The use of lipid emulsion for the treatment of local anaesthetic toxicity in paediatric patients is relatively new . A previous case report and subsequent in-vitro study suggest that carnitine deficiency may increase the risk of bupivacaine-induced cardiotoxicity [2, 3]. We describe an intra-operative cardiac arrest, where the use of lipid emulsion resulted in rapid haemodynamic improvement in a paediatric patient with undiagnosed carnitine deficiency. We discuss the potential role of carnitine deficiency in bupivacaine cardiotoxicity.
A child with cerebral palsy and carnitine deficiency developed ventricular arrhythmias with loss of cardiac output during elective surgery under general anaesthesia with concomitant epidural analgesia. Sinus rhythm was restored on administration of adrenaline, but hypotension persisted despite resuscitation. Bolus administration of 0.8 ml.kg−1 (20 ml) lipid emulsion resulted in rapid improvement in cardiac output. Blood samples taken before and after the lipid bolus did not demonstrate toxic concentrations of bupivacaine. This case suggests that carnitine deficiency may increase susceptibility to bupivacaine cardiotoxicity.
A 6-year-old, 24-kg boy with cerebral palsy was scheduled to undergo proximal femoral de-rotation osteotomies. His medications included valproic acid, clonazepam and phenobarbitone for seizure control. Pre-induction vital signs demonstrated a sinus rhythm heart rate of 100 beats.min−1, and a blood pressure of 100/40 mmHg.
General anaesthesia was induced with iv propofol 2 mg.kg−1 and fentanyl 1 μg.kg−1. Rocuronium 0.5 mg.kg−1 was used to facilitate tracheal intubation. After induction, a 21-G epidural catheter (Portex, Smiths Medical, Keene NH, USA) was inserted at the level of the L2-L3 paravertebral interspace. Neither blood nor cerebral spinal fluid was aspirated from the epidural catheter. A 3-ml test dose of 0.25% bupivacaine with 1:200 000 adrenaline did not demonstrate any changes in ECG morphology, heart rate or blood pressure. Anaesthesia was maintained with isoflurane (end-expiratory concentration of 0.5%) in nitrous oxide and oxygen (70% and 30% respectively). A mixture of 0.125% bupivacaine and fentanyl 2 μg.ml−1 was infused continuously throughout surgery, via the epidural catheter, at a rate of 6 ml.h−1 (bupivacaine 0.25 mg.kg−1.h−1).
The patient was haemodynamically stable while surgery proceeded on the right lower limb. Minimal blood loss was observed and urine output was 1 ml.kg−1.h−1. Six hours later, when surgery commenced on the left lower limb, there was an increase in heart rate from 80 to 120 beats.min−1. Following a 5-ml bolus of epidural infusate, the blood pressure decreased from 80/40 to 65/35 mmHg, with the heart rate remaining elevated at 120 beats.min−1. The heart rate returned to 80 beats.min−1 following the administration of iv fentanyl (1 μg.kg−1) and a bolus of lactated Ringer’s solution (10 ml.kg−1). The blood pressure as measured by a non-invasive cuff fluctuated between high and low readings (systolic pressure 65–90 mmHg). At this time, pulses were palpable, no arrhythmias were seen on the ECG, and no changes were observed in end-expiratory carbon dioxide concentration. There was no evidence of any further surgical blood loss, and surgery proceeded for a further 2 h to conclusion.
During the application of surgical dressings, the patient’s trachea remained intubated while he spontaneously breathed 100% oxygen. At this time, the patient was noted to be pale; venous blood gas analysis demonstrated the presence of anaemia and a lactic acidosis (Table 1). The patient then developed a sudden sinus bradycardia of 60 beats.min−1 that rapidly proceeded to a wide complex ventricular arrhythmia with a rate of 40 beats.min−1. Pulses were not palpable and the end-expiratory carbon dioxide trace decreased from baseline to 0.8 kPa. Chest compressions were commenced immediately. Atropine 0.4 mg and adrenaline 0.2 mg were given iv resulting in a palpable pulse and sinus tachycardia of 180 beats.min−1 within 10 s. The epidural infusion was discontinued at this point. Packed red cells (a total of 300 ml) were transfused over 15 min combined with a bolus of 250 ml of 5% albumin. Intra-arterial access was obtained and arterial blood gas analysis performed (Table 1). The patient remained in sinus tachycardia and required continued boluses of adrenaline (0.1 mg) to maintain a systolic pressure > 60 mmHg. When central venous access was secured, an adrenaline infusion was commenced, and incrementally increased to a rate of 0.2 μg.kg−1.min−1 to maintain systolic pressure > 60 mmHg. Further crystalloid fluid boluses were administered to a total of 20 ml.kg−1.
|Venous (pre-arrest)||Arterial (pre-lipid bolus)||Arterial (post-lipid bolus)|
Despite adrenaline infusion and fluid resuscitation, repeated boluses of adrenaline were required at 5-min intervals to maintain adequate blood pressure. Possible causes for the acute haemodynamic instability included acute bleeding, air, fat or thrombotic emboli, and anaphylaxis, but no clinical findings supported these diagnoses. The possibility of bupivacaine cardiotoxicity was considered and a 20-ml (0.8 ml.kg−1) bolus of lipid emulsion was administered (IntralipidTM 20% from Baxter Pharmaceuticals by Fresenius Kabi, Uppsala, Sweden). This resulted in a rapid increase in the systolic pressure to 100 mmHg, abolishing the need for adrenaline boluses and also facilitating the adrenaline infusion to be decreased from a rate of 0.2 μg.kg−1.min−1 to 0.02 μg.kg−1.min−1 over the next 5 min. An infusion of lipid emulsion was commenced at 0.25 ml.kg−1.min−1, and continued to a total dose of 8 ml.kg−1. The patient was subsequently sedated with 2 mg midazolam (0.8 mg.kg−1) iv as he had then begun to open his eyes and move his head and arms.
At this time, frank blood was aspirated from the epidural catheter. The epidural catheter was removed and a blood clot was observed in the most distal orifice, both proximal orifices being patent. A presumptive diagnosis of bupivacaine cardiotoxicity due to accidental intravascular placement or migration of the epidural catheter was made. Chest X-ray and echocardiogram demonstrated no abnormalities.
The patient was subsequently transferred to the intensive care unit. Analysis of blood samples demonstrated that total plasma bupivacaine concentrations immediately before and 2 h after the administration of lipid emulsion were 0.58 and 0.32 mg.ml−1, respectively. Concentrations of bupivacaine greater than 2–4 mg.ml−1 are considered toxic [4–6]. In view of the sub-toxic concentrations of measured serum bupivacaine, the cause of the patient’s intra-operative cardiac arrest remained uncertain. Blood was analysed to investigate an underlying metabolic condition that may have predisposed the patient to cardiac arrest. The metabolic screen was normal except for the free serum carnitine concentration of 20.4 μm (normal 26.0–60.0 μm). It was subsequently elicited that the patient had chronic carnitine deficiency secondary to long-term valproic acid use although he had not received L-carnitine supplementation.
On the first postoperative day, the patient returned to his baseline neurological state. However, on day 3, despite initial improvement, his neurological status deteriorated suddenly and progressively. Computed tomography scan demonstrated diffuse cerebellar oedema consistent with acute ischaemia. On the eighth post-operative day, following confirmation of brain stem death, the decision was made to withdraw all medical care. The findings of post-mortem examination were consistent with cerebral ischaemic injury. There was no evidence of spinal cord injury, dural puncture or haematoma in the lumbar spine segment.
Total plasma levels of bupivacaine in excess of 2–4 mg.l−1 are associated with central nervous system and cardiovascular toxicity [4–6]. This patient’s plasma bupivacaine levels before and after the administration of lipid emulsion were well below that which is considered toxic, and were in keeping with the total dose of 74 mg of bupivacaine (3.1 mg.kg−1) administered via the epidural catheter over an 8-h period. A case report, previously published by Weinberg et al. , describes a case of presumed bupivacaine cardiotoxicity with a 22-mg dose of bupivacaine in a 60-kg patient, with known carnitine deficiency secondary to isovaleric acidaemia. Shortly after a subcutaneous injection of bupivacaine, that patient demonstrated ECG changes from a normal sinus rhythm of 80 beats.min−1 to a wide complex ventricular arrhythmia at 20 beats.min−1. The patient was successfully resuscitated with ephedrine, adrenaline and lidocaine. Plasma free carnitine level was 32 μm (normal 26.0–60.0 μm) the day following the event, but had been 7.8 μm six weeks previously.
Carnitine is a naturally occurring amino acid derivative. It plays an essential role in the transfer of long-chain fatty acids into the mitochondria for beta-oxidation . Weinberg et al. demonstrated that bupivacaine inhibits lipid-based respiration in myocardial mitochondria in rats via inhibition of acylcarnitine exchange . Other studies have supported the finding that bupivacaine toxicity is related to the bioenergetics function of cardiac mitochondria [8–11]. These findings suggest that carnitine deficiency may increase susceptibility to bupivacaine-induced cardiotoxicity.
The exact aetiology of our patient’s intra-operative cardiac arrest is uncertain. It is not known if carnitine deficiency sensitises the myocardium to the toxic effects of bupivacaine, or how cardiotoxicity may manifest clinically. The pronounced haemodynamic response to lipid emulsion administration after a limited response to fluid resuscitation and adrenaline may suggest that bupivacaine cardiotoxicity was the cause of this patient’s arrest. Whilst a lipid bolus has been used successfully in the treatment of cardiac arrest from overdose of other classes of drugs (e.g. antidepressants, antipsychotics and anticonvulsants [12, 13]), it has not been demonstrated to restore haemodynamic stability in a cardiac arrest of non-toxic aetiology [14–16].
The use of lipid emulsion in the treatment of local anaesthetic toxicity originates from animal studies [17–19], and a few case reports describe its success in refractory cardiac arrest associated with local anaesthetic toxicity [1, 20–23]. The mechanism of action remains undetermined. There are two prevalent theories of its effect. Firstly, lipid emulsion may have a direct inotropic or metabolic effect on the heart [8–14]. The myocardium is dependent on lipids for the majority of its energy requirements, and as bupivacaine has been shown to inhibit lipid substrate availability in cardiac mitochondria , the administration of lipid emulsion may overcome bupivacaine-induced blockade of fatty acid transport by mass action. Secondly, lipid emulsion may artificially create a lipid phase in blood, and thus reduce the effective plasma concentration of the lipophilic bupivacaine molecules by a partitioning effect – the so called ‘lipid sink’ theory [14, 24–27].
In summary, we report a case of peri-operative cardiac arrest in a carnitine deficient paediatric patient, in the context of inadvertent intravascular administration of bupivacaine. Evidence elucidating the mechanism of bupivacaine cardiotoxicity suggests that it may be due to selective inhibition of lipid substrate oxidation occurring in cardiac mitochondria [3, 8–11]. As carnitine plays an essential role in transport of fatty acid substrate to the site of oxidative metabolism, carnitine deficiency may result in toxicity at otherwise non-toxic plasma levels of bupivacaine. Further research is required to determine if carnitine deficiency sensitises the myocardium to bupivacaine-induced cardiotoxicity.
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