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      Retrospective study of short-term complications associated with early morphine use in intubated premature infants

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          Abstract

          Relieving neonatal pain is essential for the management of premature infants. Morphine is the most frequently used analgesic in neonatal intensive care. Here we report the relationship between early morphine infusion and the composite outcome of intraventricular hemorrhage and/or death in intubated premature infants. Infants (gestational age ≤ 32 weeks and birth weight < 1,500 g) intubated on admission were retrospectively evaluated in a large tertiary neonatal intensive care unit. Modified log-Poisson regression with robust variance estimator and Cox regression was applied to adjust the relative risk for infants’ outcomes. Of 420 premature infants, 230 (54.7%) received continuous morphine infusion in the first 72 h. Of these, 153 were < 28 gestational weeks; of the 190 patients who did not receive morphine, 63 were < 28 gestational weeks. The analysis revealed that infants < 28 gestational weeks who received morphine were significantly associated with an increased risk for IVH and/or death [adjusted relative risk (aRR) 1.37, 95% confidence interval (CI) 1.1–1.71)], and mortality (aRR 1.83, 95% CI 1.17–2.89). Moreover, in infants < 28 gestational weeks, survival was low in those infants who were exposed to morphine infusion in the first 72 h (hazard ratio 2.11; 95% CI 1.19–3.73). Early morphine infusion is associated with an increased risk for IVH and/or death; however, further studies are required to verify our findings.

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          Intraventricular hemorrhage in premature infants: mechanism of disease.

          Intraventricular hemorrhage (IVH) is a major complication of prematurity. IVH typically initiates in the germinal matrix, which is a richly vascularized collection of neuronal-glial precursor cells in the developing brain. The etiology of IVH is multifactorial and is primarily attributed to the intrinsic fragility of the germinal matrix vasculature and the disturbance in the cerebral blood flow (CBF). Although this review broadly describes the pathogenesis of IVH, the main focus is on the recent development in molecular mechanisms that elucidates the fragility of the germinal matrix vasculature. The microvasculature of the germinal matrix is frail because of an abundance of angiogenic blood vessels that exhibit paucity of pericytes, immaturity of basal lamina, and deficiency of glial fibrillary acidic protein (GFAP) in the ensheathing astrocytes endfeet. High VEGF and angiopoietin-2 levels activate a rapid angiogenesis in the germinal matrix. The elevation of these growth factors may be ascribed to a relative hypoxia of the germinal matrix perhaps resulting from high metabolic activity and oxygen consumption of the neural progenitor cells. Hence, the rapid stabilization of the angiogenic vessels and the restoration of normal CBF on the first day of life are potential strategies to prevent IVH in premature infants.
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            Neonatal intensive care unit stress is associated with brain development in preterm infants.

            Although many perinatal factors have been linked to adverse neurodevelopmental outcomes in very premature infants, much of the variation in outcome remains unexplained. The impact on brain development of 1 potential factor, exposure to stressors in the neonatal intensive care unit, has not yet been studied in a systematic, prospective manner. In this prospective cohort study of infants born at <30 weeks gestation, nurses were trained in recording procedures and cares. These recordings were used to derive Neonatal Infant Stressor Scale scores, which were employed to measure exposure to stressors. Magnetic resonance imaging (brain metrics, diffusion, and functional magnetic resonance imaging) and neurobehavioral examinations at term equivalent postmenstrual age were used to assess cerebral structure and function. Simple and partial correlations corrected for confounders, including immaturity and severity of illness, were used to explore these relations. Exposure to stressors was highly variable, both between infants and throughout a single infant's hospital course. Exposure to a greater number of stressors was associated with decreased frontal and parietal brain width, altered diffusion measures and functional connectivity in the temporal lobes, and abnormalities in motor behavior on neurobehavioral examination. Exposure to stressors in the Neonatal Intensive Care Unit is associated with regional alterations in brain structure and function. Further research into interventions that may decrease or mitigate exposure to stressors in the neonatal intensive care unit is warranted. Copyright © 2011 American Neurological Association.
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              Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial.

              Opioid analgesia is commonly used during neonatal intensive care. We undertook the Neurologic Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) trial to investigate whether pre-emptive morphine analgesia decreases the rate of a composite primary outcome of neonatal death, severe intraventricular haemorrhage (IVH), and periventricular leucomalacia (PVL) in preterm neonates. Ventilated preterm neonates (n=898) from 16 centres were randomly assigned masked placebo (n=449) or morphine (n=449) infusions. After a loading dose (100 microg/kg), morphine infusions (23-26 weeks of gestation 10 microg kg(-1) h(-1); 27-29 weeks 20 microg kg(-1) h(-1); 30-32 weeks 30 microg kg(-1) h(-1)) were continued as long as clinically justified (maximum 14 days). Open-label morphine could be given on clinical judgment (placebo group 242/443 [54.6%], morphine group 202/446 [45.3%]). Analyses were by intention to treat. Baseline variables were similar in the randomised groups. The placebo and morphine groups had similar rates of the composite outcome (105/408 [26%] vs 115/419 [27%]), neonatal death (47/449 [11%] vs 58/449 [13%]), severe IVH (46/429 [11%] vs 55/411 [13%]), and PVL (34/367 [9%] vs 27/367 [7%]). For neonates who were not given open-label morphine, rates of the composite outcome (53/225 [24%] vs 27/179 [15%], p=0.0338) and severe IVH (19/219 [9%] vs 6/189 [3%], p=0.0209) were higher in the morphine group than the placebo group. Placebo-group neonates receiving open-label morphine had worse rates of the composite outcome than those not receiving open-label morphine (78/228 [34%] vs 27/179 [15%], p<0.0001). Morphine-group neonates receiving open-label morphine were more likely to develop severe IVH (36/190 [19%] vs 19/219 [9%], p=0.0024). Pre-emptive morphine infusions did not reduce the frequency of severe IVH, PVL, or death in ventilated preterm neonates, but intermittent boluses of open-label morphine were associated with an increased rate of the composite outcome. The morphine doses used in this study decrease clinical signs of pain but can cause significant adverse effects in ventilated preterm neonates.
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                Author and article information

                Contributors
                m.almouqdad@ksmc.med.sa
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                2 July 2020
                2 July 2020
                2020
                : 10
                : 10874
                Affiliations
                [1 ]ISNI 0000 0004 0445 6726, GRID grid.415998.8, Neonatal Intensive Care, NICU Department, Hospital of Paediatrics, , King Saud Medical City, ; Al Imam Abdul Aziz Ibn Muhammad Ibn Saud, Riyadh, 12746 Saudi Arabia
                [2 ]ISNI 0000 0004 0445 6726, GRID grid.415998.8, Obstetric and Gynecology Department, , Maternity Hospital, King Saud Medical City, ; Riyadh, Saudi Arabia
                [3 ]ISNI 0000 0004 0445 6726, GRID grid.415998.8, Clinical Pharmacy Department, Pharmaceutical Care Services, , King Saud Medical City, ; Riyadh, Saudi Arabia
                Article
                67891
                10.1038/s41598-020-67891-w
                7331726
                32616894
                394c46f4-3d80-455f-bd05-7dfccd01154f
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 24 February 2020
                : 10 June 2020
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                © The Author(s) 2020

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                diseases,medical research
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                diseases, medical research

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