Physiological, hormonal, and behavioral responses to a single fentanyl dose in intubated and ventilated preterm neonates. Routine use of fentanyl infusions for pain and stress reduction in infants with respiratory distress syndrome. Pain relief can reduce hypoxemia in distressed neonates during routine treatment procedures. Morphine increases synchronous ventilation in preterm infants. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. Analgesia and sedation in preterm neonates who require ventilatory support: results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates. Randomised controlled trial of low dose fentanyl infusion in preterm infants with hyaline membrane disease. Randomised double-blind controlled trial of effect of morphine on catecholamine concentrations in ventilated pre-term babies. Effect of morphine and pancuronium on the stress response in ventilated preterm infants. Alfentanil as procedural pain relief in newborn infants.
To study the responses of ventilated preterm neonates to a single dose of opioid.
                In a randomized, double-blind, controlled trial, 22 mechanically ventilated preterm infants (< or = 32 weeks) were observed before medication and at 30 and 60 minutes after administration of fentanyl (3 micrograms/kg) or placebo. Heart rate, blood pressure, arterial blood gases, ventilator settings, and behavioral measures (Neonatal Facial Coding System and Modified Postoperative Comfort Score) were recorded during each period. Blood cortisol, growth hormone, glucose, and lactate were measured before and at 60 minutes after analgesia. Behavioral measures were assessed at the bedside and from video films recorded during each observation period.
                Patients presented high basal levels of cortisol, growth hormone, and lactate. Behavioral scales indicated the presence of pain before any medication. In the fentanyl group, the maximum and minimum heart rate decreased and growth hormone level increased after analgesia. At the video analysis of behavioral measures, postoperative comfort score increased and neonatal facial coding system score decreased in the fentanyl group.
                Single doses of fentanyl analgesia can reduce the physiologic/behavioral measures of pain and stress associated with mechanical ventilation in preterm infants. To determine whether fentanyl infusions given to premature infants with respiratory distress syndrome reduce stress and improve long- and short-term outcome.
                Twenty premature infants undergoing mechanical ventilation for respiratory distress syndrome were randomly assigned, in a double-blind fashion, to receive fentanyl by continuous infusion or a volume-matched placebo infusion. A behavioral state score was used to assess the infants' behavior. Cortisol and 11-deoxycortisol levels were measured as physiologic markers of stress. Urinary 3-methyl histidine/creatinine molar ratio was determined and the fractional excretion of urea was measured to assess catabolic state. Ventilatory indexes were recorded for each infant.
                Infants receiving fentanyl showed significantly lower behavioral state scores (p < 0.04) and lower heart rates (p < 0.001) than those receiving placebo. 11-Deoxycortisol levels were lower in the fentanyl group on days 3, 4, and 5 of the study (p < 0.003). 3-Methyl histidine/creatinine ratios and fractional excretion of urea were not significantly different between the two groups. On the third day of the study, infants receiving fentanyl required a higher ventilator rate (p < 0.01), higher peak inspiratory pressures (p < 0.001), and higher positive end-expiratory pressure (p < 0.0001) than those receiving placebo. There was no difference in long-term outcome with respect to the incidence of bronchopulmonary dysplasia, intraventricular hemorrhage, or sepsis or with respect to the duration of ventilator use.
                Although there was a reduction in stress markers in the infants receiving fentanyl, we were unable to demonstrate an improvement in catabolic state or long-term outcome. In addition, the infants receiving fentanyl required higher ventilatory support in the early phase of respiratory distress syndrome than did those receiving placebo. To determine whether the use of opioids could reduce the hypoxemia and hemodynamic instability associated with routine intensive care procedures in neonates with respiratory distress.
                Randomized and placebo-controlled study.
                Physiological, plasma beta-endorphin, cortisol, and glucose responses to routine treatment procedures were studied in 84 mechanically ventilated distressed neonates randomized into groups receiving 1 mg/kg meperidine or 0.9% saline 15 minutes before tracheal suction or routine nursing care.
                The duration of hypoxemia (transcutaneous partial pressure of O2 < 6.6 kPa (< 50 mm Hg) and/or arterial blood oxygen saturation < 80%) during treatment procedures was significantly longer in the saline group (mean 82 vs 36 seconds, P = .001) and distress quantified by a novel behavioral scoring method was much higher. Changes in arterial blood pressure, heart rate, or plasma beta-endorphin, cortisol, and glucose concentration did not show any statistically significant differences between the groups.
                Newborns with respiratory difficulties often suffer from hypoxemia during essential treatment procedures. The use of opioid analgesia may reduce the duration of hypoxemia and the associated distress and, therefore, may improve the long-term results of neonatal intensive care. To examine the short-term cardiorespiratory effects of intravenous morphine infusion in ventilated preterm infants.
                A randomized double-blind placebo-controlled trial in a neonatal intensive care unit. Twenty-six preterm infants (29-36 weeks gestation) with hyaline membrane disease requiring ventilatory assistance on the first day after birth were included in the study. A loading dose of morphine 100 micrograms/kg over 30 min followed by a continuous intravenous infusion at 10 micrograms/kg per hour was given. Primary measures were heart rate, blood pressure, respiratory rate and interaction of spontaneous respiration with mechanical ventilation. Secondary measures were durations of oxygen therapy, ventilator therapy and hospitalization as well as incidence of bronchopulmonary dysplasia, periventricular haemorrhage and pneumothorax.
                Morphine-treated infants spent a significantly greater percentage of total ventilated time breathing in synchrony with their ventilators (median [IQ] = 72[58-87] vs 31[17-51]%; P = 0.0008). Heart rate and respiratory rate, but not blood pressure, were reduced in morphine-treated infants. Duration of oxygen therapy was reduced (median [IQ] = 4.5[3-7] vs 8[4.75-12.5] days; P = 0.046).
                Intravenous morphine infusion increases synchronicity of spontaneous and ventilator-delivered breaths in preterm infants. Morphine reduces heart rate and respiratory rate without reducing blood pressure, and may help to reduce duration of oxygen therapy in preterm infants with hyaline membrane disease. Newborns admitted to neonatal intensive care units (NICUs) undergo a variety of painful procedures and stressful events. Because the effect of continuous morphine infusion in preterm neonates has not been investigated systematically, there is confusion regarding whether morphine should be used routinely in this setting.
                To evaluate the effects of continuous intravenous morphine infusion on pain responses, incidence of intraventricular hemorrhage (IVH), and poor neurologic outcome (severe IVH, periventricular leukomalacia, or death).
                A randomized, double-blind, placebo-controlled trial conducted between December 2000 and October 2002 in 2 level III NICUs in the Netherlands of 150 newborns who had received ventilatory support (inclusion criteria: postnatal age younger than 3 days and ventilation for less than 8 hours; exclusion criteria: severe asphyxia, severe IVH, major congenital malformations, and administration of neuromuscular blockers).
                Intravenous morphine (100 microg/kg and 10 microg/kg per hour) or placebo infusion was given for 7 days (or less because of clinical necessity in several cases).
                The analgesic effect of morphine, as assessed using validated scales; the effect of morphine on the incidence of IVH; and poor neurologic outcome.
                The analgesic effect did not differ between the morphine and placebo groups, judging from the following median (interquartile range) pain scores: Premature Infant Pain Profile, 10.1 (8.2-11.6) vs 10.0 (8.2-12.0) (P =.94); Neonatal Infant Pain Scale, 4.8 (3.7-6.0) vs 4.8 (3.2-6.0) (P =.58); and visual analog scale, 2.8 (2.0-3.9) vs 2.6 (1.8-4.3) (P =.14), respectively. Routine morphine infusion decreased the incidence of IVH (23% vs 40%, P =.04) but did not influence poor neurologic outcome (10% vs 16%, P =.66). In addition, analyses were adjusted for the use of additional open-label morphine (27% of morphine group vs 40% of placebo group, P =.10).
                Lack of a measurable analgesic effect and absence of a beneficial effect on poor neurologic outcome do not support the routine use of morphine infusions as a standard of care in preterm newborns who have received ventilatory support. Follow-up is needed to evaluate the long-term effects of morphine infusions on the neurobehavioral outcomes of prematurity. 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.
                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.
                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.
                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 chi2 = 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 (P<.001) and midazolam (P = .002) infusions compared with the placebo group.
                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 pilot study suggest that these results should be confirmed in a large multicenter randomized trial. To evaluate the effects of low dose fentanyl infusion analgesia on behavioural and neuroendocrine stress response and short term outcome in premature infants ventilated for hyaline membrane disease.
                Twenty seven ventilated preterm infants were randomly assigned to receive a mean fentanyl infusion of 1.1 (0.08 SE) micrograms/kg/h for 75 (5) hours, and 28 untreated infants were considered a control group. A behavioural sedation score was used to assess the infants' behaviour. Urinary metanephrine and the normetanephrine:creatinine molar ratio were determined at 0, 24, 48 and 72 hours. Outcome data and ventilatory indexes were recorded for each infant.
                The fentanyl group showed significantly lower behavioural stress scores and O2 desaturations than controls and lower urinary concentrations of metanephrine and normetanephrine at 24, 48, 72 hours. The two groups showed no significant difference in ventilatory variables or short term outcome.
                A short course of low dose fentanyl infusion reduces behavioural sedation scores, O2 desaturations and neuroendocrine stress response in preterm ventilated infants. A sick premature baby who requires intensive care will undergo many uncomfortable procedures. It is now accepted that such babies perceive pain and need adequate analgesia, but little is known about the effects of sedation in these patients. We investigated the use of morphine to provide analgesia and sedation for ventilated preterm babies in a randomised, double-blind, placebo-controlled trial. 41 mechanically ventilated babies who had been treated with surfactant (Curosurf) for hyaline membrane disease were randomly assigned morphine in 5% dextrose (100 micrograms/kg per h for 2 h followed by 25 micrograms/kg per h continuous infusion) or 5% dextrose (placebo). Plasma catecholamine concentrations were measured 1 h after the first dose of surfactant and 24 h later. Blood pressure was measured at study entry and after 6 h. The morphine and placebo groups showed no differences in method of delivery, Apgar scores, birthweight, gestation, or catecholamine concentrations at baseline. Morphine-treated babies showed a significant reduction in adrenaline concentrations during the first 24 h (median change -0.4 [95% CI -1.1 to -0.3] nmol/L p < 0.001), which was not seen in the placebo group (median change 0.2 [-0.6 to 0.6] nmol/L, p = 0.79). There was a non-significant reduction in noradrenaline concentration in the morphine group. Blood pressure showed a slight but non-significant fall (median -4 mm Hg) in morphine-treated babies. The incidence of intraventricular haemorrhage, patent ductus arteriosus, and pneumothorax, the number of ventilator days, and the numbers of deaths did not differ significantly between the groups. Morphine, in the dose regimen we used, is safe and effective in reducing adrenaline concentrations in preterm ventilated babies. Ninety-five premature newborns who had hyaline membrane disease and were struggling against the ventilator were randomised to one of three treatment groups: morphine (group M), pancuronium (group P) or morphine with pancuronium (group M+P). The dose of morphine was 50 micrograms/kg per h but was increased to 100 micrograms/kg per h in group M infants if they continued to struggle. The dosage of pancuronium was 100 micrograms/kg given as required to inhibit spontaneous respiration. Plasma catecholamine levels were measured on entry and at 24 h. Blood pressure and ventilatory requirements were determined on entry and at 6 h. The clinical outcome of the infants was documented. Group M infants (n = 29) showed a significant reduction in noradrenaline levels (median change -2.2 nmols/l (range -47.2 to +7.2 nmols/l), although seven were withdrawn from this group because of failure to settle. Group P (n = 28) and group M+P (n = 38) showed no significant change in noradrenaline levels. Comparison between the groups showed that group M infants had a significant reduction in noradrenaline levels compared with group P. The immediate effects of treatment on blood pressure and ventilatory requirements were similar in the three groups. The clinical outcome did not differ for any of the measured parameters. When adequate sedation is achieved, morphine may reduce the stress of newborn intensive care. To assess the need for, and the suitability of, alfentanil for pain relief during tracheal suction used in assisted ventilation in newborn infants.
                In a randomised, controlled, double blind, crossover trial, placebo (10 micrograms/kg) and 20 micrograms/kg alfentanil were infused in random order two minutes before three separate endotracheal suctions, at least six hours apart, to 10 infants. Measurements were made of physiological variables, behaviour, and stress hormones.
                After placebo infusion heart rate significantly increased (median 14; interquartile range 12-16 beats/minute) as did behavioural pain score (5; 3-5). Alfentanil (20 micrograms/kg) attenuated the heart rate increase, normalised the pain score, and caused a decrease in plasma adrenaline activity (0.3; 0.2-0.7 nmol/l). Noradrenaline concentration showed a nonsignificant decreasing trend with increasing alfentanil dose and beta endorphin was unchanged. Rigidity was noted in the placebo (n = 2), 10 micrograms/kg (n = 2), and 20 micrograms/kg (n = 5) alfentanil groups, respectively.
                Tracheal suction is a painful procedure. The dose of alfentanil required for pain relief (20 micrograms/kg) causes a high incidence of rigidity and thus should be used only with muscle relaxant.
There is insufficient evidence to recommend routine use of opioids in mechanically ventilated newborns. Opioids should be used selectively, when indicated by clinical judgment and evaluation of pain indicators. If sedation is required, morphine is safer than midazolam. Further research is needed.