Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates

Abstract

Aims-To compare the safety and eVectiveness of morphine and diamorphine for the sedation of ventilated preterm neonates in a double blind, randomised trial. Methods-Eighty eight babies were allocated to receive either morphine (n = 44) or diamorphine (n = 44) by bolus infusion (200 or 120 mcg/kg, respectively, over two hours), followed by maintenance infusion (25 or 15 mcg/kg/h, respectively) during the initial phase of their respiratory disease. Serial monitoring of physiological, behavioural, and biochemical variables over the first 24 hours of the infusions was performed. Longer term outcomes were also monitored. Results-Morphine, but not diamorphine, was associated with a mean (SEM) decrease in mean arterial blood pressure of 2.2 (1.0) mm Hg (p = 0.05) over the initial loading infusion. Physiological (blood pressure variability) and behavioural measures of sedation (clinical assessment and sedation scoring) indicated that the two drug regimens were equally eVective after 24 hours, but the sedative eVects of diamorphine were evident more quickly than those of morphine. Both regimens significantly reduced plasma adrenaline concentrations over the first 24 hours of the infusions. No significant diVerences in mortality, ventilator days, chronic lung disease or intracranial lesions were noted. Conclusions-Both drug regimens reduce the stress response to ventilation in preterm neonates. However, diamorphine's more rapid onset of sedation and morphine's hypotensive tendency suggest that diamorphine is preferable for the sedation of mechanically ventilated preterm neonates. (Arch Dis Child Fetal Neonatal Ed 1998;79:F34-F39) Keywords: sedation; opiates, hypotensionThe use of intermittent positive pressure ventilation (IPPV) for the management of respiratory failure in preterm babies is common place, but various strategies have been developed to minimise the potential risks associated with the problems of babies struggling against the ventilator. Neuromuscular paralysis has been recommended to reduce complications such as pneumothorax and intraventricular haemorrhage (IVH).1 2 Sedation with opiates or opioids has also been used to stop babies struggling against the ventilator, possibly through a respiratory depressant eVect. This may be preferable to paralysis with pancuronium, as shown by a reduction in the catecholamine stress response associated with the first 24 hours of IPPV. 3We have studied the use of morphine in this situation before but noted two potential problems with its use. There was a trend towards a small but potentially important drop in blood pressure over the initial six hours of the morphine infusion.4 5 A proportion of babies also continue to struggle against the ventilator despite the drug treatment and may require further measures such as neuromuscular paralysis in the initial phases of their illness. Diamorphine (3,6-diacetylmorphine) is more lipid soluble than morphine and this property has been considered responsible for the perception that diamorphine works more quickly than morph...

Morphine Administration and Short-term Pulmonary Outcomes Among Ventilated Preterm Infants

“…In a randomized, double-blind trial of morphine versus diamorphine among ventilated preterm neonates (n ϭ 88), the 2 drug regimens were equally effective in terms of sedation, with no significant differences in mortality rates, ventilator days, or BPD rates. 18 In the NOPAIN pilot study, no significant differences in ventilatory outcomes among the morphine (n ϭ 24), midazolam (n ϭ 22), and placebo (n ϭ 21) groups were noted, but the durations of ventilation, nCPAP, and oxygen therapy were lowest in the morphine group. 5 Ventilatory indices were unchanged in a shortterm study comparing ventilated infants with RDS who received midazolam (n ϭ 24) versus placebo (n ϭ 22).…”

“…24 Most studies examining respiratory outcomes among ventilated neonates receiving analgesia enrolled a small number of infants [5][6][7]19,20 and/or lacked a placebo arm. 3,18,20 A recent randomized trial of morphine (n ϭ 77) versus placebo (n ϭ 73) among premature ventilated infants did not show any differences in the duration of ventilation or the incidence of BPD between the 2 groups. 25 The large cohort of infants in the NEOPAIN trial (with a placebo arm) provided a more definitive opportunity to assess the effects of opioid analgesia on the respiratory outcomes of ventilated preterm infants.…”

“…21 On the basis of currently available physiologic/ behavioral markers, opioid analgesia seems definitely to reduce pain/stress among ventilated preterm neonates. [5][6][7]18 In terms of pulmonary outcomes, previous data suggested that opioid analgesia may be preferable over sedation, 5,20 but the combination of opioid analgesia and muscle relaxation and/or sedative agents should be used with caution among ventilated neonates. 22,23 Furthermore, a meta-analysis has raised concerns regarding the use of midazolam infusions among neonates.…”

The development of potentially better practices to support the neurodevelopment of infants in the NICU

“…258 The use of morphine decreases catecholamine levels in ventilated newborns. 259,260 These findings and anecdotal opinions have been the basis for recommendations for the use of narcotics and sedatives in the management of the sick newborn.…”

Is morphine a suitable analgesia for the ventilated neonate? A discussion of the research findings the alternatives and their implications upon neonatal intensive care

“…This reduces need for the use of inotropes to correct blood pressure irregularities (Boxwell, 2000;Mupanemunda and Watkinson, 1999;Goldsmith and Karorkin, 2003). Wood et al (1998), however, studied the effects of diamorphine and morphine infusions on the neonatal brain. They concluded that there was an increase in IVH seen in those neonates receiving diamorphine, although there were less of the more severe and debilitating parenchymal lesions.…”