Analgesia and Sedation in Preterm Neonates Who Require Ventilatory Support

Abstract

Background: Preterm neonates are exposed to multiple painful procedures after birth and exhibit acute physiological responses to pain. Occurrence of early intraventricular hemorrhage within 24 to 72 hours after birth suggests a role of pain and stress in the multifactorial causation of severe intraventricular hemorrhage and periventricular leukomalacia. We proposed that such neurologic outcomes in preterm neonates who require ventilatory support may be reduced by morphine analgesia or midazolam sedation compared with a placebo. Objectives: To define the incidence of clinical outcomes in the target study population, to estimate the effect size and adverse effects associated with analgesia and sedation, and to calculate the sample size for a definitive test of this hypothesis. Methods: Sixty-seven preterm neonates were randomized in a pilot clinical trial from 9 centers. Neonates of 24 to 32 weeks' gestation were eligible if they had been intubated and required ventilatory support for less than 8 hours and if they were enrolled within 72 hours after birth. Exclusion criteria included major congenital anomalies, severe intrapartum asphyxia, and participation in other research studies. Severity of illness was assessed by the Clinical Risk Index for Babies, and neonates were randomized to receive continuous infusions of morphine sulfate, midazolam hydrochloride, or 10% dextrose (placebo). Masked study medications were continued as long as clinically necessary, then weaned and stopped according to predefined criteria. Levels of sedation (COMFORT scores) and responses to pain (Premature Infant Pain Profile scores) were measured before , during, and 12 hours after discontinuation of drug infusion. Cranial ultrasound examinations were performed as part of routine practice, and poor neurologic outcomes were defined as neonatal death, severe intraventricular hemorrhage (grade III or IV), or periventricular leukomalacia. Results: No significant differences occurred in the demographic, clinical, and socioeconomic variables related to mothers and neonates in the 3 groups or in the severity of illness at birth as measured by Clinical Risk Index for Babies scores. Two neonates in the placebo group and 1 neonate in the midazolam group died; no deaths occurred in the morphine group. Poor neurologic outcomes occurred in 24% of neonates in the placebo group, 32% in the midazolam group, and 4% in the morphine group (likelihood ratio 2 = 7.04, P = .03). Secondary clinical outcomes and neurobehavioral outcomes at 36 weeks' postconceptional age were similar in the 3 groups. Responses elicited by endotracheal tube suction (Premature Infant Pain Profile scores) were significantly reduced during the morphine (PϽ.001) and midazolam (P = .002) infusions compared with the placebo group. Conclusions: This pilot trial suggests that preemptive analgesia given by continuous low-dose morphine infusion may reduce the incidence of poor neurologic outcomes in preterm neonates who require ventilatory support. Limitations in the sample size of this pil...

Freqüência do emprego de analgésicos em unidades de terapia intensiva neonatal universitárias

“…5,26 A multicenter study, however, published in 2004 by Anand et al 27 on the preemptive use of morphine in premature infants on mechanical ventilation reported an increased frequency of severe ventricular hemorrhage among patients with gestational ages from 27 to 29 weeks. Overall, even though the literature indicates that pain and discomfort in neonates on assisted ventilation exists and also that pain is possibly associated with long-term consequences, only one third of the ventilated patient-days studied here were given some type of analgesic.…”

Prevention and Management of Procedural Pain in the Neonate: An Update

“…97 Midazolam was associated with adverse short-term effects in the NOPAIN (Neonatal Outcome and Prolonged Analgesia in Neonates) trial. 98 A systematic review in 2012 found insufficient evidence to recommend midazolam infusions for sedation in the NICU and raised safety concerns, particularly regarding neurotoxicity. 97 Alternative medications, such as methadone, 99 ketamine, propofol, and dexmedetomidine, have been proposed for pain management in neonates; however, few, if any, studies of these agents have been performed in this population, and caution should be exercised when considering them for use because of concerns about unanticipated adverse effects and potential neurotoxic effects.…”

Newborns should be receiving premedication before elective intubation

“…The use of midazolam has also been associated with hypotension and adverse neurological outcomes. [19,20] A Cochrane review found no evidence to support the use of midazolam as a sedative for infants, particularly preterm ones. [21] Infants receiving midazolam had longer hospital stays, and there were more adverse effects in the midazolam group when compared with placebo.…”