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Meta-Analysis
. 2008 Jan 23;2008(1):CD004212.
doi: 10.1002/14651858.CD004212.pub3.

Opioids for neonates receiving mechanical ventilation

R Bellù  1 , K A de Waal, R Zanini
Affiliations
Meta-Analysis

Opioids for neonates receiving mechanical ventilation

R Bellù et al. Cochrane Database Syst Rev. .

Abstract

Background: Mechanical ventilation is a potentially painful and discomforting intervention widely used in neonatal intensive care units. Newborn babies (neonates) demonstrate increased sensitivity to pain, which may affect clinical and neurodevelopmental outcomes. The use of drugs that reduce pain might be important in improving survival and neurodevelopmental outcomes.

Objectives: To determine the effect of opioid analgesics (pain-killing drugs derived from opium e.g. morphine), compared to placebo, no drug, or other non-opioid analgesics or sedatives, on pain, duration of mechanical ventilation, mortality, growth and neurodevelopmental outcomes in newborn infants on mechanical ventilation.

Search strategy: Electronic searches included: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007); MEDLINE (1966 to June 2007); EMBASE (1974 to June 2007); and CINAHL (1982 to 2007). Previous reviews and lists of relevant articles were cross-referenced.

Selection criteria: Randomised controlled trials or quasi-randomised controlled trials comparing opioids to a control, or to other analgesics or sedatives in newborn infants on mechanical ventilation.

Data collection and analysis: Data were extracted independently by two review authors. Categorical outcomes were analysed using relative risk and risk difference; and continuous outcomes with weighted mean difference or standardised mean difference. A fixed effect model was used for meta-analysis except where heterogeneity existed, in which case a random effects model was used.

Main results: Thirteen studies on 1505 infants were included. Infants given opioids showed reduced premature infant pain profile (PIPP) scores compared to the control group (weighted mean difference -1.71; 95% confidence interval -3.18 to -0.24). Differences in execution and reporting of trials mean that this meta-analysis should be interpreted with caution. Heterogeneity was significantly high in all analyses of pain, even when lower quality studies were excluded and analysis limited to very preterm newborns. Meta-analyses of mortality, duration of mechanical ventilation, and long and short-term neurodevelopmental outcomes showed no statistically significant differences. Very preterm infants given morphine took significantly longer to reach full enteral feeding than those in control groups (weighted mean difference 2.10 days; 95% confidence interval 0.35 to 3.85). One study compared morphine with a sedative: the treatments showed similar pain scores, but morphine had fewer adverse effects.

Authors' conclusions: 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.

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Conflict of interest statement

None

Figures

1.1
1.1. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 1: Pain (PIPP)
1.2
1.2. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 2: Pain (NFCS)
1.3
1.3. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 3: Pain (NIPS)
1.4
1.4. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 4: Pain (other scales)
1.5
1.5. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 5: Duration of ventilation (days)
1.6
1.6. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 6: Neonatal mortality
1.7
1.7. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 7: Mortality to discharge
1.8
1.8. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 8: Neurodevelopmental outcome (NAPI)
1.9
1.9. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 9: Neurodevelopmental outcome at 5‐6 years (disability)
1.10
1.10. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 10: Oxygen at 28 days of life
1.11
1.11. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 11: Oxygen at 36 weeks postconceptional age
1.12
1.12. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 12: Days to reach full enteral feeding
1.13
1.13. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 13: Weight gain at discharge (g/kg per day)
1.14
1.14. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 14: Length of stay in hospital (days)
1.15
1.15. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 15: Necrotising enterocolitis
1.16
1.16. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 16: Any intraventricular haemorrhage (IVH)
1.17
1.17. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 17: Severe intraventricular haemorrhage (Papile grade 3/4)
1.18
1.18. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 18: Periventricular leucomalacia (PVL)
1.19
1.19. Analysis
Comparison 1: Opioids versus placebo or no treatment, Outcome 19: Hypotension requiring medical treatment
2.1
2.1. Analysis
Comparison 2: Opioids versus sedatives, Outcome 1: Pain (PIPP)
2.2
2.2. Analysis
Comparison 2: Opioids versus sedatives, Outcome 2: Pain (COMFORT)
2.3
2.3. Analysis
Comparison 2: Opioids versus sedatives, Outcome 3: Duration of mechanical ventilation (days)
2.4
2.4. Analysis
Comparison 2: Opioids versus sedatives, Outcome 4: Mortality to discharge
2.5
2.5. Analysis
Comparison 2: Opioids versus sedatives, Outcome 5: Neurodevelopmental outcome (NAPI)
2.6
2.6. Analysis
Comparison 2: Opioids versus sedatives, Outcome 6: Days to reach full enteral feeding
2.7
2.7. Analysis
Comparison 2: Opioids versus sedatives, Outcome 7: Weight gain at discharge (g/kg per day)
2.8
2.8. Analysis
Comparison 2: Opioids versus sedatives, Outcome 8: Length of stay in hospital (days)
2.9
2.9. Analysis
Comparison 2: Opioids versus sedatives, Outcome 9: Any intraventricular heamorrhage (IVH)
2.10
2.10. Analysis
Comparison 2: Opioids versus sedatives, Outcome 10: Severe intraventricular heamorrhage (Papile grade 3/4)
2.11
2.11. Analysis
Comparison 2: Opioids versus sedatives, Outcome 11: Periventricular leucomalacia (PVL)
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Update of

References

References to studies included in this review

Anand 1999 {published data only}
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Anand 2004 {published data only}
    1. Anand KJ, Hall RW, Desai N, Shepard B, Bergqvist L, Young TE et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. The Lancet 2004;363:1673-82. - PubMed
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Guinsburg 1998 {published data only}
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Lago 1998 {published data only}
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Lago 1999 {published data only}
    1. Lago P, Benini F, Salvadori S, Bettiol T, Agosto C, Zacchello F. Effect of administering low-dose fentanyl infusion on respiratory dynamics in the premature ventilated for respiratory distress syndrome - A randomized double-blind trial. Pediatric Research 1999;45:308A.
Orsini 1996 {published data only}
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Pokela 1994 {published data only}
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Quinn 1992 {published data only}
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Quinn 1993 {published data only}
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Saarenmaa 1996 {published data only}
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Simons 2003 {published data only}
    1. Simons SH, Dijk M, Lingen RA, Roofthooft D, Duivenvoorden HJ, Jongeneel N et al. Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial. JAMA 2003;290:2419-27. - PubMed
    1. Simons SHP, Roofthooft DWE, Diyk M, Linden RA, Duivenvoorden HJ, van den Arken JN et al. Morphine in ventilated neonates: its effects on arterial blood pressure. Archives of Disease in Childhood Fetal Neonatal Ed 2006;91:F46-F51. - PMC - PubMed
    1. Simons SHP, Dijk M, Lingen RA, Roofthooft DWE, Boomsma F, van der Anker JN et al. Randomised controlled trial evaluating effects of morphine on plasma adrenaline/noradrenaline concentrations in newborns. Arch Dis Child Fetal Neonatal Ed 2005;90:F36-F40. - PMC - PubMed
Siwiec 1999 {published data only}
    1. Siwiec J, Porzucek J, Gadzinowski J, Bhat R, Vidyasagar D. Effect of short term morphine infusion on premature infant profile (PIPP) and hemodynamics. Pediatric Research 1999;45:69A.

References to studies excluded from this review

Barker 1995 {published data only}
    1. Barker DP, Simpson J, Pawula M, Barrett DA, Shaw PN, Rutter N. Randomised, double blind trial of two loading dose regimens of diamorphine in ventilated newborn infants. Archives of Disease of Childhood Fetal Neonatal Edition 1995;73:F22-6. - PMC - PubMed
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References to other published versions of this review

Bellu 2005
    1. Bellu R, Waal KA, Zanini R. Opioids for neonates receiving mechanical ventilation. Cochrane Database of Systematic Reviews 2005, Issue 1. Art. No: CD004212. [DOI: 10.1002/14651858.CD004212.pub2] - DOI - PubMed

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