Opioids and benzodiazepines in the NICU: Sophie’s Choice
Myron Yaster, MD
Sophie’s choice: From the novel and film of the same name, an impossibly difficult choice, especially when forced onto someone. The choice is between two unbearable options, and it's essentially a no-win situation.
Puia-Dumitrescu M, Comstock BA, Li S, Heagerty PJ, Perez KM, Law JB, Wood TR, Gogcu S, Mayock DE, Juul SE, Consortium P: Assessment of 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants Receiving Opioids and Benzodiazepines. JAMA Netw Open 2021 Jul 1;4(7):e2115998. doi: 10.1001/jamanetworkopen.2021.15998 PMID: 34232302
Christopher McPherson, Steven P Miller, Mohamed El-Dib, An N Massaro, Terrie E Inder. The influence of pain, agitation, and their management on the immature brain. Pediatr Res. 2020 Aug;88(2):168-175. PMID: 31896130
As a child of holocaust survivors, the book Sophie’s Choice by William Styron was always a stab in the heart (I couldn’t even bring myself to see the movie). What do you do, what would I do, when you have 2 impossible choices? And if we are honest, as doctors, we often face impossible choices. Which is my segue into the question how or should we treat pain in the NICU (or PICU)? On the one hand, pain produces brain injury in the newborn (see Christopher McPherson et al. above), on the other hand, are opioids and benzodiazepines safe, particularly when used for prolonged periods of time?
The recent article by Puia-Dumitrescu et al. demonstrates what I’ve feared. Indeed, I’ve got to admit that I’ve been waiting for this shoe to drop for a while. Since the “sturm and drang” raised by the effects of anesthetics on the developing brain were first raised almost 20 years ago, I’ve been a very vocal skeptic. “How could one or two hours of a general anesthetic in the newborn or young infant produce life-long brain damage”? I just didn’t believe it. Fortunately, the GAS and PANDA studies have not borne out the lab studies on neuroapoptosis, vindication for my view perhaps, and yet, I’ve always wondered about the NICU (or PICU) where opioids and benzodiazepines are used for days or weeks or months at a time in infants who are mechanically ventilated, sleep deprived, and subject to all manner of iatrogenesis imperfecta.
Puia-Dumitrescu et al. report that “In this multicenter clinical trial of contemporary extremely premature infants, exposure to both opioids and benzodiazepines during their NICU stay were more likely to have increased in-hospital morbidities, prolonged hospitalization, and ultimately lower BSID-III cognitive, motor, and language scores compared with infants exposed to opioids or benzodiazepines alone or infants with no exposure. Prolonged exposure to any of the medications of interest (ie, morphine, fentanyl, midazolam, and lorazepam) had a negative association with all BSID-III scores at 2 years’ corrected age when compared with infants with no exposure. BSID-III scores for infants with short exposure to opioids and/or benzodiazepines were not significantly different compared with infants without exposure”. Ouch!
This study wasn’t actually designed to evaluate the impact of opioids and benzodiazepines on 2-year outcomes, rather it was designed to study the effects of erythropoietin in these infants. So information about dosing, drugs used, why they were used, duration, etc. were not standardized, nor was pain quantified. Further, the authors found wide variation in all of these issues. Nor did they include exposure to anesthesia and/or surgery as possible confounders, potentially a critical omission. They did find “that more than half of the infants in this cohort were exposed to fentanyl and nearly half to morphine. Benzodiazepines were used less frequently than opioids, with similar distribution between midazolam and lorazepam. This is consistent with data showing the decreasing use of benzodiazepines in the NICU, given the link to severe IVH, periventricular leukomalacia, or death in preterm infants”.
What to do? We can’t possibly go back to the dark ages of no pharmacologic management of pain and sedation, or worse, awake paralysis. Which will also produce brain injury… Sophie’s choice.
Or is there another way? Wearing my former PICU hat, I’ve often wondered why do patients in the NICU and PICU need such extraordinary amounts of sedation and analgesia in the first place? And why so much and for so long? Indeed, many of these children, who are a fraction of my size, receive staggering amounts of opioids and benzodiazepines, doses that would put me in a coma and yet they are awake AND agitated. My friend, colleague, and mentee, Dr. Sapna Kudchadkar, at Johns Hopkins, has been thinking about and studying this issue in Baltimore for the last 10+ years.
Perhaps the problem is not pain or agitation per se, perhaps it is a problem of airway management, how we mechanically ventilate patients, and the resultant inherent need for immobility. Perhaps, If instead of endotracheal intubation, we could simply perform tracheostomies in these patients and allow them to get up and out of bed, we could eliminate much of the need for sedation and analgesia. Indeed, some of these ideas were championed by Drs. Jack Downes and Russ Raphaely at the Children’s Hospital of Philadelphia in the 1970s and then forgotten. Additionally, it would be interesting to look at the potential mitigating and sparing effects of the increasing use of dexmedetomidine in both the NICU and PICU on the duration and magnitude of opioid and benzodiazepine use and correlation with neurodevelopmental outcomes.
With the publication of this paper it’s obvious to me that we need a third and better choice for patients in the NICU and PICU.
What do you think?
Myron Yaster MD