (171–536) pg/mL, p = 0.04]. BDNF concentrations negatively correlated with the use of PNS at D30 (r = −0.53, p = 0.002) and at D60 (r = −0.55, p = 0.009). PNS use was associated with reduced concentrations of BDNF at D30 [733 (101–1983) versus 2224 (1677–4400) pg/mL, p = 0.004] and at D60 [1149 (288–2270) versus 2560 (1337–5166) pg/mL, p = 0.01]. BDNF concentrations on D60 in infants who developed ROP (n = 16) were lower than those who did not develop ROP (n = 7) [1417 (553–2540) versus 3593 (2620–7433) pg/mL, respectively, p = 0.005]. Our data suggests that BDNF concentrations rise beyond the first week of age. BDNF concentrations correlate with factors that influence neurodevelopment outcomes.

Occult Spinal Dysraphism in the Infant Clinical and Sonographic Review

The progressive neurologic dysfunction caused by occult spinal dysraphism can be prevented with early clinical recognition, radiographic diagnosis, and neurosurgical treatment. However, detection of occult spinal dysraphism in the infant is difficult because neurologic symptoms often are not apparent until the child becomes ambulatory. Occult spinal dysraphism, however, can be suspected in the asymptomatic neonate when cutaneous stigmata, such as hemangiomas, hairy patches, deep and/or eccentric dimples, or subcutaneous masses are seen over the lumbosacral spine. Because of the serious, often irreversible, sequelae of a delayed diagnosis, spinal sonography of high-risk infants with midline, lumbosacral, cutaneous stigmata should be considered as an effective, noninvasive screening method.