A 12-month-old, 8-kg girl presented for the repair of a giant omphalocele. Apart from gut malrotation and feeding difficulties necessitating supplemental tube feeds, she was otherwise healthy and had no congenital anomalies. Because of the size of her abdominal wall defect (Fig. 1), the surgeon anticipated a complex procedure with the insertion of mesh or component separation of fascia with a relatively long hospitalization requiring at least temporary postoperative intubation. After uneventful induction of general anesthesia and endotracheal intubation, an epidural catheter was placed via the thoracic route under sterile conditions with the loss-of-resistance technique. The correct position of the epidural catheter tip at T6/7 was confirmed by an epidurogram after negative aspiration for blood or cerebrospinal fluid. Peri-incision, the epidural catheter was bolused with 2 mL of 0.125% bupivacaine (0.31 mg/kg) and an infusion of 0.125% bupivacaine with 2 μg/mL fentanyl was started at a rate of 2.5 mL/h (corresponding to 0.39 mg/kg/h bupivacaine and 0.6 μg/kg/h fentanyl). The patient remained hemodynamically stable throughout the operation. The surgeon performed an internalization of omphalocele and closure of the massive ventral hernia with prosthetic mesh, a Ladd procedure for malrotation, and an appendectomy (Fig. 2). Because of increased inspiratory pressures after abdominal wall closure, the patient was taken to the pediatric intensive care unit (ICU) tracheally intubated with the epidural infusion of bupivacaine and fentanyl as described earlier. On the third postoperative day, she had a period of agitation while sedated with dexmedetomidine and morphine followed by a single witnessed episode of generalized convulsions and lip smacking lasting approximately 10 minutes, which was terminated with IV lorazepam. There was no witnessed hemodynamic instability preceding or after the seizure, and no electrocardiogram changes or arrhythmias were noted by the ICU personnel. A neurologic, metabolic, and infectious workup was unrevealing, except for elevated transaminases and mildly decreased serum albumin. In the absence of any other findings explaining epileptic activity, a diagnosis of suspected bupivacaine toxicity was made, the epidural infusion was stopped, and the catheter was removed. A test for plasma bupivacaine levels is unfortunately unavailable at our institution. No further seizure activity occurred. The patient’s hospital course was further complicated by pneumonia and respiratory failure requiring tracheostomy. She was eventually discharged with a home ventilator and continues to make progress with weaning off of ventilatory support.
Several multicenter studies have reported on the safety of neuraxial anesthesia and continuous epidural catheters in the pediatric population with most common adverse events related to catheter dislodgement or kinking, inadvertent dural punctures, local skin infections, or drug errors.1–3 Serious complications such as epidural hematomas or persistent neurologic symptoms are rare. Although the amide local anesthetic bupivacaine has a low margin of safety in the pediatric population, seizures from prolonged epidural infusions are exceedingly rare. Evidence of seizures is limited to case reports in neonates or higher rates of bupivacaine infusion than the usually proposed range of 0.2 to 0.4 mg/kg/h.4–6 As far as we are aware, this is one of the few reported cases of seizures with a standard infusion of bupivacaine in a pediatric patient well beyond the neonatal age.
The toxicity of amide local anesthetics such as bupivacaine is mediated by their action at sodium channels in myocardial tissue and in the central nervous system (CNS). Neonates and young infants receiving prolonged epidural infusions of bupivacaine are at greater risk than adults for toxicity. Total and free plasma concentrations of bupivacaine have been shown to be higher in neonates and infants compared with older children during continuous infusions of epidural bupivacaine.7 This is the consequence of several physiologic differences between neonates and adults. First, hepatic metabolism by the CYP3A4 cytochrome is low at birth and increases through the first year of life. Second, bupivacaine is highly protein-bound to α1-glycoprotein with approximately 4% to 7% existing in the free and unbound form.8 Relatively low levels of serum α1-gylcoprotein in the neonate compared with adults predispose to increased bupivacaine toxicity because the unbound local anesthetic is the active and toxic moiety. This may be mitigated to some extent by an increase in α1-gylcoprotein, a stress protein, in the immediate postoperative period. However, higher protein binding also leads to a decrease in total body hepatic clearance of free bupivacaine.8 Levels of total plasma bupivacaine are often still on the rise several days after initiation of an epidural infusion, although an accumulation of the unbound form has not been observed.9–11 Last, in neonates and infants, there is significant interindividual variability in blood bupivacaine levels even when recommended dosages are used.10,11
Higher plasma levels of bupivacaine may be because of the infant-specific pharmacokinetics of bupivacaine clearance as outlined earlier and also because of the effect of abdominal surgery on hepatic elimination. With a low to moderate hepatic extraction ratio, the elimination of bupivacaine is in part dependent on hepatic blood flow, which can be decreased after abdominal surgery and with positive pressure ventilation. Surgery near the liver, as was the case in our patient, can potentially reduce bupivacaine clearance. In a study performed in neonates, a substantial number of patients still had rising levels of plasma bupivacaine at 48 hours of infusion.10 Those patients undergoing intra-abdominal procedures with the potential to decrease hepatic blood flow had higher levels of plasma bupivacaine than comparison subjects, although the difference was not statistically significant. Our patient remained intubated postoperatively because of high airway pressures, likely caused by internalization of omphalocele content into a contained abdominal cavity (Fig. 3). We presume that the elevated intra-abdominal pressure postoperatively with a resulting decrease in hepatic perfusion followed by liver injury as evidenced by a temporary increase in serum transaminase levels predisposed our patient to accumulation of toxic levels of bupivacaine.
Our patient’s seizure terminated after administration of IV lorazepam and discontinuation of the epidural infusion. Lipid emulsion was not given because the diagnosis of local anesthetic systemic toxicity was only made after a brief delay as a diagnosis of exclusion, at which point further treatment was deemed unnecessary by the bedside team. The seizure occurred “after hours” in the ICU, where anesthesiologists are not immediately present. It is likely that intensivists are less familiar with the diagnosis and treatment of local anesthetic systemic toxicity compared with anesthesia providers. In general, lipid emulsion is the treatment of choice for cases of recalcitrant hemodynamic collapse in neonates and adults, but it has also been used successfully to treat isolated CNS toxicity in the adult.12–14 Benzodiazepines raise the seizure threshold and are commonly used to treat seizures in the pediatric ICU setting, but do nothing to address the underlying process of rising levels of local anesthetic. In our patient’s case, CNS toxicity could very well have been followed by hemodynamic instability. Consideration should have been given to administration of intralipids to prevent progression to potentially life-threatening cardiac toxicity. The absence of electrocardiogram changes suggestive of cardiac toxicity might be explained by a very gradual increase in bupivacaine levels in our patient, allowing diagnosis after the onset of CNS symptoms but before cardiac toxicity levels were reached.
In summary, we present here the case of a 12-month-old patient experiencing a seizure attributed to the infusion of epidural bupivacaine at a rate of 0.39 mg/kg/h in the context of postoperative hepatic compromise. Our infusion rate was within the range of 0.2 to 0.4 mg/kg/h proposed by Berde6 for older infants, toddlers, and children. An obvious limitation of our report is that plasma bupivacaine levels could not be measured. Nevertheless, our case highlights several key points of caution with regard to prolonged infusions of bupivacaine in the pediatric population. Neonates and infants are more susceptible to local anesthetic toxicity with prolonged infusions because of decreased protein binding and hepatic clearance. We propose that particular caution should be used after intra-abdominal procedures with the potential to compromise hepatic blood flow and function. In these cases, infusion rates may need to be reduced below recommended maximal rates.
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© 2016 International Anesthesia Research Society
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