Throwback Thursday, March 25, 2021
Welcome to another edition of PAAD’s Throwback Thursday, where we welcome back eminent professor Myron Yaster. He will revisit a real oldie that established the way in which we dose neuromuscular blockers in neonates and small children.
D M Fisher, C O’Keeffe, D R Stanski, R Cronnelly, R D Miller, G A Gregory. Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology 1982 Sep;57(3):203-8 PMID: 7114542
This article, written almost 40 years ago, remains one of the most important pharmacokinetic and pharmacodynamic papers ever published in pediatric anesthesia. The authors include a who’s who of giants in the fields of anesthesiology and pharmacology, including Dennis Fisher, Don Stanski, Ron Miller, and George Gregory. The authors solved a vexing problem at the time, namely, how to dose non-depolarizing muscle relaxants in infants (and children). The neuromuscular blocking agent (NMBA) used in the study was d-tubocurarine (dTc or curare), a once common NMBA that is no longer used. However, the results remain true for the NMBAs we use today. The problem they solved was a thorny one: in some studies investigators found that infants and children were more sensitive to dTc (compared to adults) and in others they were more resistant. How to square this circle?
Before getting to the results, I urge you to read the METHODS sections of this paper. It is a model of clarity and the techniques used, including a quantitative measure of neuromuscular blockade which can and should be used in our practice today (albeit without the 27-gauge needles and paper recorders!). Measuring dTc concentrations, the authors fitted their results into a 2-compartment, first-order pharmacokinetic model and determined, t1/2 alpha and beta, volume of distribution at steady state (Vdss) and clearance. The paralysis data was then fitted to the kinetic data. The key findings were that the Vdss was much greater in neonates than the other age groups and the plasma concentration required to produce paralysis was much lower. These 2 results basically cancel each other out so that even though less dTc may be required to produce paralysis, the larger volume of distribution requires a higher dose! So, the mg/kg dose would be the same in neonates and adults. These results would be similar for other ionized molecules which remain in the plasma and extracellular fluid (ECF), including all of the NMBAs used in our current practice. As the authors point out, the changes in Vdss mirror the changes in increased ECF in neonates. Another interesting finding was that clearance did not change with age but the t1/2 beta (elimination) was longer in neonates which again is related to the larger Vdss and means that recovery from neuromuscular blockade may be slower in neonates, particularly if multiple doses of NMBA are given.
A final thought to the readers. This study was performed while Dennis Fisher (my former senior resident and good friend) was a fellow at University of California San Francisco. He went on to have a remarkable career as an investigator, author, editor, and consultant and is a testament to his mentors and the institution in which he trained.
PAAD Editor’s Note: I have one funny story about Stanski: when I was in Rochester I was in charge of the visiting professor program. This played a huge role in the trajectory of my career, as I developed relationships with many notable and academically successful people that in many cases carry to this day. But Stanski (then Chair at Stanford) was different – he was serious and a little aloof, and hard to talk with. At that time, I had an old Porsche 911 convertible, which I used to take him back to the airport on a beautiful spring day. I always drove very slow and safe with the VP in the passenger seat, and it gave me time to pepper them with more questions. Upon doing so, Stanski got visibly frustrated and snapped at me: “Enough with the damn questions! How about you put your foot on the gas and let’s see how fast this baby can go!” So I did.