Postoperative morphine infusion in newborn infants: Assessment of disposition characteristics and safety

Koren, Gideon; Butt, Warwick; Chinyanga, H. M.; Soldin, Steven J.; Tan, Yok-Kwang; Pape, Karen E.

doi:10.1016/s0022-3476(85)80205-5

Cited by 171 publications

(62 citation statements)

References 9 publications

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“…Hence, premature and full-term neonates may be at risk for CNS drug toxicity due to the limited BBB P-gp expression in the brain microvessels. Furthermore, neonates and young infants have been shown to be more sensitive to the central depressive effects of morphine compared to older children and adults in both animal and human studies (14)(15)(16)(17)(18)(19). Taken together with the findings from the present study, differences in BBB P-gp expression during brain development most likely enhance the CNS passage into the brain.…”

Section: Resultssupporting

confidence: 58%

“…Neonates have been shown to have a heightened sensitivity to the central depressive effects of opioids compared to older infants and adults in both animal and human studies (14)(15)(16)(17)(18)(19). Furthermore, recent studies have documented that the newborn infant is sensitive to the respiratory effects of morphine when the mother is breastfeeding while taking codeine (20,21).…”

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confidence: 99%

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The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates

et al. 2015

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Background:Neonates have been shown to have a heightened sensitivity to the central depressive effects of opioids compared to older infants and adults. The limited development of P-glycoprotein (P-gp) may limit the ability of the neonate to efflux morphine from the brain back to the systemic circulation. The objective of the study was to determine the ontogeny of P-gp in the human brain. Methods: Postmortem cortex samples from gestational age (GA) 20-26 wk, GA 36-40 wk, postnatal age (PNA) 0-3 mo, PNA 3-6 mo, and adults were immunostained for P-gp. results: The intensity of P-gp staining in adults was significantly higher compared to at GA 20-26 wk (P < 0.05), GA 36-40 wk (P < 0.05), and PNA 0-3 mo (P < 0.05). P-gp intensity at GA 20-26 wk (P < 0.05), GA 36-40 wk (P < 0.05), and PNA 0-3 mo (P < 0.05) was significantly lower compared to at PNA 3-6 mo. conclusion: P-gp expression in the brain is limited at birth, increases with postnatal maturation, and reaches adult levels at ~3-6 mo of age. Given the immaturity of blood-brain barrier (BBB) P-gp after birth, morphine may concentrate in the brain. This provides mechanistic support to life threatening opioid toxicity seen with maternal codeine use during breastfeeding.

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Section: Resultssupporting

confidence: 58%

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confidence: 99%

The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates

et al. 2015

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“…Koren et al 6 reported 12 neonates who received a morphine infusion. Two of these patients developed generalized seizure activity associated with the morphine administration at high continuous infusion rates.…”

Section: Discussionmentioning

confidence: 99%

“…Seizures stopped a few hours after discontinuation of the drug, and the investigations failed to reveal other reasons for convulsion. 6 A question remains as to the exact etiology of seizure activity in these complex patients receiving concomitant infusion of opioids.…”

Section: Discussionmentioning

confidence: 99%

“…1 Seizure activity as a complication of opioid administration has been reported in the literature in laboratory animals, 2 adult humans [3][4][5] and neonates. 6 Electrical seizure activity induced by opiates has been well documented with electroencephalogram (EEG) recording in animals. 2 The correlation between abnormal movements and electrical seizures is less consistent in adult humans receiving opiates 5,[7][8][9] and is lacking in the neonatal patient.…”

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Seizure and Electroencephalographic Changes in the Newborn Period Induced By Opiates and Corrected By Naloxone Infusion

Alexandrou

Knoppert

et al. 1999

J Perinatol

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OBJECTIVE:To describe the association between opioid administration in the newborn period and neurologic abnormalities STUDY DESIGN:Case reports of two infants who presented with seizure activity and abnormal electroencephalograms associated with opiate administration, and reversed by naloxone RESULTS:The first was a preterm infant who developed a burst-suppression pattern on the electroencephalogram while receiving a continuous infusion of morphine and muscle paralysis. Naloxone injection during the electroencephalogram recording reversed the burst-suppression pattern. The second was a term infant receiving fentanyl infusion for pain control following surgery, who presented with motor seizure that was only partially controlled with barbiturates. An abnormal electroencephalogram recording during the opiate infusion improved with naloxone administration. CONCLUSION:Our observations indicate a potential for neurologic abnormalities, including induction of seizure activity and electroencephalogram abnormalities, suggesting caution when opiates are used for sedation and/or pain control in the newborn period.Opiates are widely used in neonatal intensive care units for routine sedation/analgesia of critically ill neonates receiving mechanical ventilation, as well as for postoperative pain control. 1 Seizure activity as a complication of opioid administration has been reported in the literature in laboratory animals, 2 adult humans 3-5 and neonates. 6 Electrical seizure activity induced by opiates has been well documented with electroencephalogram (EEG) recording in animals. 2 The correlation between abnormal movements and electrical seizures is less consistent in adult humans receiving opiates 5,7-9 and is lacking in the neonatal patient. The objective of our study is to report on two infants with abnormal electroencephalographic findings while receiving opioids. One infant presented with clinical and electroencephalographic seizure activity. The second infant had a grossly abnormal EEG pattern. CASE 1Baby girl M was born at 39 weeks' gestation by elective cesarean section to a 34-year-old mother. The birth weight was 3975 gm, the cord arterial pH was 7.34, and the Apgar scores were 9 and 9 at 1 and 5 minutes, respectively. The baby was admitted to the normal newborn nursery for routine care. She was transferred to the neonatal intensive care unit (NICU) at 24 hours of age due to abdominal distention and bilious vomiting. Radiologic studies revealed a small bowel obstruction and she was operated at 35 hours of age for congenital ileal atresia. She received a cumulative dose of 20 g (5 g/kg) of fentanyl for anesthesia and 1 mg (0.25 mg/kg) of morphine in the operating suite for pain control (increased heart rate and increased blood pressure during operation). There were no complications during the surgery. Fifteen minutes postoperatively she was noted to have abnormal movements (fasciculation of the tongue and lips). A continuous infusion of fentanyl was started at a rate of 5 g/kg per hour beginning 30 minutes postsur...

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Variation Among Neonatal Intensive Care Units in Narcotic Administration

Kahn¹,

Richardson²,

Gray³

et al. 1998

Arch Pediatr Adolesc Med

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Objectives: To compare rates of narcotic administration for medically treated neonates in different neonatal intensive care units (NICUs) and to compare treated and untreated neonates to assess whether narcotics provided advantages or disadvantages for short-term outcomes, such as cardiovascular stability (ie, blood pressure and heart rate), hyperbilirubinemia, duration of respiratory support, growth, and the incidence of intraventricular hemorrhage. Study Design: The medical charts of neonates weighing less than 1500 g, admitted to 6 NICUs (A-F), were abstracted. Neonates who had a chest tube or who had undergone surgery were excluded from the study, leaving the records of 1171 neonates. We modeled outcomes by linear or logistic regression, controlling for birth weight (Ͻ750, 750-999, and 1000-1499 g) and illness severity (low, 0-9; medium, 10-19; high, Ն20) using the Score for Neonatal Acute Physiology (SNAP), and adjusted for NICU.

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Postoperative morphine infusion in newborn infants: Assessment of disposition characteristics and safety

Cited by 171 publications

References 9 publications

The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates

The ontogeny of P-glycoprotein in the developing human blood–brain barrier: implication for opioid toxicity in neonates

Seizure and Electroencephalographic Changes in the Newborn Period Induced By Opiates and Corrected By Naloxone Infusion

Variation Among Neonatal Intensive Care Units in Narcotic Administration

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