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Meta-Analysis
. 2021 Mar 17;3(3):CD013732.
doi: 10.1002/14651858.CD013732.pub2.

Opioids for newborn infants receiving mechanical ventilation

Roberto Bellù  1 , Olga Romantsik  2 , Chiara Nava  1 , Koert A de Waal  3 , Rinaldo Zanini  1 , Matteo Bruschettini  2   4
Affiliations
Meta-Analysis

Opioids for newborn infants receiving mechanical ventilation

Roberto Bellù et al. Cochrane Database Syst Rev. .

Abstract

Background: Mechanical ventilation is a potentially painful and discomforting intervention that is widely used in neonatal intensive care. Newborn infants 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 benefits and harms of opioid analgesics for neonates (term or preterm) receiving mechanical ventilation compared to placebo or no drug, other opioids, or other analgesics or sedatives.

Search methods: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 9), in the Cochrane Library; MEDLINE via PubMed (1966 to 29 September 2020); Embase (1980 to 29 September 2020); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 29 September 2020). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria: We included randomised and quasi-randomised controlled trials comparing opioids to placebo or no drug, to other opioids, or to other analgesics or sedatives in newborn infants on mechanical ventilation. We excluded cross-over trials. We included term (≥ 37 weeks' gestational age) and preterm (< 37 weeks' gestational age) newborn infants on mechanical ventilation. We included any duration of drug treatment and any dosage given continuously or as bolus; we excluded studies that gave opioids to ventilated infants for procedures.

Data collection and analysis: For each of the included trials, we independently extracted data (e.g. number of participants, birth weight, gestational age, types of opioids) using Cochrane Effective Practice and Organisation of Care Group (EPOC) criteria and assessed the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). We evaluated treatment effects using a fixed-effect model with risk ratio (RR) for categorical data and mean difference (MD) for continuous data. We used the GRADE approach to assess the certainty of evidence.

Main results: We included 23 studies (enrolling 2023 infants) published between 1992 and 2019. Fifteen studies (1632 infants) compared the use of morphine or fentanyl versus placebo or no intervention. Four studies included both term and preterm infants, and one study only term infants; all other studies included only preterm infants, with five studies including only very preterm infants. We are uncertain whether opioids have an effect on the Premature Infant Pain Profile (PIPP) Scale in the first 12 hours after infusion (MD -5.74, 95% confidence interval (CI) -6.88 to -4.59; 50 participants, 2 studies) and between 12 and 48 hours after infusion (MD -0.98, 95% CI -1.35 to -0.61; 963 participants, 3 studies) because of limitations in study design, high heterogeneity (inconsistency), and imprecision of estimates (very low-certainty evidence - GRADE). The use of morphine or fentanyl probably has little or no effect in reducing duration of mechanical ventilation (MD 0.23 days, 95% CI -0.38 to 0.83; 1259 participants, 7 studies; moderate-certainty evidence because of unclear risk of bias in most studies) and neonatal mortality (RR 1.12, 95% CI 0.80 to 1.55; 1189 participants, 5 studies; moderate-certainty evidence because of imprecision of estimates). We are uncertain whether opioids have an effect on neurodevelopmental outcomes at 18 to 24 months (RR 2.00, 95% CI 0.39 to 10.29; 78 participants, 1 study; very low-certainty evidence because of serious imprecision of the estimates and indirectness). Limited data were available for the other comparisons (i.e. two studies (54 infants) on morphine versus midazolam, three (222 infants) on morphine versus fentanyl, and one each on morphine versus diamorphine (88 infants), morphine versus remifentanil (20 infants), fentanyl versus sufentanil (20 infants), and fentanyl versus remifentanil (24 infants)). For these comparisons, no meta-analysis was conducted because outcomes were reported by one study.

Authors' conclusions: We are uncertain whether opioids have an effect on pain and neurodevelopmental outcomes at 18 to 24 months; the use of morphine or fentanyl probably has little or no effect in reducing the duration of mechanical ventilation and neonatal mortality. Data on the other comparisons planned in this review (opioids versus analgesics; opioids versus other opioids) are extremely limited and do not allow any conclusions. In the absence of firm evidence to support a routine policy, opioids should be used selectively - based on clinical judgement and evaluation of pain indicators - although pain measurement in newborns has limitations.

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Conflict of interest statement

RB has no interest to declare.

KAdW has no interest to declare.

RZ has no interest to declare.

OR has no interest to declare.

CN has no interest to declare.

MB has received research funding from an ALF grant (non‐profit ‐ Lund University) and from the Crafoord Foundation (non‐profit) for research projects not related to Cochrane.

Figures

1
1
Study flow diagram: review update.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Comparison 1 (Any opioid compared to control). Outcome 1.1: PIPP = Premature Infant Pain Profile scale
5
5
Comparison 1 (Any opioid compared to control). Outcome 1.5: Duration of mechanical ventilation (respiratory support with an endotracheal tube)
6
6
Comparison 1 (Any opioid compared to control). Outcome 1.6: Neonatal mortality is defined as mortality during the first 28 days of life
1.1
1.1. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 1: Pain (PIPP)
1.2
1.2. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 2: Pain (NFCS)
1.3
1.3. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 3: Pain (NIPS)
1.4
1.4. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 4: Pain (COMFORTneo)
1.5
1.5. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 5: Duration of ventilation (days)
1.6
1.6. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 6: Neonatal mortality
1.7
1.7. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 7: Mortality to discharge
1.8
1.8. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 8: Neurodevelopmental outcome at 18 to 24 months (moderate to severe disability)
1.9
1.9. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 9: Neurodevelopmental outcome at 5 to 6 years (disability)
1.10
1.10. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 10: Weight gain at discharge (g/kg per day)
1.11
1.11. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 11: Days to reach full enteral feeding
1.12
1.12. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 12: Length of stay in hospital (days)
1.13
1.13. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 13: Oxygen at 28 days of life (BPD any grade)
1.14
1.14. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 14: Oxygen at 36 weeks' postmenstrual age (BPD moderate or severe)
1.15
1.15. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 15: Necrotising enterocolitis
1.16
1.16. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 16: Any intraventricular haemorrhage (IVH)
1.17
1.17. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 17: Severe intraventricular haemorrhage (Papile grade 3/4)
1.18
1.18. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 18: Periventricular leukomalacia (PVL)
1.19
1.19. Analysis
Comparison 1: Any opioid (e.g. morphine, diamorphine, fentanyl, alfentanil, sufentanil, pethidine, meperidine, codeine) compared to control (placebo or no intervention), with or without other non‐pharmacological measures, Outcome 19: Hypotension requiring medical treatment
2.1
2.1. Analysis
Comparison 2: Morphine compared to midazolam, Outcome 1: Pain (PIPP)
2.2
2.2. Analysis
Comparison 2: Morphine compared to midazolam, Outcome 2: Pain (COMFORTneo)
2.3
2.3. Analysis
Comparison 2: Morphine compared to midazolam, Outcome 3: Duration of ventilation (days)
2.4
2.4. Analysis
Comparison 2: Morphine compared to midazolam, Outcome 4: Neonatal mortality
2.5
2.5. Analysis
Comparison 2: Morphine compared to midazolam, Outcome 5: Weight gain at discharge (g/kg per day)
2.6
2.6. Analysis
Comparison 2: Morphine compared to midazolam, Outcome 6: Days to reach full enteral feeding
2.7
2.7. Analysis
Comparison 2: Morphine compared to midazolam, Outcome 7: Length of stay in hospital (days)
2.8
2.8. Analysis
Comparison 2: Morphine compared to midazolam, Outcome 8: Any intraventricular haemorrhage (IVH)
2.9
2.9. Analysis
Comparison 2: Morphine compared to midazolam, Outcome 9: Severe intraventricular haemorrhage (Papile grade 3/4)
2.10
2.10. Analysis
Comparison 2: Morphine compared to midazolam, Outcome 10: Periventricular leukomalacia (PVL)
3.1
3.1. Analysis
Comparison 3: Morphine vs fentanyl, Outcome 1: Mortality to discharge
3.2
3.2. Analysis
Comparison 3: Morphine vs fentanyl, Outcome 2: Severe intraventricular haemorrhage (Papile grade 3/4)
3.3
3.3. Analysis
Comparison 3: Morphine vs fentanyl, Outcome 3: Necrotising enterocolitis
3.4
3.4. Analysis
Comparison 3: Morphine vs fentanyl, Outcome 4: Hypotension requiring medical treatment
4.1
4.1. Analysis
Comparison 4: Morphine vs diamorphine, Outcome 1: Neonatal mortality
4.2
4.2. Analysis
Comparison 4: Morphine vs diamorphine, Outcome 2: Any intraventricular haemorrhage (IVH)
4.3
4.3. Analysis
Comparison 4: Morphine vs diamorphine, Outcome 3: Bronchopulmonary dysplasia (BPD) defined as oxygen required at 28 days
5.1
5.1. Analysis
Comparison 5: Fentanyl vs sufentanil, Outcome 1: Duration of mechanical ventilation
6.1
6.1. Analysis
Comparison 6: Fentanyl vs remifentanil, Outcome 1: Hypotension requiring medical treatment
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013732

References

References to studies included in this review

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References to studies excluded from this review

Akkermans 2015 {published data only}
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References to other published versions of this review

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