Management of Neonatal Abstinence Syndrome in an Extremely Premature Infant
Mark Greenberg, M.D. Associate Professor, Departments of Anesthesiology and Pediatrics University of California, San Diego, USA
Neil Finer M.D. Professor, Department of Pediatrics University of California, San Diego, USA
Edward Mc Feely B.S. Assistant Clinical Professor, School of Pharmacy University of California, San Diego and San Francisco, USA
Vol. 4, N. 2, Maggio 2006
Abstract
The neonatal abstinence syndrome (NAS) is usually a disorder of term or near-term infants. Premature infants, born to narcotic dependent mothers and who may require additional medical support secondary to organ immaturity may also display narcotic withdrawal. We report a 24 week preterm infant exposed in utero to large doses of maternal methadone. The infant displayed withdrawal symptoms within 24 hours of birth and initially required intravenous opioids until enteral feeds were commenced, Treatment of withdrawal was prolonged and eventually required oral methadone and clonidine. Maternal breast milk was utilized both for its nutrient value and as a source of opioid. After a prolonged course the baby was discharged, and successfully weaned off opioids. Also discussed was the potential problem of recognizing NAS in the extremely premature infant.
Introduction
In utero methadone exposure, if of a significant duration will usually lead to signs of opioid withdrawal shortly after birth (1). Most infants require treatment with opioids to prevent the neonatal abstinence syndrome (NAS). Oral methadone is often utilized for detoxification due to its long duration of action, and ease of clinical control. The role of breastfeeding in the management of the opioid withdrawing infant can be complicated. Breastfeeding provides both nutritional and behavioral advantages to the mother and infant, but the amount of methadone that passes into human breast milk is usually insufficient to treat withdrawal symptoms alone (2). However such breastfeeding may permit a reduction in the infant's oral methadone dose. Premature infants may show symptoms of withdrawal differently that term infants, and are known to be more sensitive to the respiratory depressive effects of opioids. We present the case of an extremely premature infant who required prolonged opioid therapy for the neonatal abstinences yndrome complicated by intermittent periods of fasting and intercurrent illness.
Case Report
A 615gram 24-week preterm baby was born to a 28-year-old female, who had a history of heroin use. She was treated with 100 mg per day of methadone throughout the pregnancy. Immediately after birth the baby required intubation, surfactant treatment and ongoing mechanical ventilation for the treatment of respiratory distress syndrome. On the second day of life, the baby exhibited twitching, exaggerated reflexes and hemodynamic instability, consistent with NAS. Intravenous morphine 0.1mg/kg every 8 hours was started, which ameliorated the symptoms. Trophic feeds were initiated on day of life five, consisting of 0.5mL of maternal breast milk every 12 hours. At approximately 2 weeks of age, oral methadone (0.05mg/kg every 8 hours), for maintenance therapy was started. Standard abstinence scoring, were used to monitor signs of withdrawal. During this time the intravenous morphine was tapered and discontinued. Four days after the morphine was discontinued, there was a return of withdrawal symptoms necessitating the methadone dose to be increased to 0.1mg/kg every 8 hours.
At one month of age, the baby was on full caloric feeds. Breast milk was initially supplemented with formula when supplies were unavailable. During this time the baby was having intermittent, alternating periods of apnea and agitation, which was thought to be secondary to the methadone in the mothers breast milk. Due to mother's inability to supply sufficient breast milk the infant was switched to exclusive formula feeding. After discontinuing the mothers' milk, the baby again had worsening of abstinence scores requiring the methadone dose to be increased to 0.2mg/kg every 8 hours.
The baby was extubated at 3 weeks of age and one month later developed respiratory failure, which required mechanical ventilation and a brief period of NPO. During this time the methadone was discontinued and the baby was switched to intravenous fentanyl (2 mcg/kg/hour) and hydromorphone (10mcg/kg/dose). Just prior to extuabation, after one week of mechanical ventilation, the oral methadone was restarted at the previous dose. During this time period, oral clonidine suspension of 10 mcg/kg/day given twice daily, was added due to worsening of the abstinence scores. This successfully controlled withdrawal symptoms. The patient was discharged on twice daily clonidine (10mcg/kg/day) and tapering methadone starting at 0.2 mg/kg/dose every 8 hours. After discharge, the baby's methadone dose was tapered10-20 % per week over the next six weeks, and on follow-up showed no signs of opioid withdrawal.
Discussion
This case illustrates the difficulty in managing an extremely premature infant who required treatment for NAS, after in-utero opioid exposure. There are several issues, which impacted this infant ' s care. First, was the issue o f r extreme prematurity. Like many newborn preterm infants, this baby was initially made NPO due to gastrointestinal immaturity and cardio-pulmonary instability. The inability to use the oral route to deliver opioids , complicates treatment of NAS, as intravenous drugs tend to be short acting and require frequent re-dosing. Infusions of morphine or fentanyl can be used, but newborns tend to develop increasing tolerance, necessitating escalating doses. ( This is especially true, in the case of fentanyl (3,4). Intravenous methadone is a good choice but is has been associated with prolonged qt syndrome and torsades de pointes (5).
The second issue was the fact that the baby was intermittently mechanically ventilated and needed supplemental analgesics for painful procedures. This substantially increases opioid requirements. Opioid weaning is often derailed when the total daily doses are intermittently high. Although necessary for the baby's care, this requires reevaluation by r the caretakers, as they and the family are often focused on the weaning process.
The third concern was the desire of the mother and care team to feed the infant maternal breast milk. This mother's methadone dose was quite substantial. The amount reaching the baby has been shown in studies to be very small, 1-3% of maternal dose (6,7,8). In this case, with a large maternal dose and the baby being very small, the actual amount of methadone delivered to the baby was substantial. Corroborating this assumption was the need to double the infants dose to suppress symptoms when the breast milk was discontinued. In otherwise healthy term infants, enteral nutrition by breastfeeding in opioid dependent babies has been shown to be effective, and may be the entire opioid source needed to prevent NAS (6). As the mother weans her dose so does the infant. However, as in this case when the supply and feeding of breast milk in inconsistent, the infant dosing is difficult to predict and more difficult to treat. In similar situations, where the baby is getting significant amounts of opioid through the breast milk, the dose must be increased to prevent withdrawal when the breast milk is discontinued (9).
Finally, the description of NAS in premature ture infants is very limited, and we could not find any reports of narcotic withdrawal in extremely low birth weight infants. Our experience with this infant suggests that opioid withdrawal presents in a similar fashion as in term infants, with some exceptions. These include signs of withdrawal such as yawning, sweating, hypertonia and diarrhea. These symptoms may not be as prominent in the premature baby and were not observed in this infant. We were able to use the standard abstinence scoring with good results. Seizures, which may be the only sign of withdrawal in the premature infant, fortunately were not observed in this infant (10,11).
The adequate suppression of withdrawal symptoms, despite the difficulty managing this baby is consistent with the experience at our institution, using methadone as the primary opioid to treat NAS. Clonidine, an alpha-2 agonist with opioid sparing properties was used as a supplement to help suppress the withdrawal symptoms (12). We frequently use clonidine as an adjunct to methadone in opioid dependent infants to decrease the dose, or at the end of a taper to help the weaning process.
In summary we present the case of an extremely premature infant, antenally exposed to opioids, who was successfully weaned, with minimal withdrawal symptoms despite a complicated medical course. Frequent monitoring of abstinence scores and attention to details helped detect problems quickly. Knowledge of the potential differences between NAS in premature and full term neonates can help with early detections of symptoms and initiation of early appropriate therapy. Direct and frequent communication between the neonatal care team and the pain service was essential for optimal management.
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