Low‐dose sevoflurane co‐administered with propofol‐based general anaesthesia obliterates intra‐operative neurophysiological monitoring in an infant

Summary

The influence of general anaesthetic agents on intra‐operative neurophysiological monitoring in neonates and infants has rarely been reported. Propofol‐based anaesthesia is recommended to avoid suppression of neurophysiological monitoring. However, the administration of propofol in children undergoing prolonged procedures, especially those younger than six months, should be carefully controlled due to the potential risk of propofol infusion syndrome. Adding a small dose of inhalational anaesthetic can be an option to reduce propofol requirements. Recent guidelines in Japan suggest limiting inhalational anaesthetics to less than 0.5 minimum alveolar concentrations when co‐administered with low‐dose propofol during intra‐operative neuromonitoring. However, there is still insufficient evidence regarding the impact of sevoflurane on neurophysiological monitoring when co‐administered with propofol in infants. This report describes a case of a three‐month‐old infant undergoing spinal lipoma resection in which there was a dramatic suppression of neurophysiological monitoring with the addition of 0.35–0.45% sevoflurane to propofol‐based anaesthesia.

Introduction

Intra‐operative neurophysiological monitoring, such as motor evoked potentials (MEPs) and somatosensory evoked potentials (SSEPs), is widely used to monitor spinal cord function and identify the location of spinal nerves in the surgical field. Intra‐operative neurophysiological monitoring is commonly applied to neonates and infants at risk of surgical spinal nerve injuries.

Intra‐operative neurophysiological monitoring in neonates and infants is more susceptible to inhibition due to anaesthetic agents than in adults. The developing nervous system of young children requires higher stimulation voltage than adults to ensure adequate intra‐operative neurophysiological monitoring [1]. Anaesthetists, therefore, must choose anaesthetic agents with minimal impact on intra‐operative neurophysiological monitoring and titrate doses to provide appropriate monitoring conditions while maintaining an appropriate depth of anaesthesia. Total intravenous anaesthesia (TIVA) with propofol and remifentanil has less impact on intra‐operative neurophysiological monitoring than inhalational anaesthetics and is widely used for maintenance of general anaesthesia for surgeries requiring intra‐operative neurophysiological monitoring.

Propofol infusions are difficult to use as a sole anaesthetic in neonates and young infants due to maturational changes in volumes of distribution and delayed clearance. Higher infusion rates to maintain a target effect site concentration during long operations may put the patients at risk of propofol infusion syndrome. For this reason, adding a small dose of inhalational agent (e.g. sevoflurane) to propofol‐based anaesthesia is an option to minimise the propofol dose. Recent guidelines recommend limiting inhalational anaesthesia to 0.5 minimum alveolar concentrations (MAC) or less, and supplementing anaesthetic depth with other intravenous anaesthetic agents [1]. Previous reports in infants have used low‐dose sevoflurane as a single agent during transcranial MEP monitoring with good results [2, 3, 4]. However, the interaction between inhalational and propofol‐based intravenous anaesthesia on intra‐operative neurophysiological monitoring in neonates and infants has not been documented.

This report describes an infant who underwent spinal lipoma resection lasting 12 h where intra‐operative neurophysiological monitoring was reversibly suppressed by a small doses of sevoflurane co‐administered with propofol‐based intravenous anaesthesia.

Report

A three‐month‐old girl (length, 60.2 cm; weight, 6.6 kg) presented with a skin abnormality in the lumbosacral region from birth. Magnetic resonance imaging revealed a spinal lipoma at the fourth and fifth lumber vertebrae levels (L4‐5), requiring resection. Pre‐operative symptoms of spinal cord compression were absent.

No pre‐medication was administered. Following pre‐oxygenation, inhalational induction of general anaesthesia was initiated with sevoflurane (end‐tidal concentration 7.5%) and nitrous oxide with oxygen (F_IO₂ 0.4). After obtaining peripheral intravenous access, propofol 2 mg.kg⁻¹ and fentanyl 2 μg.kg⁻¹ were administered intravenously. The patient's airway was secured with a 3.0‐mm cuffed tracheal tube. General anaesthesia was maintained with propofol 66.6 μg.kg⁻¹ min⁻¹, remifentanil 0.5 μg.kg⁻¹.min⁻¹ and sevoflurane (end‐tidal concentration 0.45%; 0.14 age‐adjusted MAC). No muscle relaxant was administered. After the patient was placed in a prone position, electrodes for transcranial MEPs were placed. Forty minutes after the anaesthesia induction, the initial nerve stimulation tests of transcranial MEPs, SSEPs and bulbocavernosus reflex were performed. The patient's vital signs were blood pressure (BP), 73/35 mmHg; heart rate (HR), 100 beats.min⁻¹; oxygen saturation (S_pO₂), 100%; body temperature, 36.0 °C with general anaesthesia maintained as described. With the initial nerve stimulation test (pulse intensity was 400 V, pulse train 2.0 s and a pulse train of 5 throughout the surgery), waveforms of transcranial MEPs in both lower extremities were absent, and transcranial MEPs in both upper extremities were also suppressed (Fig. 1a). Sevoflurane was discontinued and anaesthesia maintenance was continued with propofol 66.6 μg.kg⁻¹.min⁻¹ and remifentanil 0.5 μg.kg⁻¹.min⁻¹. Once end‐tidal sevoflurane concentration was no longer detected with 2 l.min⁻¹ of fresh flow oxygen (approximately 15 min after the discontinuation of sevoflurane), a nerve stimulation test was performed again. The patient's vital signs were BP 78/35 mmHg; HR 104 beats.min⁻¹; S_pO₂ 100%; temperature 35.8°C. Transcranial MEPs were detectable in both lower extremities and the response of transcranial MEPs in the upper extremities increased (Fig. 1b). We maintained general anaesthesia with propofol 66.6 μg.kg⁻¹.min⁻¹ and remifentanil 0.5–1.0 μg.kg⁻¹.min⁻¹ during the surgery. While the neurosurgeons manipulated the spinal cord (235 min after initiating anaesthesia), transcranial MEP amplitude was decreased by approximately 80% in the left lower extremity compared with the control amplitude measured before initiating the surgery. At this point, the surgical team determined to continue the surgery with a careful follow‐up of transcranial MEPs. During the closure of the surgical wound, we resumed administering a low dose of sevoflurane with propofol 66.6 μg.kg⁻¹.min⁻¹ and remifentanil 0.5 μg.kg⁻¹.min⁻¹. When the end‐tidal sevoflurane was stable at 0.35% (0.1 age‐adjusted MAC), we re‐evaluated transcranial MEPs; the waveforms in the right lower extremity disappeared again (Fig. 1c). We discontinued sevoflurane again, continuing anaesthesia maintenance with propofol 66.6 μg.kg⁻¹.min⁻¹ and remifentanil 1.0 μg.kg⁻¹.min⁻¹. Ten minutes later, transcranial MEPs appeared in the right lower extremity (Fig. 1d). However, the transcranial MEPs remained unresponsive in the left lower extremity. The MEPs in the upper extremities were not suppressed despite co‐administering sevoflurane (Fig. 1). The operation duration was 11 h 53 min, and the estimated intra‐operative blood loss was 15 ml. The patient was admitted to the paediatric intensive care unit postoperatively. Tracheal extubation was successfully performed the day after surgery and the patient was transferred to the general ward. Muscle strength in the left lower extremity remained impaired and rehabilitation was initiated on the seventh postoperative day.

Figure 1.

(a) Motor evoked potentials were suppressed with sevoflurane of 0.45% end‐tidal concentration (0.14 age‐adjusted MAC) with propofol‐based total intravenous anaesthesia (propofol 66 μg.kg⁻¹.min⁻¹ with remifentanil 0.5 μg.kg⁻¹.min⁻¹). (b) Motor evoked potentials emerged (black arrows) after discontinuing sevoflurane (propofol 66 μg.kg⁻¹.min⁻¹ and with remifentanil 0.5 μg.kg⁻¹.min⁻¹ maintained). (c) Motor evoked potentials were suppressed again with sevoflurane of 0.35% end‐tidal concentration (0.1 age‐adjusted MAC) with propofol‐based total intravenous anaesthesia (propofol 66 μg.kg⁻¹.min⁻¹ with remifentanil 1.0 μg.kg⁻¹.min⁻¹). (d) Motor evoked potentials emerged (black arrows) after discontinuing sevoflurane (propofol 66 mcg.kg⁻¹.min⁻¹ with remifentanil 1.0 mcg.kg⁻¹.min⁻¹ maintained). Lt: left, Rt: right.

Discussion

Above, we describe the case of a three‐month‐old girl who underwent prolonged anaesthesia for lipoma resection with intra‐operative neurophysiological monitoring in whom administration of a low concentration of sevoflurane (0.1–0.15 age‐adjusted MAC) reversibly suppressed MEPs when co‐administered with low‐dose propofol and remifentanil.

Motor evoked potentials are the result of cortical stimulation of the spinal cord and muscles through corticospinal tracts and measured as spinal and myogenic MEPs. Myogenic MEPs amplitudes reduce after spinal cord injury and ischaemia, the administration of anaesthetic agents and hypothermia. Younger children, especially those under three years of age, require a greater stimulating voltage and high pulse train frequency to induce MEPs because of their immature central nervous system (i.e. incomplete myelination, reduced conduction velocities and fewer monosynaptic connections between the corticospinal tract and alpha‐motor neurons) [1]. Physiological factors (i.e. hypotension, hypothermia, hypoxia, cerebral ischaemia and hypo‐hypercapnia) can suppress the MEPs [5]. In our case, intra‐operative mean arterial pressure was relatively low compared to awake measurements in this age group but represents values commonly seen under anaesthesia. However, blood pressure remained constant throughout the anaesthetic during the observed changes in MEPs, so we do not believe that hypotension was the cause in this case.

Propofol‐based TIVA has less effect than sevoflurane on intra‐operative neurophysiological monitoring, making it the standard of anaesthesia management for surgeries requiring intra‐operative neurophysiological monitoring in adults. However, infants especially under six months of age have reduced propofol clearance, which may result in problems associated with propofol accumulation when administered for a prolonged period (e.g. prolonged awakening times, lipidaemia, alteration of platelet function and development of metabolic acidosis) [6]. The anaesthetic effect on intra‐operative neurophysiological monitoring depends upon the effect‐site concentration (Ce). Together these issues suggest that the rate of propofol administration should be limited in neonates and infants to avoid these propofol‐related complications and the suppression of intra‐operative neurophysiological monitoring; co‐administering other agents is therefore reasonable. Remifentanil is advantageous due to its rapid metabolism by nonspecific esterases, minimal effect on intra‐operative neurophysiological monitoring and higher clearance in neonates and infants than older children [7]. Inhalational anaesthesia (e.g. sevoflurane, desflurane) is removed by ventilation at a rate based on blood–gas partition coefficient. Thus, supplementation with low‐dose inhalational anaesthesia may be useful to facilitate rapid emergence from general anaesthesia during prolonged propofol administration which will inevitably result in delayed return of consciousness.

Several previous studies in infants reported that general anaesthesia with low‐dose inhalational anaesthetics co‐administered with other anaesthetic agents were successfully performed without MEPs suppression [2, 3, 4]. In addition, the current guidelines in Japan suggest that supplementation of low‐dose of inhalational anaesthetics (i.e. less than 0.5 MAC) can be co‐administered with low‐dose propofol for anaesthesia maintenance during intra‐operative neuromonitoring [8]. In our case, intra‐operative neurophysiological monitoring was suppressed under general anaesthesia maintained with 0.1–0.15 age‐adjusted MAC sevoflurane, propofol 66.6 μg.kg⁻¹.min⁻¹ and remifentanil 0.5 μg.kg⁻¹.min⁻¹. Our findings contradict previous reports and Japan's anaesthesia guidelines [8]. The MEPs in neonates and infants can be influenced even by subtle differences in measurement conditions of MEPs monitoring and the effect‐site concentration of anaesthetics. Thus, further prospective studies regarding the influence of small doses of inhalational anaesthetics in neonates and infants under standardised MEP monitoring conditions are desired.

The optimal dose of propofol to achieve adequate amnesia with minimal suppression of MEPs in neonates and infants is still unknown. Processed electroencephalogram (PEEG) monitoring can support maintenence of the optimal anaesthetic plane and avoid excessive dose of anaesthetics in adults. However, the bispectral index in neonates and infants can be misinterpreted due to the difference in EEG waveforms between young children and adults [9]. The knowledge of pharmacokinetics and pharmacodynamics of propofol in neonates and infants can facilitate adjustment of propofol to achieve adequate amnesia without suppression of MEPs including anaesthetic fade and minimising the risk of propofol infusion syndrome. We estimate a propofol Ce of 2.0 μg.ml⁻¹ in this case, which is substantially lower than the Ce 9.0 μg.ml⁻¹ that is reported to cause anaesthetic fade (disappearance of intra‐operative neurophysiological monitoring due to accumulation of anaesthetics) in adults [10]. In addition, a propofol dosage of 66 μg.kg⁻¹.min⁻¹ is considered safe for propofol infusion syndrome [1, 11]. However, propofol Ce of 2.0 μg.ml⁻¹ alone may not be sufficient to maintain an adequate anaesthesia depth without concomitant narcotic analgesia. An additive anaesthetic effect of remifentanil when administering with propofol have been reported in children [12]. In our case, we administered a high‐dose remifentanil (0.5–1.0 μg.kg⁻¹.min⁻¹, approximate Ce of 12.5–20 ng.ml⁻¹ in adults) to reduce the propofol requirement without needing muscle relaxants. Remifentanil can reduce concomitant anaesthetic requirements and provides sufficient analgesia for more intense surgical stimulus.

Other agents can be considered to augment propofol‐based anaesthesia, including ketamine and dexmedetomidine, but these can impact the MEPs. Immaturity of liver and kidney function in neonates and infants may result in accumulation of ketamine. Small changes in the serum concentration of ketamine can affect anaesthetic depth when co‐administered with propofol [12]. These small changes of concentration could cause anaesthetic fade and delayed emergence in neonates and infants. Dexmedetomidine appears to be unpredictable when using intra‐operative neurophysiological monitoring and the interaction between dexmedetomidine and other anaesthetics on MEPs is still unknown. A previous study of teenagers demonstrated that dexmedetomidine had an inhibitory effect on MEP when administered at a rate of 0.3–0.5 μg.kg⁻¹.h⁻¹ [13]. The clearance of dexmedetomidine in neonates and infants is lower than that of older children [14]. Thus, continuous dexmedetomidine infusion can cause anaesthetic fade in neonates and infants over time despite low infusion rates. A paediatric study suggested that a combination of dexmedetomidine and propofol might inhibit the MEPs additively or synergistically [10].

In conclusion, using inhalational anaesthesia in combination with propofol‐based TIVA may suppress neuromonitoring in neonates and infants. Therefore, in these patients, anaesthetists must exercise caution when using inhalational anaesthesia combined with propofol in surgery requiring intra‐operative neurophysiological monitoring.