Intraoperative neurophysiological monitoring with myogenic motor-evoked potentials (MEPs) and somatosensory-evoked potentials provide important information for assessing spinal integrity during scoliosis surgery. However, several anaesthetic agents can produce a suppressive effect on these monitored variables. We report a paediatric patient scheduled for scoliosis surgery in whom the use of propofol had to be avoided because of her principal illness. The patient had Angelman syndrome which is a clinical manifestation of a partial defect of the paired autosomal chromosome 15 characterised by disorders of genetic coding for the β3 subunit of the γ-aminobutyric acid type A receptor.1 This syndrome is clinically manifested by mental retardation, ataxia of gait and seizures.2 It is also known to have profound implications for anaesthesia, because of the observed vagal hypertonia that can cause extreme bradyarrhythmia.1 The effects of anaesthetic drugs, especially those acting through enhancement of γ-aminobutyric acid type A receptor function, can be unpredictable in these patients.1,3,4 Marked insensitivity to propofol can greatly weaken the depth and shorten the duration of hypnosis. The use of ketamine is inadequate because of the risk of repeated seizures in these patients. Our patient exhibited an attenuated MEP amplitude as a result of high-dose dexmedetomidine administered as a sole hypnotic agent.
The 13-year-old, 150-cm, 54-kg female was scheduled for posterior spinal fusion with instrumentation from T4 to L4 for symptomatic thoracolumbar scoliosis. Seizure control was achieved with valproic acid (300 mg d−1) and no adverse effects were observed. The α2-adrenoceptor agonist dexmedetomidine was chosen as a sole hypnotic agent, and informed consent was obtained from her parents for administration of dexmedetomidine and perioperative blood sampling to measure its concentrations. The study was approved by the Ethical Committee of Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (Ethical Committee approval number 1159 on 13 December 2010). Total intravenous anaesthesia (TIVA) was induced and maintained by dexmedetomidine and remifentanil. For induction, dexmedetomidine was infused at a low dose (0.5 μg kg−1) over 20 min to confirm the absence of abnormal haemodynamic responses to this drug. Remifentanil infusion was started at a dose of 0.3 μg kg−1 min−1. Although bispectral index (BIS) values may be unpredictable in patients with abnormal brain function, her BIS value measured immediately after the induction was 49. Subsequently, to ensure a constant depth of anaesthesia, the dexmedetomidine dose was adjusted to maintain her BIS values between 40 and 50. The dexmedetomidine dose varied from 0.5 to 6.0 μg kg−1 h−1, whereas the remifentanil dose varied from 0.2 to 0.5 μg kg−1 min−1. When the dose of dexmedetomidine was increased to 3.0 μg kg−1 h−1 at approximately 1 h after the start of TIVA, her BIS value markedly decreased to 28. Simultaneously, the amplitude of MEPs obtained from the muscles of both upper and lower extremities (abductor pollicis brevis, tibialis anterior, abductor hallucis) decreased to 20% of baseline. After excluding surgical factors, we concluded that high-dose dexmedetomidine was a possible cause of this attenuation. MEPs gradually reappeared after discontinuation of dexmedetomidine and fully recovered to the baseline values after 30 min. It should be noted that, despite the use of high-dose dexmedetomidine, no bradycardia was observed in our patient. However, we did observe two brief episodes of hypotension (SBP of 75 mmHg), which were successfully managed by ephedrine (4 mg) administration. Upon completion of surgery that lasted for 5 h 40 min, the wake-up test could not be performed because of the patient's mental retardation.
During the procedure, a total of 20 arterial blood samples were collected for estimation of the dexmedetomidine concentration. The values of the measured dexmedetomidine concentration (Cm) were obtained by performing liquid chromatography-tandem mass spectrometry at the Central Research Laboratories of Maruishi Pharmaceutical Co. Ltd. (Osaka, Japan). The values of the predicted dexmedetomidine concentration (Cp) were calculated using Excel_PkPd (Version 1.42 Lite) software [available at: http://home.hiroshima-u.ac.jp/r-nacamura/Excel_PkPd.html (accessed on 3 May 2013)].
Four pharmacokinetic sets for dexmedetomidine have been reported to date (Table 1).5–8 However, no studies have evaluated their accuracy for assessing the pharmacokinetics of dexmedetomidine in adolescents. To this end, we measured the actual dexmedetomidine concentrations in our patient, and compared the obtained values with the predicted concentrations calculated using simulation analyses based on each of the four available pharmacokinetic models for dexmedetomidine.5–8 At each time point wherein Cm and Cp were available, the prediction error was calculated as follows: prediction error (%) = [(Cm − Cp)/Cp] × 100. The bias of the system was expressed as the median prediction error. The precision of the system was assessed by the median absolute prediction error. The typical accepted maximum values were 10 to 20% for bias and 30% for precision. The median prediction error and median absolute prediction error for each of the four pharmacokinetic models are summarised in Table 2. We found that the Potts and Diaz models were the most clinically acceptable, whereas the Petroz and Dyck models were not appropriate. To illustrate these findings, the Cp of dexmedetomidine at the decrease in MEP amplitude were 3.4 and 2.0 ng ml−1 for the Potts and Dyck models, respectively, and the Cm of dexmedetomidine in our patient at this time point was 3.6 ng ml−1. Thus, the Potts model was the closest to the Cm and the most accurate, whereas the Dyck model was the least accurate among the four models. To our knowledge, there have been no previous studies comparing Cp with Cm at the point when high-dose dexmedetomidine attenuated the MEP amplitude in the absence of propofol. Moreover, our simulation analysis was validated by the calculations of bias and inaccuracy relative to the actually measured concentrations of dexmedetomidine.
Although some controversy still remains, the results of several studies imply that dexmedetomidine may suppress the amplitude of MEPs. For example, when used as a hypnotic adjunct to propofol-based TIVA, dexmedetomidine was reported to significantly attenuate the amplitude of MEPs.9,10 By contrast, dexmedetomidine did not interfere with intraoperative neurophysiological monitoring during scoliosis surgery in adolescents.11 Using the Petroz model,7 Mahmoud et al.9 reported that dexmedetomidine administered at clinically relevant target plasma concentrations (0.6 to 0.8 ng ml−1) as a hypnotic adjunct to propofol-based TIVA could significantly attenuate the amplitude of MEPs in patients aged 10 to 25 years. In the latter study, the target plasma concentrations of 0.4 ng ml−1 dexmedetomidine and 2.5 μg kg−1 propofol exhibited a minimal effect on the MEP amplitude. Tobias et al.10 suggested that the interaction between propofol and dexmedetomidine might result in an increased depth of anaesthesia and cause a marked attenuation of the MEP amplitude. In our patient, dexmedetomidine administered alone at a Cp of 0.8 ng ml−1 did not attenuate the MEP amplitude. Thus, to cause attenuation of the MEP amplitude, the concentration of dexmedetomidine administered without propofol may need to be higher than that when dexmedetomidine is used in combination with propofol. Using the Potts model5 and based on the BIS values, Kunisawa et al.12 reported that, when used alone as a sedative for paediatric cardiac catheterisation, dexmedetomidine was required at a high dose of 1–15 μg kg−1 h−1, with a mean calculated Cp of 4.1 ng ml−1.
The BIS-guided anaesthetic management carried out in our patient was used to ascertain the depth of anaesthesia appropriate for the incurred surgical stress. We found that the required dose of dexmedetomidine administered in the absence of propofol was higher than that usually required when dexmedetomidine is used in combination with propofol. Also, as indicated above, our patient was taking valproate to control her epilepsy. Although no interactions between valproate and dexmedetomidine have been described to date, the possibility of an interaction being involved in the observed attenuation of MEPs cannot be completely discarded, and therefore requires further investigation.
In conclusion, high-dose dexmedetomidine was found to be useful for anaesthesia during intraoperative neurophysiological monitoring in a patient with Angelman syndrome undergoing scoliosis surgery. In this patient, the conventional anaesthetics propofol and ketamine could not be administered based upon the information available at that time. It is also suggested that high-dose dexmedetomidine causing deeper levels of anaesthesia (as indicated by low BIS values) may be accompanied by a decrease in the MEP amplitude. Accurate simulation analysis based on adequate paediatric pharmacokinetic data sets should be available to prevent attenuation of the MEP amplitude caused by high-dose treatments with dexmedetomidine.
Acknowledgements relating to this article
Assistance with the study: the authors would like to thank Dr. R. Nakamura, Department of Anaesthesiology and Critical Care, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan for providing support in the application of the Excel_PkPd software.
Financial support and sponsorship: none.
Conflicts of interest: none.
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