Combined Xenon and Epidural Anesthesia During Surgical Correction of Joint Deformities in the Lower Extremities of Children with Cerebral Palsy

1 Научно-практический центр детской психоневрологии Департамента здравоохранения г. Москвы, Россия, 119602, г. Москва, Мичуринский пр-т, д. 74 2 Морозовская детская городская клиническая больница Департамента здравоохранения г. Москвы, Россия, 119049, г. Москва, 4-й Добрынинский переулок, д. 1/9 3 Российский национальный исследовательский медицинский университет им. Н. И. Пирогова Минздрава России, Россия, 117997, г. Москва, ГСП-7, ул. Островитянова, д. 1


Introduction
Surgical correction of joint deformities in lower extremities is an important part of rehabilitation of children with cerebral palsy (CP) as it improves their mobility and self-care thus facilitating the patient care. An alternative to general anesthesia during surgery is combined general and epidural anesthesia with strong analgesic and antispastic effect which allows reducing the drug load for general anesthesia and promoting the accelerated recovery of consciousness and early activation of the patient. Due to the epidural analgesia, patients with CP do not experience pain and spastic painful muscle contraction during the postoperative period.
However, the epidural lumbar anesthesia has several disadvantages. One of them is the sympathetic block which can cause dilatation of capacitance vessels of lower limbs resulting in a decrease of circulatory volume, which is most severe in patients with CP and preexisting hypovolemia [1]. Moreover, drugs used in general anesthesia can further impair the hemodynamic parameters [2]. To maintain cardiac output when using a combination epidural anesthesia in patients with CP, a high volume fluid therapy can be used. However, the current intraoperative fluid management concepts consider the so-called «liberal» approach to administering fluid therapy as unreasonable and associated with a higher risk of perioperative complications [4,5].
Another problem concerning general anesthesia is the impact of the anesthetic drugs on neural structures. Animal studies show the direct injury effect on central nervous system (CNS) of most inhaled and non-inhaled anesthetics now in use [6,7]. Clinical trials demonstrate the ability of general anesthesia to cause delayed cognitive impairment and behavioral disorders of various intensity and duration, particularly in patients with immature CNS [8,9].

Материал и методы
В исследование включили 50 детей в возрасте от 3 до 17 лет с церебральным параличом в форме спастической диплегии или спастического тетрапа-of xenon seems to be a good remedy to reduce the hemodynamic instability and neurotoxicity during combined general and epidural anesthesia in patients with CP. Xenon is a noble gas with minimal effect on hemodynamics, myocardial function and neurohumoral response, even in heart failure [12,13]. Xenon shows no neurotoxicity. Moreover, experimental and clinical study data have demonstrated its neuroprotective properties [14,15]. The neuronal injury marker research has shown that xenon does not cause any damage to the central nervous system even in long use [16,17]. It has been shown that xenon starts to produce both cardio-and neuroprotective effect even in subanesthetic concentrations (0.25-0.5 MAC), also when combined with other inhalation anesthetics, with its positive effect on hemodynamics and central nervous system being preserved [18].
The first trials to confirm the effectiveness and safety of xenon anesthesia in children have been conducted in the Russian Federation. As a result, the Healthcare Ministry of Russia has made an amendment to the instruction for the use of XeMed ® (medical xenon, Akela-N, Russia) allowing its use in general anesthesia in children aged 1 to 18 years. However, no data are available on xenon being used as part of combined general and epidural anesthesia in children with cerebral palsy and its effects on the cardiovascular system and cognitive functions in these complex patients have not been described so far.
Research objective: comparative assessment of combination anesthesia based on xenon and epidural anesthesia for children with cerebral palsy.

Materials and Methods
The research involved 50 children aged from 3 up to 17 years with spastic diplegia or spastic tetraparesis cerebral palsy. All patients had ASA II-III classes and underwent lower limb bone or soft tissue orthopedic surgery under general xenon anesthesia combined with epidural block. Patients were divided into 2 groups comparable in age and gender (table 1).
In the first group of patients, xenon anesthesia (XeMed ® ) was used. In the second group, xenon was combined with volatile anesthetic sevoflurane. Both groups of patients were divided into 2 subgroups depending on age: from 3 to 8 and from 9 to 17 years old.
Premedication regimen adopted in our Science and Practical Center included atropine in a dose of 0,01 mg/kg and midazolam 0,25±0,01 mg/kg and was used in all of the patients under study [19].
Во 2-й группе пациентов (Хе+Sev) индукцию анестезии проводили севофлюраном по болюсной методике, фентанилом (3,9±0,14 мкг/кг) и рокуро-In the first group (group of Xenon anesthesia -Xe group) the volatile anesthetics were not used and anesthesia was performed by bolus dosing of propofol 3.1±0.2 mg/kg, fentanyl 4.1±0.13 µg/kg and rocuronium bromide 0.66±0.01 mg/kg. The tracheal intubation and transition to mechanical ventilation was followed by the denitrogenisation stage. Prior to introducing xenon into the ventilator circuit, anesthesia was being maintained by recurrent bolus dosing of propofol in a single dose of 1 mg/kg, with the bispectral index exceeding 55. With the stage of denitrogenisation completed, starting with the saturation stage and later on, xenon inhalation anesthesia was administered using the oxygen flow depending on the metabolic flow but not lower than 0.15 l/min because of the default set of options of the anesthetic machine which doesn't allow to set a lower oxygen flow.
In the second group of patients (a group of Xenon+Sevoflurane -Xe+Sev group) anesthetization was performed by bolus dosing of sevoflurane, fentanyl 3.9±0.14 µg/kg and rocuronium bromide 0.67±0.02 mg/kg. During denitrogenisation anesthesia was maintained by inhalation of sevoflurane in concentration 0.8-1.0 MAC. Again, as with the first group, starting with the saturation stage, anesthetization was done with the oxygen flow depending on the metabolic flow. Xenon saturation was being performed until reaching the target concentration of 50%, with the sevoflurane vapor being present in the breathing gas mixture.
Maintenance of anesthesia at the main stage in the group of Xe+Sev was done by xenon -oxygen mix in the xenon : oxygen ratio of 50-52% : 40-45% with vapors of sevoflurane in concentration 0.5-0.7 (0.2-0.3 MAC) during the surgery.
After the plaster application, the supply of inhalation anesthetics into the breathing contour was stopped and the oxygen flow was increased up to 6 l/min. After the appearance of adequate spontaneous breath, the patients were extubated and weaned to the spontaneous breathing in moderate sedation (BIS 70-75), without waiting for their full awakening. Having reached the level of consciousness of 8 points Aldrete score [21], the patients were transferred to the postoperative room where all of them got the prolonged anesthesia by continuous epidural infusion of ropivacaine 0.2% in a dose of 0.1-0.2 mg/kg/h.
The day before surgery, on the first and the third day after anesthesia, memory, attention and thinking were estimated by a clinical psychologist in 20 patients, 13 patients from the Xe group and 7 patients from the Xe+Sev group. The Luria memory words test, Shulte tables, Raven's progressive matrices and the children's correction task were used.
The statistical data analysis was performed using the Statistica 7.0 software. The mean of the sample (M) and the standard error of the mean (m) were calculated. To estimate the statistical significance of the mean values the Student's test was used. For assessment of significance in related data groups the Wilcoxon's test was used. The Mann-Whitney's test was used in independent data groups. The differences were considered significant with the probability value (p) not exceeding 0.05. The results obtained are presented as M±m.
In our research the combination of xenon and sevoflurane showed stronger analgesic effect than xenon alone. It resulted in a reduced need of fentanyl in the Xe+Se group. In the Xe group additional fentanyl administration was required in 20 patients (67%) in an average dose of 2.3±0.15 µg/kg/h, while in the Xe+Sev group fentanyl was used only in 7 patients (35%), in doses significantly lower (P 0.001) than in the Xe group, the mean being 1.34±0.14 µg/kg/hour.
Not only did the combination of xenon and sevoflurane in its minimal inhaled concentration provided stronger intraoperative analgesia but also it appeared to be more cost-effective allowing to significantly reduce the xenon flow (P 0.01) at all the stages of anesthesia in both age subgroups and thus decrease the general consumption of xenon by 14% (P 0.01) in the younger age subgroup and by 18% (P 0.05) in the senior one, respectively (table 2).
The combination of xenon and sevoflurane also helped reduce the dose of rocuronium bromide which was 0.11±0.04 mg/kg/h in the Xe+Sev group vs 0.23±0.02 mg/kg/h in the Xe group (P 0.01).
The BIS indices showed the depth of anesthesia to be appropriate and sufficient for surgical anesthesia in both cases.
Impact of xenon on the parameters of mechanical ventilation. As xenon is a noble gas it doesn't influence the central regulation of breath and the muscular tone of bronchi. However, due to its high density and viscosity it can change the breathing mechanics and rheological properties of the breathing gas mixture. Supplying xenon in the breathing mix caused changes in the mechanical ventilation parameters which are presented in table 3.
The xenon added to the respiratory mix caused increase of the breathing volume with constant inspiratory pressure in all patients. This was due to the indication error of the flowmeter of the anesthesia apparatus which is poorly adapted for working with xenon. However, the patients in Xe group showed both increase of breathing volume and a trend to hypercapnia which required using the hyperventilation mode by increasing inspiratory pressure to eliminate carbon dioxide.
Ксенон, добавленный в дыхательную смесь, приводил к увеличению ДО при неизменном Pinspу всех пациентов. Это связано с погрешностью показателей флоуметров (4-5.5 mm) endotracheal tube (ETT), which caused increased aerodynamic resistance of airways during the ventilation by the dense xenon-oxygen mix. In the elder Xe subgroup the trend to increased IV and Pinsp was less strong due to a wider ETT and bronchial tree lumen which is accompanied by lower resistance in the airways. Children of the Xe+Sev group showed less changes in the mechanical ventilation parameters as compared to the Xe group, which is explained by smaller xenon content in breathing mix, and thus its lower density. So, the combination of xenon and sevoflurane allowed reducing the density of breathing mixture due to lower xenon concentration and made the mechanical ventilation parameters more appropriate which is vitally important for patients of younger age.
Comparison of hemodynamics in different types of xenon anesthesia. The studied hemodynamic parameters are presented in table 4. Prior to starting anesthetization, the age subgroups (younger and elder) of both patient groups showed no significant differences in hemodynamic profiles.
The hemodynamic profile of anesthesia at the stages of induction and denitrogenisation showed differences in the decrease central hemodynamic parameters, heart rate reduction and perfusion index rise due to cardiac depression and vasodilation caused by the general anesthesia drugs in patients with CP and associated pre-existing hypovolemia [3]. However, the patients anesthetized and maintained with sevoflurane demonstrated signifi-
At the stage of skin incision the stabilization of heart rate and mean arterial pressure values was observed, with SVI and CI steadily increasing in both groups of patients due to the xenon-induced cardiac stimulation. In the Xe+Sev group this effect was less noticeable. Even when used in the 50% concentration, xenon successfully corrected the hemodynamic depression associated with epidural anesthesia and elevated the cardiac performance indices to the original values.
The terminal anesthesia and patient awakening stage was characterized by the HR and MAP rising to the reference values. The SVI grew significantly due to the increase of HRF. Thus, the hemodynamic profile at the awakening stage was stable with no tachycardia, hypertension and peripheral spasm observed. Hemodynamic profiles of different types of xenon anesthesia in children from different age groups are presented on figure.
As seen from the curves presented, xenon provided a stable hemodynamic profile of anesthesia both when used alone and in combination with sevoflurane. Xenon-asociated cardiac stimulation appears to compensate the negative impact of epidural block on hemodynamics.
Recovery period assessment. With stopping the supply of xenon and sevoflurane into the breathing circuit of the anesthesia machine, recovery of spontaneous breath and awakening of patients was fast. The time from the end of the inhaled anesthetics supply to extubation was about 3.1±0.4 min in patients of the Xe group. The time of recovery of consciousness up to the level of 8 points according to the Aldrete scale was 5.46±0.52 min, that of up to 10 points being 7.9±0.81 min. Awakening occurred immediately to clear consciousness with no remaining sedation observed.
Как видно из представленных графиков, ксенон обеспечивал стабильный гемодинамический профиль анестезии как в качестве единственного ингаляционного анестетика, nificantly longer: the time to reach 8 points Aldrette scale was 7.11±0.61 min. and the time to reach 10 points was 11.18±0.79 min (P 0.05). Sevoflurane in low concentration does not depress breathing and thus does not prolong time till extubation. But since it has higher gas/blood solubility index as compared to xenon, elimination of the former from the body occurs more slowly, which provided a longer and more smooth recovery of consciousness in the Xe+Sev patients.
Though the xenon association with the postoperative agitation syndrome is considered uncommon, we have repeatedly faced this adverse event in the early postoperative period when using xenon in practice. The intensity of this syndrome was estimated according to the Watcha scale [27]. The syndrome of postoperative agitation scoring 2 points and more was found in 6 patients (20%) of Xe group (1 of the elder subgroup and 5 of the younger one). Frequent postoperative agitation is probably due to the pre-existing cognitive and emotional disorders typical of CP. Abrupt awakening to clear consciousness may be stressful for such patients and provoke postoperative agitation. Recovery of consciousness in the Xe+Sev group occurred more slowly and postoperative sedation was more common, which explains the postoperative agitation syndrome being observed only in two patients of this group (10%). Postoperative sedation is responsible for smooth recovery of patients with CP and in this case may be regarded as a benefit. так и в сочетании с севофлюраном. Кардиостимулирующий эффект ксенона способен компенсировать отрицательное воздействие эпидуральной блокады на гемодинамику.
Когнитивные функции оценивали у 13 больных из группы Хе и у 7 больных из группы We estimated cognitive functions of 13 patients from the Xe group and 7 patients from the Xe+Sev group. Memory, attention and thinking indices were assessed as percentage of the age-appropriate normal values. Reduced indices of memory, attention and thinking with respect to the average age values were initially found in 12 patients (60%). The average deficiency of these highest mental functions was 28.1% (table 5).
On the first day of the postoperative period all the patients demonstrated increased exhaustion of attention and emotional lability. Productive operating time with the psychologist averaged 17.25±0.42 min. During the first day a non-significant rise in cognitive deficiency was noted based on a small decrease in memory indices in the Xe+Sev group and attention parameters in the Xe group of Xe. On Day 3 all the indicators of the cognitive status were nearly similar to the baseline, and thinking indexes in the Xe group exceeded the baseline ones by 4.2%, which was considered as minor reduction of cognitive deficiency. Meanwhile, the cognitive assessment in children with CP after combination anesthesia with sevofluran and epidural block showed considerable negative influence of this intraoperative anesthesia on postoperative cognitive functions [11]. Particularly, the overall cognitive deficiency was seen in 44.6% patients the morning after surgery. However, on Day 3 after the operation these abnormalities disappeared in 75% of patients, but persisted in 25% of them with the severity even superior to the baseline.
The data obtained in neuropsychological testing indicate no neurotoxic properties of xenon both as a single anesthetic agent and in combination with sevoflurane.

Conclusion
The use of xenon as part of combined anesthesia in children with CP provides stable hemodynamic parameters during the entire intervention, quick recovery of consciousness, and does not affect the cognitive functions. The cardiovascular effect of xenon compensates the negative hemodynamic effect of epidural block. However, anesthesia with xenon has some disadvantages. Analgetic effect of xenon is insufficient in pediatric anesthesia. When using xenon in the respiratory mix it is difficult to ensure normal ventilation in younger children and proper respiratory monitoring. In our study the following undesirable effects of xenon anesthesia in the recovery period were noted: postextubation laryngospasm, postoperative agitation syndrome, postoperative nausea and vomiting. High xenon consumption in the absence of specialized anesthesia equipment leads to a significant increase in cost of anesthesia.
Xenon-associated cardiac stimulation combined with sevoflurane provides stable hemodynamics throughout the surgery. Addition of sevoflurane reduces the incidence of adverse events in the postoperative period such as agitation, laryngospasm, nausea and vomiting. Combination of xenon and sevoflurane makes anesthesia cost-effective by reducing the xenon consumption. Xenon anesthesia in all studied applications did not significantly affect the cognitive function of patients with cerebral palsy.