Remembering the Classics: Bupivacaine toxicity secondary to continuous caudal epidural infusions in children.
John J. McCloskey MD
Pediatric regional anesthesia is a recurrent hot topic that we’ve frequently reviewed in the PAAD and, thanks to Google analytics, is a topic I know is of great interest to our readership. Once a niche pediatric practice, regional anesthesia exploded and has become virtually ubiquitous in current practice. The pioneering work by many investigators, particularly our French colleagues, like Drs. Claude Ecoffey, Bernard Dalens, Isabel Murat, JX Mazoit, Joelle Desparmet and others, set the pharmaco-kinetic and -dynamic ground work for how we practice today.1-5 Over the past few weeks, I’ve thought that reviewing some classic pediatric regional anesthesia papers and local anesthetic pharmacology studies would not only be a journey into our past but prepare us for our future.
The work of the early pioneers in pediatric regional anesthesia focused primarily on how to do various central (really caudals) and peripheral nerve blocks and the pharmacokinetics of single local anesthetic dosing. As the practice matured, catheters for continuous infusions became increasingly popular for both intra- and post-operative use. What wasn’t initially clear though was how to dose continuous infusions and several cases of local anesthetic toxicity (LAST) began to pop up in the literature.
One of these initial case reports was written by some of my former fellows and colleagues at the Johns Hopkins Hospital, namely John McCloskey, Steve Haun, and Jay Deshpande.6 I’ve asked Dr. McCloskey to discuss his case report and the roadblocks and challenges he faced when he submitted the report for publication.
Currently, Dr. McCloskey is on the faculty of the Children’s Hospital of Philadelphia. Along with Drs. Hal Shaffner, Robert Tasker, and Betsy Hunt he edited the recently released Sixth Edition of the Rogers’ Textbook of Pediatric Critical Care Medicine. Myron Yaster MD
Original article
McCloskey JJ, Haun SE, Deshpande JK. Bupivacaine toxicity secondary to continuous caudal epidural infusion in children. Anesth Analg. 1992 Aug;75(2):287-90. doi: 10.1213/00000539-199208000-00024. PMID: 1340763.
The 1980s were the dawn of pediatric regional anesthesia. “Kiddie caudals” were proven to be safe and effective for intraoperative anesthetic management and postoperative pain. Bupivacaine, an amide local anesthetic, was synthesized in 1957 and was incorporated into clinical practice in 1963. It became the drug of choice for kiddie caudals at that time because of its excellent pharmacodynamic profile and presumed good safety profile. The 1980s and early 1990s were also a time when pediatric pain programs were being developed and spreading throughout the world. At Hopkins, we were looking at various modalities to provide effective postoperative pain relief. One was the incorporation of epidural catheters from the OR to the pediatric wards to help manage postoperative pain. It made sense to consider using continuous infusions of bupivacaine via a caudal catheter but what dose? We were flying by the seat of our pants in considering a dosage range. At the time there were no pharmacokinetic studies of administering bupivacaine in this fashion, only pharmacokinetic studies of single caudal injections in infants and children.1-3,5 As demonstrated today’s PAAD, we chose a dose of 1.25 – 2.5 mg/kg/hr.6 We were wrong! And several patients developed LAST at a time when LAST was poorly understood and intralipid therapy was unknown. One infant in the series suffered ventricular tachycardia and two older children developed seizures. Fortunately, they all survived and without sequelae. This series of adverse events caused us to put a moratorium on the postoperative use of continuous caudal infusions of bupivacaine and investigate why this happened.
As mentioned above, Mazoit et al.1 had examined the pharmacokinetics of a single injection of caudal bupivacaine in infants, and Ecoffey et al.2 examined the same in older children. Using the data from these studies and assuming a safe, steady-state serum concentration (Css) of 1 -1.5 mcg/mL pharmacokinetic equation for a steady-state infusion relating the rate of a drug infusion (Ro) is the product of Css and clearance (Cl)
Ro = Css x Cl
We calculated that safe and effective caudal bupivacaine levels could be achieve with epidural infusions in infants of 0.2 – 0.4 mg/kg/hr and 0.2 – 0.75 mg/kg/hr in older children. We did point out that these calculations were based on linear pharmacokinetics and have the possibility of changing when tissue sites are saturated as Richter et al7 would suggest. Further, based on Richter’s study, we also suggested that caudal bupivacaine infusions should not exceed 48 hrs.
Ah, now what to do with the data and our calculations? Some of our colleagues at Hopkins were hesitant for us to publish this paper; they were concerned we were “airing our dirty laundry” and we would end up on a TV commercial: “have you or your child been the victim of medical malpractice?” However, we decided to proceed and shortly after submitting our manuscript for consideration of publication to Anesthesia & Analgesia, I received a call from Dr. Paul Hickey, the editor for the Pediatric Section of the journal. He told me he wanted to publish it right away because it had the potential of saving kids receiving a caudal infusions of bupivacaine! He showed the paper to Dr. Charles (“Chuck”) Berde who confirmed the recommendations were consistent with what was recorded in his own database which was one of the earliest predecessors to the Pediatric Regional Anesthesia Network (PRAN) database. In an accompanying editorial, Dr. Berde suggested reducing the upper limit of the children dosing range because his database contained several children who developed seizures when infusion rates rose above 0.5 mg/kg/hr. As a pediatric fellow at the time, I was blown away by the attention this paper received from such giants of Pediatric Anesthesia. Our and Dr Berde’s recommendations have formed the basis of caudal epidural bupivacaine infusions in infants and children that we continue to use today.
If you are interested in further historical reading on this subject, I would suggest reading the special article written by Philip Larson, former Chairman of Anesthesiology at Stanford and Editor of Anesthesiology regarding his former faculty member, George Albright.8 In 1978, Dr. Albright submitted a manuscript to Dr. Larson describing immediate cardiovascular collapse in four patients in the San Francisco area after injection of 0.5% bupivacaine for regional anesthesia.9 Dr. Albright sent the manuscript to three journal and they all rejected it. Their reasons for rejection included there was nothing unique regarding bupivacaine or etidocaine, unrecognized hypoxia was probably the cause in all the cases, and the resuscitation was inadequate. Despite the rejections, and like Dr. Hickey, Dr. Larson published the manuscript as a lead article in the October 1979 issue of Anesthesiology to bring attention to this potential problem with bupivacaine and to make its administration to patients safer. Over several years, Dr. Albright continued to publish on the potential for bupivacaine. His voice in this area led to the use of lower concentrations of bupivacaine for regional anesthesia, incremental dosing when administering the drug, and the eventual work regarding lipid emulsions as a rescue agent for bupivacaine toxicity.
PS from Myron: As demonstrated by today’s PAAD, reporting complications is important and an essential method of communication to members of our profession. We are all so fortunate that Dr McCloskey and his colleagues reported this complication and in the process probably saved the lives of many of our patients. Send your thoughts and comments to me and I will post in a Friday reader response.
References
1. Mazoit JX, Denson DD, Samii K. Pharmacokinetics of bupivacaine following caudal anesthesia in infants. Anesthesiology 1988;68(3):387-391.
2. Ecoffey C, Desparmet J, Maury M, Berdeaux A, Giudicelli JF, Saint-Maurice C. Bupivacaine in children: pharmacokinetics following caudal anesthesia. Anesthesiology 1985;63(4):447-448.
3. Ecoffey C, Desparmet J, Berdeaux A, Maury M, Giudicelli JF, Saint-Maurice C. Pharmacokinetics of lignocaine in children following caudal anaesthesia. BrJAnaesth 1984;56(12):1399-1402.
4. Dalens B, Hasnaoui A. Caudal anesthesia in pediatric surgery: success rate and adverse effects in 750 consecutive patients. AnesthAnalg 1989;68(2):83-89.
5. Murat I, Esteve C, Montay G, Delleur MM, Gaudiche O, Saint-Maurice C. Pharmacokinetics and cardiovascular effects of bupivacaine during epidural anesthesia in children with Duchenne muscular dystrophy. Anesthesiology 1987;67(2):249-252.
6. McCloskey JJ, Haun SE, Deshpande JK. Bupivacaine toxicity secondary to continuous caudal epidural infusion in children [see comments]. AnesthAnalg 1992;75(2):287-290.
7. Richter O, Klein K, Abel J, Ohnesorge FK, Wüst HJ, Thiessen FM. The kinetics of bupivacaine (Carbostesin) plasma concentrations during epidural anesthesia following intraoperative bolus injection and subsequent continuous infusion. Int J Clin Pharmacol Ther Toxicol 1984;22(11):611-7. (In eng).
8. Larson CP, Jr., Youssefzadeh K, Moon JS. The Bupivacaine Story: A Tribute to George A. Albright, MD (1931-2020). Anesthesia and analgesia 2022;135(5):1115-1119. (In eng). DOI: 10.1213/ane.0000000000006161.
9. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology 1979;51(4):285-7. (In eng). DOI: 10.1097/00000542-197910000-00001.