Transplacental lidocaine intoxication

1 Introduction

Seizures are common in the neonatal period. The incidence is about two to three per 1000 term newborns [1]. The most common cause is hypoxic-ischemic encephalopathy. Other causes are metabolic disturbances, central nervous system infections, cerebrovascular incidents, genetic disorders, and rarely intoxications.

A full diagnostic work-up is important as etiology is, apart from severity of brain injury, the most important predictor of outcome [2].

2 Case

A term male infant was born by uncomplicated vaginal delivery to a primigravid woman. Prenatal care visits revealed no abnormalities.

The mother received epidural anesthesia after local infiltration of the skin with lidocaine 2% 10 ml. Epidural anesthesia consisted of a loading dose with lidocaine 1% 20 ml and 4 ml epinephrine 1/200.000. There after the mother was able to add a bolus every 20 min consisting of Sufentanyl 25 mcg, ropivacain 100 mg and NaCl 0.9 % ad 50 ml. During second stage of labor a perineal nerve block with 20 ml lidocaine 2% was given as an episiotomy was intended. Eventually episiotomy was not performed. The arterial pH on cord blood was within normal range (7.24).

Although meconium stained amniotic fluid was present, external intrapartum fetal monitoring showed no signs of fetal distress. Apgar scores were 9, 9 and 10 after 1, 5 and 10 minutes, respectively. Birth weight (3420 g), birth length (52,5 cm) and head circumference (33 cm) were all within normal ranges.

During skin-to-skin care after birth, the baby was found in apnea, pale and floppy. Neurological examination revealed a hypotonic infant with bilateral mydriasis and symmetric tonic seizures. A first work-up showed normal electrolytes and a glycaemia of 126 mg/dL. The baby was intubated, phenobarbital 20 milligrams per kilogram was giving intravenously and he was transferred to a neonatal intensive care unit. As there were no signs of perinatal asphyxia, a further diagnostic work-up was performed. General clinical examination was normal. Glycaemia, liver and renal function tests were all normal. Lactate was at most 3.9 mmol/L at arrival on the neonatal intensive care unit and gradually decreased in the following hours. No heart arrhythmias were observed during cardiorespiratory monitoring. The first twelve hours after birth arterial blood pressure and heart rate were relatively low. Values for mean arterial blood pressure were between 35 and 40 mmHg and for heart rate between 110 and 120 bpm. This did not need any treatment.

Empirical antibiotics were started but cultures of blood and cerebrospinal fluids remained negative. Antibiotics were stopped after 72 hours. Brain ultrasound and MRI were normal. No obvious abnormalities on amplitude integrated EEG monitoring were remarked. The full EEG at the age of 18 hours showed a symmetric low voltage pattern.

Urine toxicology screening was positive for lidocaine. At that point, a blood sample of 8 hours postpartum was analyzed and revealed a serum lidocaine level of 2 mg/L. To confirm lidocaine intoxication, a cord blood sample was analyzed. The level of lidocaine in the cord blood was 7.2 mg/L. This confirmed our diagnosis of transplacental passage of lidocaine with intoxication of the fetus.

The infant was extubated 24 h after birth and no seizures were observed afterwards. EEG 72 h postpartum showed a normal background pattern with still some spikes. The boy was normotonic and alert with normal reflexes. There were no injection sites visible on the scalp. The mother never showed any signs of intoxication during or after delivery. The baby was discharged home on the fifth day of life. General and neurological evaluations at 3 weeks and 12 weeks of age were normal.

3 Discussion

The case presented above reveals an unexpected and rare cause of neonatal seizures. There are only a few case reports concerning perinatal lidocaine intoxication of the neonate. The clinical features in all cases are similar. They all had apnea, hypotonia, mydriasis and tonic-clonic movements of the four limbs shortly after birth. All the infants required intubation and recovered within 24 hours [3]. These symptoms can be explained by different receptors blocked at different levels of lidocaine serum concentrations. In higher serum concentrations a blockade of nicotinic-acetylcholine receptors and N-methyl-D-aspartate receptors is seen which can cause unconsciousness, hypotension, bradycardia and mydriasis [4]. Toxic effects of lidocaine in newborns are described at lidocaine blood levels of 3 mg/L [5]. In our case the lidocaine concentration in cord blood was 7.2 mg/L, which can certainly explain our clinical features.

There are different routes of possible neonatal intoxication after local use of lidocaine. First, direct injection of lidocaine into the fetal scalp is a known complication after local anesthesia for episiotomy. Another mode of entry is transplacental passage which may occur after perineal nerve block, local infiltration with lidocaine or use of lidocaine crème [3]. In the sequence of this case the route of intoxication was a transplacental passage after perineal nerve block.

Pharmacokinetic studies show diverse fetal/maternal lidocaine ratios depending of the route of administration (perineal infiltration, lumbar epidural anesthesia, pudendus block or paracervical block). There are different explanations for these high fetal/maternal ratio after perineal infiltration [6]. First, lidocaine is injected in a highly vascular zone. Secondly, there is anatomic proximity of the perineum to the fetus. Further, lidocaine is a weak base, which will rapidly cross the placenta in unionized state. Because of the fetal acidosis in the second stage of labor there is an increased conversion to ionized lidocaine; the ratio ionized to unionized lidocaine rises. And so there is an accumulation of lidocaine in the fetus. This entity is called ‘trapping’ of lidocaine in the ionized form. This explains the strong correlation between fetal/maternal ratio and the length of the second stage of labor and in fetal asphyxia [3–7].

Studies have shown that lidocaine concentration in fetal blood can be up to 50% of the maternal blood concentration. Additionally, half-life of lidocaine is at least four times longer in neonates than in adults, respectively 12 hours versus 0.5 to 3 hours [3, 6]. As there is no antidote available for lidocaine, only supportive and enhanced elimination therapy is indicated. To enhance lidocaine elimination, there are different methods: gastric lavage and forced diuresis, because lidocaine will accumulate preferentially in acid media, and exchange transfusion. The first method is not performed because of risk of aspiration. Gastric aspirates trap the local anesthetics in there ionized form because of an acidic pH [7]. Because of the longer period to achieve effect, forced diuresis is not indicated. Exchange transfusion is an invasive technique. As described, patients recover in a short period of time. In most cases diagnosis is made post factum, so elimination techniques are often not useful [5].

Lipid emulsion therapy is proven to be effective in resuscitation of cardiac arrest due to intoxication with local anesthetics. If the diagnosis is made immediately and there are signs of systemic toxicity then starting a lipid emulsion is recommended by the ASRA guidelines [4]. Hydrophobic molecules of the local anesthetics will be extracted from the aqueous plasma phase to the lipid phase created by this lipid infusion. Initial treatment can by started on a bolus of lipid 20% solution 1.5 ml/kg IV, if need for continuous infusion 0.25–0.5 ml/kg/min can be started and continued for a least 10 min after circulatory stability is obtained. These guidelines are based on animal and in vitro studies and several case reports of which only one describes the treatment in a pediatric patient [8].

Supportive therapies such as mechanical ventilation and anticonvulsive therapy can be necessary. As the diagnosis is often made after initiation of anticonvulsant therapy, phenobarbital is the agent of choice in newborns. In animal studies diazepam appears to be the first drug of choice in case of seizures after intoxication with local anesthetics [5].

Although short term prognosis is good, there are no long term follow-up data available of patients with intoxication by local anesthetics [3]. Neurological follow-up of patients after intoxication of local anesthetics seems recommended.

Recently several cases of sudden unexpected postnatal collapse (SUPC) during skin-to-skin care after birth are published. We believe that the use of anesthetics during labor should always be considered as a possible cause of SUPC. Therefore, toxicology screening is essential in the diagnostic approach.

4 Conclusion

Although rare, we should always consider fetal intoxication through maternal medication as a possible cause of neonatal seizures and sudden unexpected postnatal collapse. It underlines that the use of local anesthetics during labor is not without risks for the neonate. Lidocaine metabolites can be detected in urine. A dosing of lidocaine in (cord) blood can help to confirm the diagnosis. Urine toxicological screening remains an important feature in the diagnostic work-up of neonatal seizures and sudden unexpected postnatal collapse.

Disclosure statements

There are no disclosures.

We have written informed consent of the parents to publish this case report.