Today’s Pediatric Anesthesia Article of the Day is from a journal that I’ve never heard of and was suggested by Dr. Jerry Parness. Jerry recently retired as a professor of anesthesiology at the University of Pittsburgh and is well known to many of you from his relish and enthusiasm at challenging speakers at SPA meetings, and for his research work on the mechanism of action of dantrolene and malignant hyperthermia. Interestingly, as we were writing the PAAD, this article and its implications were picked up by the national news. https://www.nytimes.com/2022/05/16/well/family/sudden-infant-death-syndrome-study.html
Sudden infant death syndrome (SIDS) is an absolutely terrifying disease, killing apparently healthy infants while they sleep. Yes, changing the infant’s sleep position to the supine position has helped reduce the incidence of SIDS, but this has not eliminated the problem. Today’s paper offers a glimmer of hope for a biochemical marker that may help identify infants at risk, and allow for even more preventive behaviors to be implemented. What is the biochemical marker? It is Butyrylcholinesterase (BChE), the alternative name for our old friend pseudocholinesterase of succinylcholine fame. Will this marker and discovery pan out and make a difference? I don’t know and to be honest, I’ve been in the business long enough to be skeptical about these kind of discoveries, which often don’t pan out over time. Nevertheless, I thought you may all be interested in the results of this study...I know I was. Myron Yaster MD
Original article
Harrington CT, Hafid NA, Waters KA. Butyrylcholinesterase is a potential biomarker for Sudden Infant Death Syndrome. EBioMedicine. 2022 May 6;80:104041. doi: 10.1016/j.ebiom.2022.104041. PMID: 35533499
In the current “triple risk model”, SIDS occurs “when 3 factors occur simultaneously: a vulnerable infant, a critical developmental period for homeostatic control, and an exogenous stressor”.1 Acetylcholine (ACh) is a major neurotransmitter of the autonomic nervous system and the principal neurotransmitter of the parasympathetic nervous system. It is hydrolyzed at cholinergic synapses by one enzyme, Acetylcholinesterase (AChE), and extrasynaptically and in other tissues, by Butyrlycholinesterase (BChE) (also known as pseudocholinesterase), an esterase that has a wide range of substrates that include cocaine and the “hunger hormone”, “ghrelin”.2 Variable levels of AChE and BChE have been observed in para-sympathetic dysfunction and inflammatory disease states.1 Using dried blood spots samples routinely obtained in newborn screening, the authors found BChE was statistically lower in babies who subsequently died of SIDS compared to surviving controls and other Non-SIDS deaths. They concluded “that BChE represents a measurable, biochemical marker in SIDS infants prior to their death for SIDS”.1
Wow! It had long been suspected that the cholinergic system was involved in SIDS deaths. This study was the first to look at pseudocholinesterase. Aside from problems with succinylcholine, the role of BChE is not well understood. Low BChE activity is thought to reflect decreased availability of ACh and thus an altered cholinergic homeostasis and several studies have found that low BChE activity is associated with severe systemic inflammation and a significant higher mortality after sepsis and cardiac events. Acetylcholine is essential in the CNS’s arousal system and BChE may be involved in maintaining normal acetylcholine levels in the brain. If indeed true, low BChE levels may result in impaired arousal response to a given environmental challenge, whether it be infection, apnea, or CO2 rebreathing as a result of the prone position. Further, within the CNS, decreased BChE may also be related to the consistent finding of decreased serotonergic activity in SIDS infants. The interaction between the cholinergic and serotonergic systems play an important role in the control of breathing, and may be crucial in the development of SIDS. Alternatively, BChE may be involved in processes not yet identified (see below), and much more patho/physiologic research needs to be done to uncover hitherto unknown mechanisms.
Given what we know, however, physiologically low BChE levels in babies who develop SIDS make some sense. This preliminary data shows that while there are statistically different mean levels of BChE in the blood of children who go on to die of SIDS, there is large variability in the data presumably segregating the SIDS blood samples from the Non-SIDS and Control children’s samples, so it is not clear how predictive a tool like this will be at this moment of time. For clearer and more convincing evidence, large prospective studies will need to be done, and that will likely require a multi-institutional approach.
On the other hand, a singular view of the physiological functionality of BChE is simply not warranted by the evidence: as an enzyme, BChE is a serine hydrolase that catalyzes the hydrolysis of choline and non-choline esters, and not just acetylcholine. This enzyme also displays aryl acylamidase activity and enhances the activity of proteases such as trypsin.3 Furthermore, though the primary repository of BChE is in the blood, which is how succinylcholine is so rapidly metabolized, a study of the tissue distribution of AChE and BChE mRNA has found the highest levels of BChE mRNA in the liver and lungs, tissues known as the principal detoxication sites of the human body, suggesting that BChE may be a first line of defense against eaten or inhaled xenobiotics, as well as potentially being involved in in situ inflammatory responses that might involve serine proteases. In the human brain, BChE is expressed in substantial populations of neurons, particularly in deep layers of the cerebral cortex, hippocampal formation, amygdala and many thalamic nuclei.4 Moreover, BChE might be associated with cellular proliferation and neurite growth during the development of the nervous system, and it is logical to theorize that low levels of this enzyme might negatively affect affect the breathing and arousal pathways of the newborn.
Despite the multiplicity of potential pathophysiologic mechanisms in SIDS, these preliminary results of a potentially predictable biomarker are exciting and we’ll need to keep our eyes open as more studies are performed in the attempt to validate these findings.
References
1. Harrington CT, Hafid NA, Waters KA: Butyrylcholinesterase is a potential biomarker for Sudden Infant Death Syndrome. EBioMedicine 2022; 80: 104041
2. Zhe YH, Shintew M, Keng YY: Butyrylcholinesterase: A multifaceted pharmacological target and tool. Curr Protein Pept Sci 2020;21(1):99-109. doi: 10.2174/1389203720666191107094949.
3. Jbilo O, Bartels CF, Chatonnet A, et al: Toxicon 1994;32(11):1445-1457.
4. Darvesh, S., Hopkins, D. & Geula, C. Neurobiology of butyrylcholinesterase. Nat Rev Neurosci 4, 131–138 (2003). https://doi.org/10.1038/nrn1035