PEDIATRICS Vol. 106 No. 4 October 2000, pp. 831-834

EXPERIENCE AND REASON:
Role of Naloxone in Newborn Resuscitation

	ABSTRACT

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Objective.  Because of questions about the basis for the use of naloxone in resuscitation of the newborn, we wished to evaluate the use of naloxone at our institution and an affiliated hospital.

Methodology.  Evaluation of the actual use of naloxone at a university hospital and a community hospital: we document naloxone use by daily survey for a month in one; in the other, we perform a retrospective record review of 1 year's use.

Results.  The university hospital had 240 births during February, 1998. Naloxone was given twice: once, 7 minutes before delivery to a woman at term who had received opiates about 2 hours previously; and once, intramuscularly, to a premature infant for apnea, before being intubated. The community hospital had 2044 births during fiscal 1998. Twenty-six neonates were identified as having received naloxone. Of the 26, 13 received naloxone without needing ventilatory support; all 13 with respiratory depression had a predisposing perinatal complication.

Conclusion.  The use of naloxone in practice may not conform to the American Academy of Pediatrics' guidelines for use in resuscitation of the newborn. The use of naloxone in resuscitation of the newborn should be reevaluated.  Key words:  naloxone, resuscitation, newborn, opiates.

Naloxone, an opiate antagonist, is recommended in resuscitation of the newborn if a diagnosis is made of respiratory depression secondary to maternal opiate administration for pain control in labor. However, in our experience, there is a great deal of variability in the use of naloxone in the delivery room. In particular, less experienced physicians seem more apt than neonatologists to give naloxone to newborns. In addition, there appears to be a great deal of variation in the use of naloxone from hospital to hospital in the United States and abroad.¹ Therefore, we wished to undertake a critical review of the role of naloxone in newborn resuscitation.

In this article, as background, we review the evidence that formed the basis for the current recommendations by the American Academy of Pediatrics (AAP) Committee on Drugs² and the American Heart Association/American Academy of Pediatrics (AHA/AAP) Neonatal Resuscitation Steering Committee³ regarding the use of naloxone in newborn resuscitation. We present the results of a pilot study in which we documented the actual use of naloxone at our institution and at an affiliated community hospital and the extent to which the use conformed to the current AAP recommendations.

	BACKGROUND

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"Despite publication of `standard' recommendations for the pharmacologic aspects of neonatal cardiopulmonary resuscitation, the efficacy of many medications and their dosage and route of administration lack adequate scientific testing in newborns."⁴ Naloxone was introduced into the practice of resuscitation of the newborn in the delivery room as follows:

Meperidine, a synthetic narcotic analgesic, is commonly given for pain control in labor. In 1952, Apgar et al⁵ demonstrated, by measuring plasma levels in mothers and cord blood, that meperidine given to mothers in labor crosses the placentabut concluded that meperidine causes little or no depression of respiration in the newborn. Since that time, no blinded controlled studies have shown that opiates administered to the mother in labor affect the Apgar score or cause clinically important depression of respiration. However, subsequent studies of the neonatal effects of maternal opiates during labor have demonstrated subtle changes in newborns' ventilation and neurobehavior.^6-8 The maternal opiate dose, route of administration, and the dose to delivery interval are important factors in evaluating possible neonatal effects.⁹

Based on an uncontrolled study in infants presumed to have respiratory depression from maternal opiates given in labor, Eckenhoff et al¹⁰ recommended that normorphone, a narcotic antagonist, should be injected into the umbilical cord vein for the treatment of apnea neonatorum. Although the evidence was weak that maternal opiates substantially affect the condition of the infant at birth, narcotic antagonists (Lorphan and Nalline) were recommended in Schaffer's textbook Diseases of the Newborn¹¹ for resuscitation in the delivery room, to be given intravenously (IV) to the mother 5 to 15 minutes before delivery or IV into the umbilical vein of apneic, moderately or severely depressed infants. In 1967. Jasinski et al¹² studied a new narcotic antagonist, naloxone, in volunteer (sic) federal prisoners and concluded that, unlike prior drugs such as nalorphine, it had no agonistic activity and no abuse potential.

Naloxone hydrochloride (Narcan) was approved by the Food and Drug Administration in 1971 for neonates as well as adults, although the data to support its use in newborns were scant. The indication for naloxone was respiratory depression, as indicated by a low Apgar score, in neonates whose mothers had received opiates in labor. Despite a lack of neonatal data, in 1972 the Medical Letter¹³ consultants suggested that naloxone .01 to .015 mg/kg be injected into the umbilical vein if the newborn showed narcotic-induced respiratory depression.

In 1977 Gerhardt et al⁶ pointed out that naloxone was being used in the newborn without conclusive information about its effectiveness or adverse effects. Furthermore, they presented evidence that the Apgar score is not sufficiently sensitive to detect respiratory depression due to opiates, because the respiratory depression caused by maternal narcotics is not clinically apparent in those newborns exposed to moderately high doses in utero. They documented that maternal meperidine, up to 3 mg/kg IV within 3 hours before delivery, does not lower the Apgar score or cause demonstrable respiratory depression, with the exception of a decreased ventilatory response to breathing 4% carbon dioxide (CO₂). With the administration of naloxone, .01 mg/kg given intramuscularly (IM), there was an increase in the slope of the CO₂ response curve.¹⁴ They noted that the duration of the naloxone effect on the CO₂ response remained to be defined.

Moreland et al¹⁵ measured plasma levels of naloxone after 2 different doses that were given IV via the umbilical vein, .035 or .07 mg; and a larger dose, .2 mg, given IM. The peak level with IV administration varied from 5 to 40 minutes; after IM dosing, the peak was from .5 to 2 hours. No attempt was made to correlate these levels with clinical effectiveness.

A study¹⁶ of the placental transfer of meperidine (pethidine) showed that after an IM dose, the maternal peak plasma levels occur within 1 hour; after IV, the peak levels are at 5 to 10 minutes. Meperidine is readily transferred to the fetus with an equilibrium reached within 120 to 180 minutes after dosing. No systematic data are available on the relationship between opiate concentration and clinical effects in neonates.

In 1980, the AAP Committee on Drugs² reviewed the available data forming the basis for the use of naloxone in the newborn. They concluded that the results of the studies were inconsistent because the methods of assessment varied from study to study and maternal opiate and neonatal naloxone doses differed. There were no data regarding the use of naloxone in premature infants. In addition, the Committee raised questions of the long-term safety of naloxone and mentioned that "recent information regarding opiate receptors and endogenous opioids" raises concern. They made several recommendations to clarify the role of naloxone in the management of the depressed newborn, as follows: "1) Naloxone should be reserved for adjunctive therapy in selected infants who have not initiated or established independent respirations following ventilation, are significantly depressed, and have a high probability of being narcotized. 2) When naloxone is administered to the neonate, the recommended dose is .01 mg/kg. (In 1989, the Committee¹⁷ increased the recommended dose 10-fold to .1 mg/kg, including prematures, to be given IV or intratracheal.) The initial dose may be repeated in 3 to 5 minutes if there is no response. The dose may need to be repeated in 30 to 90 minutes, depending on the degree of depression of the infant, because of the relatively short duration of action of naloxone. Naloxone should be given intravenously, if possible. 3) Naloxone is not recommended for administration to the mother just before delivery to reverse the fetal and neonatal effects of maternally administered narcotic analgesics. 4) Naloxone should not be administered to infants of narcotic-dependent mothers as this may precipitate withdrawal in the physically dependent infant. 5) Naloxone should not be used routinely in narcotic-exposed newborns."

Chernick et al¹⁸ conducted a blinded clinical trial of naloxone in infants with low 1-minute Apgar scores to study whether endogenous opiates might play a role in the pathogenesis of perinatal asphyxia. The infants studied were born to women who had not received opiates within 4 hours of delivery and who did not receive general anesthesia. Forty-four of 85 infants with 1-minute Apgar scores of 0 to 3 received an IM injection of naloxone (.4 mg/kg) and 41 received saline solution. In 108 infants with 1-minute Apgar scores of 4 to 6, 54 received naloxone and 54 received saline solution. Naloxone had no significant effect on respiratory frequency or heart rate. They concluded that naloxone at the dose used had no apparent benefit in the resuscitation of the asphyxiated newborn infant.

Although the data to support the use of naloxone are not convincing, the possible need for it is emphasized in the teaching of neonatal resuscitation. The subsection entitled "Indication for Use" in the AHA/AAP Textbook of Neonatal Resuscitation³ states: "Naloxone is indicated when there is severe respiratory depression, and a history of maternal narcotic administration within the past 4 hours." The accompanying text states "the infant should receive prompt and adequate ventilatory assistance until naloxone can be administered and exert its effect."

Despite standard recommendations, there appears to be wide variability in the use of naloxone from one hospital to another¹ that seems unexplained by differences in maternal exposure to opiates. Having reviewed the evidence that forms the basis for the current guidelines for newborn resuscitation, we wanted to evaluate the actual use of naloxone in the delivery room of 2 hospitals. We conducted a daily survey of the use of naloxone in a university hospital (UH) for a 1-month period, followed by a retrospective chart review for quality improvement purposes of the use of naloxone for one year in a community hospital (CH) where residents in family medicine are responsible for the delivery room care of the newborns. In both hospitals, the AHA/AAP Neonatal Resuscitation Course³ is taught. We did not evaluate the condition of all infants born in the 2 time periods or attempt to identify all infants at the CH who might have been candidates for the drug. Rather, we assessed the extent to which the actual use of naloxone in these 2 hospitals conformed to the guidelines set by the AAP Committee on Drugs.²

	MATERIALS AND METHODS

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Data extracted in both sets of patients included date and time of delivery; gestational age; pregnancy complications; intrapartum complications; maternal anesthesia; dose, route, and time of maternal opiate administration; newborn Apgar scores; birth weight; resuscitation measures; time after birth, dose, and route of naloxone administration; and any newborn nursery problems. All the charts were reviewed by 1 investigator (M.H.).

At the UH, there was no system for identifying naloxone use retrospectively; therefore, in mothers in labor, we identified opiate use via the pharmacy medication dispensing system (MedStation Rx, Pyxis Corp, San Diego, CA) on a daily basis for 1 month and found naloxone use by daily chart review. Charts of the mothers who received opiates and their newborns were reviewed.

At the CH, 1 year of neonatal naloxone use was identified retrospectively by billing code. Charts were reviewed for all neonates who received naloxone and their mothers. We defined neonatal respiratory depression as the need for bag and mask resuscitation. We did not attempt to identify all mothers who received opiates over the year's time, nor did we review the outcome of all infants exposed or not exposed to opiates and those not exposed to naloxone. Statistical analyses included computation of 95% confidence intervals (CI) for the proportions reported, and a Fisher's exact test.

	RESULTS

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UH

The UH had 240 births during February 1998, the month under review. Eighty-four mothers received opiates, 52 within 4 hours of delivery. Thirty-two women out of the 84 received opiates >4 hours before delivery; of their newborns, 2 of 32 had a 1-minute Apgar score (Ap 1) <7 (6.2%, 95% CI: .8-20.8%); 1 of 32 had a 5-minute Apgar score (Ap 5) <7 (3.1%, 95% CI: .1-16.2%). Of the 52 newborns exposed to opiates within 4 hours of delivery, 3 out of 52 had Ap 1 <7 (5.8%, 95% CI: 1.2-15.9%) (2/32 vs 3/52, 2-sided Fisher's exact test; P = 1.0); none had Ap 5 <7 (0%, 95% CI: 0-6.8%). Naloxone was given twice: once, 7 minutes prior to delivery (PTD) to a woman at term who had received opiates about 2 hours previously; and once, IM, to a premature infant for apnea, before being intubated. (33 weeks, birth weight 1500 g, induction for preeclampsia, late decelerations, opiates 1 hour 10 minutes PTD, Apgar scores 8 and 9, required oxygen, sepsis suspect.)

CH

The CH had 2044 births during fiscal 1998, the year under review. Twenty-six neonates were identified as having received naloxone. All 26 gestations were 37 to 42 weeks in length, birth weights were >2500 g. Mothers of all 26 neonates had received opiates (meperidine, butorphanol, or morphine); in addition to opiate analgesia, 5 mothers received epidural anesthesia. Twenty of 26 neonates (76.9%, 95% CI: 56.4-91.0%) were exposed to opiates within 4 hours of delivery. Eleven of 26 infants had Ap 1 <7 (42.3%, 95% CI: 23.4-63.1%); 1 of 26 had Ap 5 <7 (3.8%, 95% CI: .1-19.6%). Three of the 6 (50%, 95% CI: 11.9-88.2%) of those neonates not exposed to narcotics within 4 hours of delivery had respiratory depression; likewise, 10 of 20 (50%, 95% CI: 27.2-72.8%) of those who were exposed to narcotics within 4 hours of delivery had respiratory depression. Of the 26 neonates, all 13 with respiratory depression (3 not exposed, 10 exposed to opiates within 4 hours of birth) had a predisposing perinatal complication: abruption (1), deep repetitive decelerations of the fetal heart rate (5), tight nuchal cord (5), shoulder dystocia (1), thick meconium (1). Of the 26 infants, the remaining 13 (3 not exposed, 10 exposed to opiates within 4 hours of birth) neonates received naloxone without needing ventilatory support. Naloxone was given IM in all 26 cases. Postnatal age at the time of administration of naloxone varied from immediate to 1 hour, 40 minutes (19 at 10 minutes; 5 at 11 to 30 minutes; 2 at >30 minutes).

	DISCUSSION

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In neither hospital was naloxone given as recommended by the AAP Committee on Drugs.² Namely, it was 1) given to the mother before delivery (UH); 2) given IM in all cases; 3) given when there was no significant respiratory depression (CH); 4) given when it was unlikely that the neonate was narcotized (CH); 5) given even though perinatal complications could explain the newborn's depressed condition at birth (CH); 6) given without first supporting the neonate's ventilation (UH).

Not only did the use not conform to the detailed recommendations of the AAP Committee on Drugs,² in many instances it did not conform to the much less specific recommendations of the AHA/AAP Neonatal Resuscitation Textbook.³ Naloxone was given even when opiates had not been administered to the mother within 4 hours of delivery; it was given to infants who did not have severe respiratory depression; it was given without first supporting the neonate's ventilation; and it was given IM, although IV is the preferred route.

Furthermore, in our small dataset from the UH, there was no significant difference between the Apgar scores of those exposed as compared with those not exposed to opiates within 4 hours of delivery. This finding is consistent with that of Sharma et al¹⁹ in a study of epidural versus patient-controlled meperidine analgesia during labor in which there was no evidence that the type of analgesia had any deleterious effect on neonatal Apgar scores or acid-base condition.

In the CH population, because of the retrospective design of the study, it is possible that some cases of naloxone use were not identified. However, there is nothing to suggest that the selection of the sample was biased; there is no reason to think that in patients who might have been omitted, the use of naloxone would have been any different.

Because of our small numbers and limited data collection, we can draw no conclusions and we make no generalizations about the frequency of use of naloxone in a UH versus a CH. Nor can we document, other than anecdotally, that residents are more apt to give naloxone than neonatologists; 5 of 6 members of our neonatology section say they have "never" ordered naloxone to be given, although they have seen it used by residents.

Our background review of the basis for the recommended use of naloxone for neonatal resuscitation suggests that the current teaching, as expressed in the AAP/AHA Neonatal Resuscitation Textbook,³ is founded on limited scientific evidence. The brief instructions in the text do not fully reflect the thoughtful and comprehensive evaluation of the indications for naloxone as enumerated by the AAP Committee on Drugs.² We believe that the resuscitation course instructions to give naloxone to a neonate with respiratory depression at birth (if the mother has received proximate opiate exposure) do not encourage the inexperienced physician to understand the events occurring in labor and the pathophysiology of fetal asphyxia. The physician is apt to make a diagnosis of "depressed due to maternal medication" and disregard the fact that, for example, the fetus had an abnormal heart rate pattern and the newborn has respiratory depression secondary to intrauterine hypoxia.

We found, in our pilot study, that the actual use of naloxone in 2 hospitals was not in accordance with the carefully worded recommendations for naloxone use in the newborn by the AAP Committee on Drugs.² Based on conversations with colleagues at other hospitals, we believe it is unlikely that this apparent inappropriate use is unique to our 2 hospitals, though we cannot define the scope of the problem. We believe the role of naloxone in resuscitation of the newborn needs to be reevaluated both in terms of the scientific basis for its use, its place in the teaching of neonatal resuscitation, and the way naloxone is actually being used in the delivery room.

Certainly, there is a theoretical basis for the potential need for naloxone in the resuscitation of the newborn. Pharmacologic factors should be considered when laboring mothers are given opiate analgesia. Opiates have low molecular weights and are lipid-soluble, both factors favoring transport across the placenta. The fetal pH is acidic relative to the maternal pH, which promotes ionization of these medications once in the fetal circulation and tends to inhibit reverse transport across the placenta. In addition, the meperidine disappearance rate is prolonged in the newborn.¹⁶ When the mother is given repeated doses of opiate analgesia, there could be clinically significant plasma concentrations in the fetus and newborn.

In the adult, morphine has a half-life of approximately 2 hours, while the half-life of meperidine is approximately 3 to 4 hours and that of butorphanol is about 3 hours.²⁰ When a single dose is given to the mother, the fetus is unlikely to be affected if the delivery occurs quickly after the drug is administered or after adequate time has passed to allow for maternal clearance. When the maternal-fetal pH difference is small, fetal drug can cross back to the maternal side and be eliminated. Thus, those fetuses demonstrating significant distress and acidosis whose mothers received opiates 1 to 3 hours before delivery or multiple doses might be at the greatest risk for respiratory depression, a condition that most likely would be multifactorial in origin.¹⁶

As we indicate in the "Background," there is not much information about the clinical pharmacology of naloxone in the newborn. It is not known what blood levels are required to reverse a given exposure to opiates and the duration of the naloxone effect remains to be defined. Probably one ought not to assume that neonatal naloxone use is harmless. There is growing evidence regarding the important effects of endogenous opioids and opioid receptors on fetal and neonatal neuroendocrine systems and on behavior.^21,22 Treatment of rat pups with naloxone during suckling is associated with a long-lasting increased pain responsiveness and diminished analgesic response to morphine.²³ We believe that if the carefully worded recommendations of the AAP Committee on Drugs² were followed correctly, few, if any, newborns would be suitable candidates for the use of naloxone in the delivery room. There is a need to evaluate the appropriate use of naloxone in neonatal resuscitation.

Marguerite Herschel, MD^*
Babak Khoshnood, MD, MPH^{*, §}
Nancy A. Lass, MD
^* Department of Pediatrics
 Committee on Clinical Pharmacology
University of Chicago Pritzker School of Medicine and the ^§ Irving B. Harris Graduate School of Public Policy Studies
University of Chicago
Chicago, IL 60637

	FOOTNOTES

Received for publication Oct 28, 1999; accepted Feb 8, 2000.

Reprint requests to (M.H.) MC 1051, University of Chicago Children's Hospital, 5841 S Maryland Ave, Chicago, IL 60637. E-mail: mhersche{at}midway.uchicago.edu

	ABBREVIATIONS

AAP, American Academy of Pediatrics; AHA, American Heart Association; IV, intravenous(ly); CO₂, carbon dioxide; IM, intramuscular(ly); UH, university hospital; CH, community hospital; CI, 95% confidence interval; PTD, prior to delivery.

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