Midazolam warning for preemies


A recent study in preterm infants found that exposure to midazolam, a commonly used sedative in the neonatal intensive care unit (NICU), was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation.

A recent study in preterm infants found that exposure to midazolam, a commonly used sedative in the neonatal intensive care unit (NICU), was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. With the optimal care of the individual patient in mind, clinicians could potentially use alternative sedative and narcotic medications that are available to help circumvent the adverse events associated with midazolam.

On average, very preterm infants (24 to 32 weeks of gestation) will spend approximately 3 months in the NICU, and in that time will undergo approximately 12 invasive procedures every day. Benzodiazepines such as midazolam are commonly used in the NICU to help minimize the pain and stress associated with the many clinical procedures that these preterm infants need to undergo during their several months-long stay in intensive care.

“Preterm babies often have to undergo hundreds of painful and uncomfortable procedures during the NICU stay. As shown by our group and others, pain is bad for babies and some commonly used analgesics and sedatives may also have adverse effects on brain development,” says Emma Gail Duerden, PhD, senior research associate, Neonatal Imaging Program, the Hospital for Sick Children (SickKids) and University of Toronto, Ontario, Canada.

Duerden and colleagues recently conducted a study to assess the effect of invasive procedures and analgesic-sedative exposure on hippocampal growth, as well as hippocampal growth on neurodevelopmental outcome.1 The study included 138 neonates (51% male; median gestational age, 27.7 weeks) who underwent magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) scans early in life (postmenstrual age [PMA], 32.3 weeks) and at term-equivalent age (PMA, 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development-III at 18.7 months median correlated age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries.

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Data showed that midazolam exposure predicted slower development of the hippocampus, a key brain structure for memory, as preterm neonates grew to term-equivalent age. In addition, it was found that poorer cognitive development at 18 months was associated with slower hippocampal growth and midazolam exposure. Given these findings, Duerden says that the use of midazolam in very preterm neonates is cautioned, as more research is needed in the area.

Current research is, in part, aimed at finding more optimal strategies for analgesia and sedation that could be used in place of midazolam. According to the senior author of the study, Steven Miller, MD, further prospective long-term studies in multiple NICUs need to be performed to determine how the current neonatal analgesic and sedative practices impact functional outcomes.

“There is a growing recognition that pain and stress during neonatal intensive care predicts less robust brain development in the preterm neonate. So it is imperative that we find ways to minimize the pain and stress, and to identify ways of caring for the preterm neonate that promote optimal brain development,” says Miller, senior scientist and head, Division of Neurology, SickKids, and professor, Department of Paediatrics, University of Toronto, Ontario, Canada.

The findings of this study appear to caution against the use of midazolam in very preterm neonates, Miller says, especially those not undergoing surgery. Fortunately, the variability in sedative and narcotic use across NICUs suggests that alternatives are available, but care should be individualized for each patient.

In addition to the heightened awareness of the importance to prevent pain and ameliorate stress, Miller says that there is a trend in Canadian NICUs to promote nonpharmacologic management of pain and stress in preterm babies, such as skin-to-skin contact, bundling, nonnutritive sucking, and kangaroo care.

“Our challenge is how to identify which pharmacological and nonpharmacological strategies provide effective analgesia and sedation, while promoting optimal brain development. Pain and stress in preterm babies are of significant concern for families and healthcare providers in the NICU. We should be doing all we can to prevent pain and stress in the preterm neonate to promote their brain health and support their families,” Duerden says.



1. Duerden EG, Guo T, Dodbiba L, et al. Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. Ann Neurol. 2016;79(4):548-559.

Dr Petrou is a freelance medical writer based in Budapest, Hungary. He has nothing to disclose in regard to affiliations with or financial interests in any organizations that may have an interest in any part of this article.

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