PEDIATRICS Vol. 116 No. 2 August 2005, pp. 492-493 (doi:10.1542/peds.2005-0441)
COMMENTARY |
Morphine Sedation in Ventilated Newborns: Who Are We Treating?
Department of Paediatrics and Child Health
Leeds General Infirmary
University of Leeds
Leeds LS2 9NS, United Kingdom
Abbreviations: AA, additional analgesia • EM, endomorphin
The use of sedation in ill, ventilated preterm infants is common,1 and its use in recent years seems to have increased in frequency.2 The reason that opiates have become more widely prescribed is the belief that infants adversely respond to painful stimuli associated with neonatal intensive care and that this may have adverse long-term consequences. In addition, evidence has been presented to indicate that sedation may reduce both respiratory and neurologic complications; unfortunately, none of these propositions have been reported consistently to be correct. Is there sufficient evidence that we are benefiting infants, or rather reassuring staff that infants are not suffering pain during intensive care?
In this issue of Pediatrics, Bhandari and colleagues3 present data on the largest randomized, control trial (NEOPAIN) performed to date on the short-term respiratory effects of morphine infusion in 898 ventilated very preterm infants. They report that for all but the most immature infants, the duration of time on the ventilator was prolonged in the morphine-treated group compared with controls. The overall difference was 1 day longer of positive-pressure ventilation. The study design allowed open-label morphine (additional analgesia [AA]) to be given as mandated by the physician caring for the infant. When all the data were analyzed in a logistic-regression model including perinatal complications that might explain lung damage, AA was independently associated with increased air leaks and prolonged need for nasal continuous positive airway pressure and oxygen therapy, as well as longer duration of mechanical ventilation. Their article raises important questions as to whether additional morphine may have a toxic effect on lung function in ventilated preterm infants, and because of the serious implications of this possibility, the study must be analyzed carefully.
The study attempted to compare standardized dosage-infusion regimens of morphine based on published pharmacokinetic and pharmacodynamic data in premature infants. When their data were analyzed on a basis of intention to treat, there were few differences other than a slight increase in duration of ventilation in the morphine group. Infants allocated morphine did not show an increase in bronchopulmonary dysplasia, air leak, duration of nasal continuous positive airway pressure, or length of stay in the nursery compared with controls. Ethical considerations required the researchers to permit clinicians to administer morphine to infants who were thought to be in pain. Consequently, a secondary analysis considered 4 groups of infants: control and no AA, morphine and no AA, control with AA, and morphine with AA. Worse respiratory outcome was found only in those with AA exposure irrespective of the group to which they were randomized. In an earlier report4 on the same database, AA was also associated with increased risk of death, severe intraventricular hemorrhage, or periventricular leukomalacia in preterm infants.
At least 3 possible mechanisms require consideration to analyze these findings: a toxic effect of morphine, a para-phenomenon with the perceived need for AA, and morbidity related to additional agents to which the infants were exposed.
Morphine has been used therapeutically for 200 years, and its pharmacological effects have been extensively investigated, although they still are not fully understood. The effect of morphine is predominately mediated through the µ-opioid receptor, but 
- and 
-opioid receptors also have some actions.5 Specific µ-opioid antagonists have recently been identified and termed endomorphin (EM) 1 and EM2.6 The EM1 subsite may have more specific cardiovascular effects (bradycardia and hypotension), and EM2 has mainly respiratory effects (depression) resulting in a decrease in minute ventilation at analgesic doses of morphine.7 There is evidence that the cardiovascular effects act on peripheral receptors, but the respiratory effects are a result of central receptor stimulation.7 Although morphine-induced histamine release has been suggested,8 its effects on neonatal pulmonary function seem not to have been investigated.
No direct effects of morphine on the lungs have been described, and so any respiratory changes induced by the use of this drug are most probably mediated through brainstem µ-opioid receptors. Prolongation of the need for respiratory support in preterm infants is at least in part due to its central effects on respiratory drive, and consequently, any respiratory complications may ensue as a result of the longer duration of ventilation; however, whether the average of 1 day longer of ventilation in the morphine-exposed infants increases the risk of lung damage remains uncertain.
No serum morphine drug levels were reported from the NEOPAIN study, so it is not possible to determine if there is a direct association between morphine levels and lung disease. If there is a biological effect of morphine on lung function, a dose-response relationship would be expected.
Additional morphine exposure in the study may be a marker for the infant who is at higher risk of complications. The indication for the staff to give open-label morphine was the observation of "pain." This was largely measured by neonatal activity and distress, which may have been a result of the infant's underlying clinical condition. This is not supported by the Clinical Risk Index for Babies scores measured 12 hours after birth (no differences were found), but morphine infusion may have been started before this score was performed. Therefore, it is still possible that the need for AA is simply a marker of the sicker infant who is more likely to develop respiratory complications.
A third confounding factor is whether the use of other drugs may have independently impaired respiratory function. Neuromuscular blocking drugs such as pancuronium or vecuronium are widely used to treat ill preterm infants who are mechanically ventilated. Studies have shown that the use of pancuronium9 or fentanyl (without morphine)10 changes respiratory function mechanics including a significant reduction in pulmonary resistance (both inspiratory and expiratory) and increase in dynamic respiratory compliance,9 higher rates of ventilation, increased peak inspiratory pressure, increased ventilatory index, and higher positive end-expiratory pressure compared with a placebo group.10
In the NEOPAIN study published in Pediatrics, the number of infants receiving neuromuscular paralysis is not given, but the authors state that it was used "sparingly." Listed indications included fast ventilator rates, high-frequency ventilation, high peak inspiratory pressure, and an oxygenation index of >0.2. Infants who required AA were smaller, of lower gestational age, and born in poorer condition. This raises the question of whether these infants received neuromuscular blockade and whether the effect of this rather than the AA morphine was the factor that exacerbated lung disease. Use of paralyzing agents was not included in the logistic-regression model to predict worse respiratory outcome.
The authors of the NEOPAIN study must be congratulated for the excellent design and execution of their large study. Their conclusion that AA is associated with worsening respiratory outcome is of concern and requires additional analysis; the results may be confounded by other variables rather than being causal in nature. Additional research on the effects of morphine on respiratory function is required before clear guidelines for the routine use of opiates are made. In 1999, an editorial on the use of opiates in mechanically ventilated infants concluded that routine use could not be recommended in light of concerns about as-yet-unidentified adverse effects.11 Unfortunately, this issue still remains unresolved in 2005.
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FOOTNOTES |
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Accepted Feb 28, 2005.
Address correspondence to Malcolm Levene, MD, FRCPCH, Department of Paediatrics and Child Health, Leeds General Infirmary, D Floor, Clarendon Wing, Leeds LS2 9NS, United Kingdom. E-mail: m.i.levene{at}leeds.ac.uk
No conflict of interest declared.
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
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