Alpha-1-acid glycoprotein and local anesthetics in the neonate
Myron Yaster MD and Lynne G. Maxwell MD
The 1980s and early 90s marked a remarkable period of the rediscovery of regional anesthesia in pediatric anesthetic practice. Much of the early work was performed by French clinician scientists (Drs. Bernard Dalens, Claude Ecoffey, Isabelle Murat), the faculty at the Children’s National Medical Center in Washington D.C. (Drs. Lynn Broadman, Rafaat Hannallah, Linda Jo Rice), and others (Drs. Charles Berde, Adrian Bosenberg, Dick Tibboel, Olli Meretoja, Estella Melman, Joe Tobias, Lynne Maxwell, and me) to name a few. One of the key issues was not only how to perform neural blockade (remember there was no ultrasound back then) but how to dose local anesthetics for single and continuous infusions.
A teaching point I always liked to make with trainees was that local anesthetics were unusual in that unlike almost all other drugs used in medicine, local anesthetics had to be physically deposited at their site of action in order to work. Almost all other drugs used in medicine must first get into the blood (IV, IM, oral, inhalation, etc.) and the blood carries the drug to its site of action. On the other hand, the amount and speed of uptake of local anesthetics into the blood determines toxicity rather than than efficacy. Thus, in very vascular areas or in direct injection into blood, very small doses of local anesthetics can cause toxicity and in relatively avascular areas like fat (liposuction), large amounts of local anesthetics can be administered relatively safely. Based on this, initial doses of local anesthetics, particularly amide local anesthetics, into the epidural space, for example, could be large but subsequent doses or infusions have to be reduced because the subsequent doses add to the total body burden of drug and accumulation could thereby cause toxicity. And toxicity did/does occur.
A great discovery by Dr. Quinton Fisher et al.1 and subsequently confirmed by many others found that intravascular injection of local anesthetics with epinephrine would produce elevated T waves on the ECG and monitoring the ECG during fractionated, divided doses could reduce the risk of toxicity. There is so much more to say about this journey of discovery. I will ask some of the early pioneers to recount their experiences in future Remembering the Classics PAADs.
In today’s PAAD, we will review an article by Linnarsson et al.2 on changes in alpha-1 acid glycoprotein (AAGP) levels in the first days and weeks of life and the implications of these changes in local anesthetic dosing and toxicity. Myron Yaster MD
Original article
Linnarsson, C, Bartocci, M, Larsson, BA, Eksborg, S, von Horn, H, Olofsson, MA. Alpha-1-acid glycoprotein and its potential impact on local anesthetic dose in neonates. Pediatr Anaesth. 2023; 33: 571- 576. doi:10.1111/pan.14672
“The effect and toxicity of local anesthetics (LA) are both exercised by its unbound (‘free”) fraction, which subsequently is dependent on binding to plasma proteins. Alpha-1-acid glycoprotein (AAGP) is an acute-phase protein with high affinity to amide LA. It is known that neonates have low concentrations of AAGP compared to adults.”2, 3 These low level of AAGP and the resultant large, unanticipated amounts of unbound LA in the blood is a primary source of toxicity and is one of the reasons we reduce the dose of amide LA in regional anesthesia in neonates. (This isn’t an issue with ester local anesthetics because the esters are primarily and rapidly broken down by plasma esterases and don’t accumulate).
“In adults, as well as in children, AAGP plasma concentrations rise as a response to stress, not only in patients undergoing major surgery, but also in some inflammatory conditions. It has been shown that AAGP concentrations in newborns increase with gestational age, and are also influenced by mode of delivery, with higher values related to vaginal birth.”2, 4
The aim of this prospective study was to compare “the plasma concentrations of AAGP pre- and postoperatively in neonates undergoing major surgery. Secondary aims were to determine any correlation between AAGP concentrations and sex, birthweight, mode of delivery, C-reactive protein (CRP) concentrations or gestational age.”2
OK, what did they find? “Higher plasma concentrations of alpha-1-acid-glycoprotein were found 48 h postoperatively compared to preoperatively [median (inter-quartile range) 0.815 g L−1 (0.663–0.983 g L−1) vs. 0.300 g L−1 (0.205–0.480 g L−1 p < 0.001)], respectively. It was not possible to detect any influence of sex, postnatal age, gestational age, or delivery mode on alpha-1-acid-glycoprotein concentrations in our data.”2 In English this means that the risk of developing amide LA toxicity in neonates may not be as great as previously reported because AAGP levels are higher than previously reported and therefore less free unbound LA. This then raises the question do we really need to significantly reduce LA doses in neonates? Since surgery requiring regional anesthesia is commonly performed on the first day of life (think TE fistula repair), the AAGP levels on that day are indeed low (half the amount present at 48 hours), so caution may still be advisable. In addition, as the authors point out, there are factors other than AAGP binding that affect the metabolism and blood levels of LA in neonates, among which are reduced metabolism and clearance. The authors plan future investigations in which both AAGP and plasma LA concentrations will be measured.
Having lived through the period when this was not so well known or understood, we would take a conservative approach and not recommend changing current practice and we would urge you to continue to use lower doses of amides in neonates either for single or continuous infusions. Indeed, because of the risk and because of the difficulty in measuring the plasma concentration of amide local anesthetics in real time (especially bupivacaine and ropivacaine), many pediatric anesthesiologists use chloroprocaine in this population.5, 6
What do you do in your practice? Send your comments to Myron who will post in the Friday Reader Response.
References
1. Fisher QA, Shaffner DH, Yaster M. Detection of intravascular injection of regional anaesthetics in children [see comments]. CanJAnaesth. 1997 1997;44(6):592-598. Not in File.
2. Linnarsson C, Bartocci M, Larsson BA, Eksborg S, von Horn H, Olofsson MA. Alpha-1-acid glycoprotein and its potential impact on local anesthetic dose in neonates. Pediatric Anesthesia. 2023;33(7):571-576. doi:https://doi.org/10.1111/pan.14672
3. Lerman J, Strong HA, LeDez KM, Swartz J, Rieder MJ, Burrows FA. Effects of age on the serum concentration of alpha 1-acid glycoprotein and the binding of lidocaine in pediatric patients. ClinPharmacolTher. 1989 1989;46(2):219-225. Not in File.
4. Anell-Olofsson M, Ahmadi S, Lönnqvist PA, Eksborg S, von Horn H, Bartocci M. Plasma concentrations of alpha-1-acid glycoprotein in preterm and term newborns: influence of mode of delivery and implications for plasma protein binding of local anaesthetics. British journal of anaesthesia. Aug 2018;121(2):427-431. doi:10.1016/j.bja.2018.01.034
5. Veneziano G, Tobias JD. Chloroprocaine for epidural anesthesia in infants and children. Paediatric anaesthesia. Jun 2017;27(6):581-590. doi:10.1111/pan.13134
6. Heydinger G, Tobias J, Veneziano G. Fundamentals and innovations in regional anaesthesia for infants and children. Anaesthesia. Jan 2021;76 Suppl 1:74-88. doi:10.1111/anae.15283