Clinical trial of naloxone in birth asphyxia. Use of nalotone to to reverse narcotic respiratory depression in the newborn infant. Effects of naloxone on pethidine-induced neonatal depression. Part I--Intravenous naloxone. Effects of naloxone on pethidine-induced neonatal depression. Part II--Intramuscular naloxone. Effects of naloxone on newborn infant behavior after maternal analgesia with pethidine during labor. Naloxone reversal of mild neurobehavioral depression in normal newborn infants after routine obstetric analgesia. Reversal of narcotic depression in the neonate by nalozone. A randomised controlled trial of morphine versus phenobarbitone for neonatal abstinence syndrome. Intravenous fentanyl PCA during labour.
To determine whether endogenous opiates play a role in the pathogenesis of perinatal asphyxia, a blinded clinical trial of naloxone, a competitive opiate receptor blocker, was undertaken in infants with low 1-minute Apgar scores. Of 85 infants with 1-minute Apgar score 0 to 3, 44 received an injection of naloxone (approximately 0.4 mg/kg) and 41 received saline solution. In 108 infants with 1-minute Apgar score 4 to 6, 54 received naloxone and 54 saline solution. In neither group was there a significant effect of naloxone on respiratory frequency or heart rate up to 30 minutes after injection, nor at 24 hours of age. In both groups active muscle tone of upper and lower limbs was increased by naloxone, a response that may not be beneficial in the face of inadequate oxygen delivery to vital organs. We conclude that naloxone at this dose had no readily apparent benefit in the resuscitation of the asphyxiated newborn infant. Twenty neonates whose mothers had received meperidine (1.0 to 1.5 mg/kg) intravenously within three hours of delivery were studied to determine the effectiveness of naloxone in reversing neonatal respiratory depression. The following measurements were carried out within 20 to 30 minutes after delivery: minute ventilation, end tidal CO2, and ventilatory response to CO2. These determinations were repeated after administration of either placebo or naloxone, 0.01 mg/kg intramuscularly. Minute ventilation and PAco were within a normal range before medication in both groups, but the slope of the CO2 response curve was decreased, indicating mild-to-moderate respiratory depression. After administration of placebo the test results did not change significantly. After administration of naloxone, VE increased significantly (P less than 0.05) and the slope of the CO2 response curve doubled (P less than 0.001). Naloxone effectively reverses narcotic depression of the respiratory center in the newborn infant. Infants whose mothers had had pethidine during labour were given either naloxone 40 microgram or isotonic saline administered intravenously double-blind within one minute of birth. Peak alveolar carbon dioxide tension, carbon dioxide excretion, alveolar ventilation, feeding behaviour, and habituation to a specific sound stimulus were measured regularly up to 48 hours after birth. Alveolar carbon dioxide tension was significantly lower and alveolar ventilation significantly higher half an hour after birth in the naloxone-treated group than in the saline-treated group, but these differences between the groups were not significant at any other time, and there were no significant differences in sucking frequency or pressure, milk consumption, or habituation to the auditory stimulus. Thirty full-term infants whose mothers had had pethidine during labour were given either naloxone 200 microgram or normal saline intramuscularly. The drugs were chosen blindly and administered within one minute of birth. Naloxone produced a significant reduction in mean alveolar carbon dioxide tension and an increase in carbon dioxide excretion and mean alveolar ventilation at all times up to 48 hours after birth. The mean rate of habituation to a repeated auditory stimulus, the mean sucking frequency, the sucking pressure, and the mean consumption of milk were all significantly higher in the naloxone-treated group than in the placebo-treated group up to 48 hours after birth. Intramuscular naxolone therefore seemed to reverse the undesirable effects of pethidine. Infants born to mothers receiving 100 mg of pethidine during labor, were randomly given either 100 micrograms of naloxone (n = 14) or 0.25 ml 0.9% NaCl (n = 13) one hour post partum. Infant behavior was assessed with the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) and the Broussard Neonatal Perception Inventory (NPI). No differences in cluster scores on the BNBAS were found between the two groups. Both groups improved scores over time in 4 out of 7 clusters. On the NPI, mothers assessed naloxone infants as having less optimal behavior than did the control mothers. The results of this study on the effects of naloxone on infant behavior and maternal perception of newborn behavior do not warrant administration of naloxone after maternal analgesia with pethidine in the absence of clinical evidence of respiratory depression in the newborn. To investigate the presence of subtle narcotic depression following maternal narcotic analgesia, we have evaluated the effects of naloxone versus placebo in a double-blind parallel group study in 43 normal term newborn infants whose mothers had received routine narcotic analgesia within six hours prior to delivery. Infants were given either an intramuscular injection of 20 microgram/kg naloxone or 0.20 ml/kg placebo after determination of the one-minute Apgar score, and the following measurements were compared: Apgar scores at one and five minutes, capillary blood gas values at one, 60, 120, and 240 minutes, and neurobehavioral assessments at one, 4, and 24 hours. No adverse effects from naloxone were observed. Neither Apgar scores nor capillary blood gas determinations differed significantly between the two groups. Response to sound was significantly higher in the naloxone group at 24 hours. The alertness score was significantly higher for the naloxone group at one and four hours; the general assessment score for the naloxone group was significantly higher at four and 24 hours. Average scores of naloxone and placebo groups were also different at four and 24 hours of age. These data demonstrate that maternal narcotic analgesia may produce subtle changes in alertness and general behavior not reflected by Apgar scores or respiratory status, potentially reversible by administration of naloxone shortly following delivery. Naloxone 40 mug was administered intravenously one minute after birth to 20 out of 44 neonates whose mother had been given pethidine in labour. These neonates were compared with 20 others whose mothers had had only lumbar epidural block. Alveolar PCO2, alveolar ventilation, and ventilatory rate were measured 10 and 30 minutes after birth. The untreated neonates of mothers who had had pethidine showed significant ventilatory depression compared with infants in the epidural and naloxone-treated groups. The naloxone-treated neonates were comparable with the epidural group, although the effects of naloxone were diminishing at 30 minutes. Naloxone is an effective narcotic antagonist which should be considered to be the drug of choice for treating narcotic depression in the neonate. The incidence of neonatal abstinence syndrome (NAS) has increased 10-fold over the last decade in Glasgow. In the Princess Royal Maternity Hospital, it now accounts for 17% of special care baby unit (SCBU) admissions.
                To compare opiate replacement therapy (morphine sulphate) with the present standard treatment (phenobarbitone) for management of NAS. The primary study end point was duration of pharmaceutical treatment. Secondary end points were the requirement for additional drugs and the requirement for SCBU admission.
                Double blind, randomised controlled clinical trial.
                Differential diagnoses were excluded, and two consecutive Lipsitz scores > 4 defined NAS requiring treatment. Infants were randomised to receive morphine sulphate or phenobarbitone. Treatments were identical in appearance, odour, and volume. Increments, decrements, and discontinuation of treatments were protocol driven.
                Seventy five infants participated. All mothers received opiate replacement therapy (methadone) during pregnancy and most used other drugs (n = 62, 83%). No significant difference in maternal drug use patterns was observed between treatment groups. Median treatment duration was four days shorter with opiate replacement (8 v 12 days, Mann-Whitney U test, p = 0.02). Phenobarbitone treated infants tended to require second line treatment (47% v 35%, chi(2) test, p = 0.11) and SCBU admission (62% v 30%, chi(2) test, p = 0.04) more often.
                Opiate replacement therapy appears to be superior for management of symptomatic NAS when maternal opiate use is prevalent. The shorter treatment duration and lower requirement for higher intensity nursing may have significant cost implications. Tailoring NAS treatment to local maternal drug use may result in similar benefits. To evaluate the usefulness of intravenous patient-controlled analgesia (PCA) fentanyl for labour analgesia, its effectiveness for maternal pain and safety for the fetus and newborn.
                Twenty primigravidas were randomised to receive intravenous PCA fentanyl or epidural analgesia for labour pain. Maternal pain, heart rate and arterial oxyhaemoglobin saturation (SpO2) were monitored. Fetal and neonatal monitoring included cardiotocogram (CTG), APGAR, neurological scoring and static-charge-sensitive bed (SCSB) recording for 12 hr postnatally with ECG and SpO2. Fentanyl concentrations and pH of umbilical artery and vein were analysed.
                Initially, epidural analgesia was more effective (P = 0.01), and three patients in the fentanyl group were given epidural due to unsatisfactory pain relief. Overall satisfaction for analgesia did not differ between the groups. Maternal side-effects were more frequent in the fentanyl group (dizziness and tiredness most often, P = 0.0001). Severe side-effects were not reported. In CTG there were no differences between groups. All the newborns were healthy, APGAR and pH were normal. Naloxone was not used. Neurological scoring was similar in both groups. In 12 hr monitoring heart rate, breathing frequency and movement time were similar in both groups, but SpO2 was lower in the fentanyl group (P < 0.001). Umbilical cord fentanyl concentrations were low or beyond the detection limit.
                Intravenous fentanyl can be used for labour analgesia with the doses reported here as an alternative to epidural analgesia. However, the fetus and neonate must be appropriately monitored. Naloxone and oxygen should be available if neonatal distress occurs.
The existing evidence from randomised controlled trials is insufficient to determine whether naloxone confers any important benefits to newborn infants with cardiorespiratory or neurological depression that may be due to intrauterine exposure to opiate. Given concerns about the safety of naloxone in this context it may be appropriate to limit its use to randomised controlled trials that aim resolve these uncertainties.