Drug use and abuse in the NICU

The title does not refer to”drugs of abuse” but rather to how we use and choose medications for use in newborns, particularly the very immature. A new publication has just appeared on-line which focuses of medication use in the NICU, and the changes over an 8 year period. (Stark A, et al. Medication Use in the Neonatal Intensive Care Unit and Changes from 2010-2018. The Journal of Pediatrics. 2021).

The enormous database of the Pediatrix medical group has been trawled to find medication exposure data for nearly 800,000 newborns.

There are a number of striking findings, in particular the amazing relative growth of the use of dexmedetomidine. Practically speaking use was 0 in 2010, now 5 per 1000 NICU patients are exposed to it, and 23 per 1000 extremely low birth weight infants.

Dexmedetomidine is routinely touted as being “neuro-protective”, but that assertion is based on questionably relevant animal models, some of which show reduced neuronal apoptosis. I don’t believe there is any long term human outcome data with which to make the assertion that dexmedetomidine is neuro-protective in humans. But of course we don’t have much similar data for any of the sedative/analgesic medications that we use. Morphine probably being the only exception, but the data for morphine are not very robust or very reassuring.

One recent animal study showed that adding dexmedetomidine to a reduced concentration of sevoflurane reduced apoptosis, but if enough dexmedetomidine was given to achieve the same level of anaesthesia as the higher concentration of sevoflurane, then the neuronal apoptosis was identical. (Lee JR, et al. Effect of dexmedetomidine on sevoflurane-induced neurodegeneration in neonatal rats. Br J Anaesth. 2021;126(5):1009-21). So, in this model at least, dexmedetomidine was not neuro-protective. In contrast, this review article found several animal studies that did seem to show neuro-protection (van Hoorn CE, et al. A systematic review and narrative synthesis on the histological and neurobehavioral long-term effects of dexmedetomidine. Paediatr Anaesth. 2019;29(2):125-36) but it was not universal, the details of the animal models and experimental procedures vary greatly. How relevant each one is to the sick newborn is very uncertain.

Multiple use, prolonged infusions, and use in the most fragile babies are all things which need to be better investigated for dexmedetomidine, and for our other sedative/analgesia drugs.

In contrast the same article showed the reduction in use of other medications. Three of them because they are no longer available, (at least in the USA) THAM, chloral hydrate, and ranitidine. No great loss to neonatology, I think. I was pleased to see a dramatic reduction in metoclopramide use, for which I think there is no indication in neonatology. Also, and a little more surprising to me, a marked reduction in lansoprazole use. Again I don’t think that there is much role for the medication; treatment for babies with reflux by prescibing lansoproazole ignores the fact that 50% of reflux in the preterm is non-acid, and the clinical signs attributed to reflux are both non-specific for reflux, and not necessarily caused by acid. Also gastric acid is an important barrier to GI colonisation, helps to prevent respiratory infections, and is probably important for absorption of iron and calcium.

Although it hasn’t changed much over this period, there is still a lot of midazolam being used, being the 9th most frequently prescribed medication overall, and the 13th most frequent in the ELBW. I can’t remember the last time I prescibed midazolam, other than a case of status epilepticus unresponsive to 3 other anticonvulsants in a baby at term. 21% of ELBW babies were exposed to this drug, with a total of 3,700 days of use per 1,000 patients. My comments about sedative/analgeisc medications apply here. What little data we have for long term effects of midazolam are worrying.

The study points out how much we still need to know about the common medications that we use, the majority of which are not specifically licensed for the newborn.

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
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