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April 1997
Plasma concentrations of bupivacaine in neonates after continuous epidural infusion.
Larsson BA, Lonnqvist PA, Olsson GL; Anesth Analg 1997;84:501-5.
[ see abstract below ]
Five years ago, there were several reports of bupivacaine toxicity in infants and children. As a result dosage recommendations for continuous infusion of bupivacaine in infants were reduced from a maximum of 0.45 mg/kg/hr to 0.2 mg/kg/hr. Larsson and colleagues at the Karolinska Hospital in Sweden now report their evaluation of the safety and efficacy of the new bupivacaine doses.
They measured concentrations of total and free bupivacaine as well as levels of a1-acid glycoprotein (AAG) during lumbar epidural anesthesia in 13 neonates, aged less than one month. The infants were given a bolus of 1.8 mg/kg of 1/4% bupivacaine during abdominal or thoracic surgery, followed 60 minutes later by an infusion of 0.2 mg/kg/hr of 1/8% bupivacaine.
All patients had excellent analgesia during surgery, all but one were very comfortable postoperatively and no adverse reactions associated with bupivacaine were noted. The investigators found substantial (more than 5-fold) inter-individual variation in maximum total plasma concentrations of bupivacaine; large interindividual variability is commonly observed in many pharmacologic and physiologic parameters in neonates.
Total plasma concentrations never exceeded 3.1 mcg/ml. However, more than half the patients (5/9), particularly those with increased intra-abdominal pressure, with infusions lasting more than 48 hours did not achieve steady state plasma levels.
AAG is an acute phase protein which, with albumin, binds 95% of bupivacaine in adults. It s is elevated after trauma and surgery. The levels of AAG in these infants almost doubled between 1 and 24 hours after the bupivacaine infusion was started. Free plasma bupivacaine concentrations were measured in 4 patients at 1 and 24 hours. In 3/4 of these, free bupivacaine levels were lower at 24 hours than at 1 hour, probably due to increases in AAG.
Because interindividual variation in plasma bupivacaine during continuous epidural infusion in neonates is so substantial and because many patients had total plasma levels that were still increasing at 48 hours, close monitoring of these infants and perhaps the use of lidocaine (with more rapidly available plasma levels in most hospitals) are warranted. Further work is needed to evaluate and more clearly delineate the levels of free bupivacaine in these patients and the toxic thresholds of total and free bupivacaine in infants and children.
See also: The Pharmacologic Basis of Anesthesiology: Basic Science and Practical Applications. (Bowdle TA, Horita A, Kharasch ED; Churchill Livingstone, New York, 1994) for an in-depth discussion of opioid and local anesthetic pharmacokinetics in adults.
Return to the Current Literature Review Front Page, or read the abstract:
ABSTRACT
This study reports plasma bupivacaine concentrations in 13 neonates who received lumbar epidural anesthesia during major abdominal surgery.
A bolus of 1.8 mg/kg of bupivacaine (2.5 mg/mL) was administered after induction of anesthesia, followed by a continuous infusion of 0.2 mg - kg-1 - h-1 (1.25 mg/mL). Plasma concentrations of total and free bupivacaine and a1-acid-glycoprotein (AAG) were determined. Results are presented as mean (+/- SEM). At 48 h, five of nine patients still had increasing total plasma concentrations, and the total bupivacaine concentrations ranged between 0.7 and 3.1 ug/mL. The plasma levels of AAG increased significantly between 1 and 24 h (4.3 +/- 2.3nm and 7.7 +/- 2.3 nm, respectively) (P = 0.018). The free concentrations of bupivacaine were relatively unchanged at 1 and 24 h (84 +/- 20ng/mL and 58 +/- 15 ng/mL, respectively). No adverse events occurred during the study period.
In conclusion, the dose administered in this study appears to be safe. However, a substantial number of patients still had increasing concentrations of total plasma bupivacaine at 48 h. Furthermore, the interindividual variation was considerable. These observations cause concern about the safety of epidural infusions longer than 48 h in the age group studied.
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