Dexmedetomidine: Acquiring Pharmacokinetic Data to Safely Treat Preterm Neonates
Summary
Neonates undergoing assisted ventilation often require analgesia and sedation for pain, anxiety and ventilator asynchrony. Increasingly younger neonates are resuscitated and receive life-saving intensive care, some as early as 22 weeks gestational age. Generally, opiates (commonly morphine, fentanyl) and benzodiazepines (commonly midazolam, lorazepam) are used for these immature neonates. However, these drugs are fraught with complications to include prolonged time on the ventilator, hypotension, adverse neurodevelopmental sequelae, prolonged time to full feeds, and a host of other complications. Treating neonatal pain is important as it adversely affects neurodevelopment; it leads to upregulation of the hypothalamic-pituitary-adrenal axis later in life, increasing the risk of subsequent metabolic syndrome and stress; and it is inhumane not to treat these babies. In the short term, ineffective treatment leads to ventilator asynchrony and ultimately hypoxia. Thus, the search is ongoing for an effective but safer drug that can be used in this population.
Dexmedetomidine (Precedex) is a centrally acting alpha-2 agonist with sedative, anxiolytic, sympatholytic and analgesia properties. It has shown promise in treating older neonates receiving mechanical ventilation by dramatically decreasing the need for opiates and benzodiazepines. It is metabolized by the liver by hydroxylation and glucuronidation and the metabolites are excreted in the kidney. The pharmacokinetics (PK) of dexmedetomidine have been described as one, two and three compartment models in children and adults. There are no descriptions in younger neonates, although the drug is being used increasingly in the neonatal population. Of concern, adverse effects such as bradycardia and hypotension can occur with elevated blood levels of dexmedetomidine.
We propose to initiate a PK study in younger neonates who are being mechanically ventilated. Neonates less than 25 weeks are now placed on high frequency (12 – 15 tiny breaths per second) as first intention ventilation as a lung protective strategy. As a result, ventilator asynchrony is a huge problem in this population. These babies require frequent blood gas monitoring for ventilator adjustment. We will collaborate with Jeff Moran (Pharmacology) to obtain drug levels in this population. Our assays only use 0.05 ml of blood, which can be obtained with little effect on even the smallest neonates. We will obtain blood after a loading dose of dexmedetomidine, then obtain blood levels of the drug when obtaining routine labs noninvasively through an umbilical catheter. We will also record opiate and benzodiazepine use through Epic. We will then develop PK data as a pilot project, which would be publishable and useful. We will also collect data regarding time to full enteral feeds and time on the ventilator.
After obtaining pilot PK data we will correlate levels of opiates, benzodiazepines and dexmedetomidine to obtain pharmacodynamic data, which can be used to inform dosing in this population. We would use standardized pain assessment tools (PIPP scores), and standard pain stimuli (heel sticks), to assess pain responses. The platform and methodology, using small amounts of blood, could be commercialized for those doing pain research as well as for clinical use.
Keywords:
- dexmedetomidine
- infant, premature
- pharmacokinetics
- pain