Monitoring of the Effectiveness of Intensive Care and Rehabilitation by Evaluating the Functional Activity of the Autonomic Nervous System in Patients with Brain Damage

Цель: оценка клинической значимости параметрического мониторинга эффективности интенсивной терапии и реабилитации на основании анализа функционального состояния автономной нервной системы у пациентов с повреждениями головного мозга различного генеза. Материал и методы. В исследование включили 66 пациентов на 20—50-е сутки после черепно-мозговой травмы, аноксического повреждения головного мозга; острого нарушения мозгового кровообращения. Выделение клинических групп и последующий анализ клинического статуса основали на оценке функционального состояния автономной нервной системы (АНС) исходя из динамики параметров вариабельности ритма сердца (ВРС). В качестве параметров нормы и патологии функционального состояния АНС апробировали цифровые значения, полученные у 500-а пациентов в периоперационном периоде при 5-и минутной длительности записи ВРС [1]. Парасимпатическую гиперактивность принимали в пределах значений для SDNN (стандартное отклонение от средней длительности всех синусовых R-R интервалов) > 41,5 мс; для rMSSD (среднеквадратичное отклонение разности двух смежных отсчетов R-R кардиоинтервалов) > 42,4 мс; для pNN50% (доля соседних синусовых R-R интервалов, которые различаются более чем на 50 мсек) > 8,1%; для SI (стресс-индекс напряжения Баевского, нормализованные единицы) < 80 н. е.; для TP (общая мощность спектра частот) > 2000 мс2. Симпатическая гиперактивность принималась в пределах значений для SDNN < 4,54 мс; для rMSSD < 2,25 мс; для pNN50% < 0,109%; для SI >900 н.е.; для TP < 200 мс2. Норма параметров ВРС принималась в пределах значений для SDNN [13,31—41,4 мс]; для rMSSD [5,78—42,3мс]; для pNN50% [0,110—8,1%]; для SI [80—900 н.е.]; для TP [200—2000 мс2]. Для верификации парасимпатической или симпатической гиперактивности в указанных пределах принимали 3 из 5 параметров [1]. Результаты. По динамике параметров ВРС до и на 30—60-е сутки интенсивной терапии и реабилитации пациентов с травматическими и нетравматическими повреждениями головного мозга выявили 5 клинических групп пациентов. 1-я группа (n=27) — пациенты с нормальными показателями функциональной активности АНС, как в момент поступления в стационар, так и на 30—60-е сутки интенсивной терапии и реабилитации. 2-я группа (n=9) — пациенты с показателями симпатической гиперактивности АНС исходно при поступлении в отделение интенсивной терапии и нормой функциональной активности АНС на 30—60-е сутки проведения курса интенсивной терапии и реабилитации. 3-я группа (n=8) — пациенты с исходными показателями нормы функционального состояния АНС и показателями симпатической гиперактивности АНС на 30—60-е сутки проведения курса интенсивной терапии и реабилитации. 4-я группа (n=15) — пациенты с показателями симпатической гиперактивности АНС как исходно, так и на 30—60-е сутки проведения курса интенсивной терапии и реабилитации. 5-я группа (n=7) — пациенты с показателями парасимпатической гиперактивности АНС (по параметрам ВРС) как исходно при поступлении в отделение интенсивной терапии, так и на 30—60-е сутки проведения интенсивной терапии и реабилитации.


Introduction
The autonomous nervous system is the most important regulator of homeostasis under physiological, pathological and extreme conditions.
Despite the multicausal and heterogeneous nature of a brain damage (trauma, anoxia, hemorrhage, surgical trauma), the HRV registration method allows to assess the adaptive response of the central hypothalamic parts of the ANS and, consequently, the level of neuro-endocrine response to acute and chronic critical condition [2]. Electrophysiological neuromonitoring of the functional state of the autonomous nervous system (ANS) as the main regulator of homeostasis increases the accuracy of assessment of the level of consciousness, dynamics of social reintegration, prognosis of the patient's state ции, прогноза оценки состояния пациента и эффективности методик лекарственной, немедикаментозной интенсивной терапии и реабилитации. Исследование посвящено разработке автоматизированной системы оценки динамики сознания, тяжести состояния и эффективности интенсивной терапии путем анализа характеристик ВРС у пациентов с повреждениями головного мозга.
The study is intended to develop an automated system for assessing the dynamics of consciousness, the severity of the condition and the effectiveness of intensive care by analyzing the characteristics of HRV in patients with brain damage.
The purpose of this study is evaluation of the clinical significance of parametric monitoring of the intensive care and rehabilitation effectiveness based on the analysis of the functional state of the autonomous nervous system in patients with brain damage of different genesis.

Materials and Methods
66 patients were enrolled in the study, which was carried out on day1-3 after patient's admission and on day 30-60 of the intensive care and rehabilitation in the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology.
All patients were admitted on day 20-50 after brain damage of different origin.
Parameters of the functional state of the autonomous (vegetative) nervous system, obtained on the basis of computer analysis of the heart rate variability (HRV) were the criteria for the formation of clinical study groups. The evaluation of HRV was performed by the Polyspektr-8 EX apparatus (Neurosoft, Russia) with the protocol of the wireless Bluetooth connection between the cardioanalyser and a personal computer. The accepted ranges of normal and abnormal HRV parameters for a 5-minute record are presented in table 1.
In each study period, at least 300 intervals were analyzed (the HRV parameters were calculated according to corresponding formulas of distribution of cardiac intervals). The following HRV parameters were determined: SDNNstandard deviation of normal-to-normal R-R intervals, in ms; rMSSD -root mean square of successive differences, in ms; pNN50% -the percentage of interval differences in successive NN intervals greater than 50 ms (NN50) / total number of NN intervals; SI -Baevsky stress-index in n.u.; LF/HF-low frequency/high frequency ratio in n.u.; VLF very low frequency spectrum, in ms 2 ; LF low frequency spectrum in ms 2 ; HF high frequency spectrum in ms 2 ; TP total power spectrum, in ms 2 .
The dynamics of patient's general condition was evaluated according to the following clinical criteria: 1) the level of consciousness, 2) the level of muscle hypertonicity (spasticity), 3) the dependence of patients on mechanical ventilation (MV), 4) the presence of tracheostomy, 5) the quantitative characteristics of disability, 6) the frequency of patients' transfer from intensive care units to the neurorehabilitation units, 6) the overall mortality rate.
The level of consciousness was assessed using 3 scales: Glasgow, Four, Giocino [3][4][5][6][7][8]. Changes in patient's level of consciousness by one or more level according to the Giocino scale (2002) (vegetative state; a state of minimal consciousness; minimal consciousness «+»; normal consciousness) were taken as significant positive dynamics. The level of muscular hypertonicity (spasticity) was recorded bilaterally in 3 joints for upper and lower extremities (elbow, wrist joints, fingers, hip, knee, and ankle joints). We estimated the sum of scores of the Modified Ashworth Scale (MAS) [9]. The dynamics of the neuropsychological status from vegetative state to social reintegration of the patient was evaluated by the DRS (disability rating scale). The maximum value of DRS (29 points) corresponds to the extreme level of vegetative status, the minimum value of DRS (0 points) corresponds to the status of health [10,11]. All patients included in the study underwent the same type of rehabilitation and a standard multi-component intensive therapy.
Statistical processing of data was carried out using the Statistica 13 software (StatSoft Russia). Differences were considered significant at P<0.05. The «null» hypothesis was assessed by applying the Pearson's chi-squared test (χ 2 ) and  Таблица 2. Динамика 5-ти минутной записи показателей временного анализа вариабельности ритма сердца у обследованных пациентов (M±m). Table 2. Dynamics of a 5-minute recording of time analysis of the heart rate variability in patient groups (M±m).

Results and Discussion
According to the HRV parameters recorded on day 1-3 after patient's admission to the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology and re-evaluation of heart rate variability on day 30-60 of intensive therapy, 5 groups of patients were formed. Parameters of HRV dynamics of both time (SDNN, rMSSD, pNN50, SI) and frequency range (LF/HF, HF, LF, VLF, TP) are presented in tables 2 and 3, fig. 2.
The 1 st group (n=27, men -19; women -8; median age: 49.1±3.5 years) consisted of patients with normal functional activity of the ANS according to the HRV parameters over the whole observation period, both at admission and on day 30-60 of a standard intensive therapy and rehabilitation.
Normal values of the functional state of the autonomic nervous in the 1st group of patients were associated with better values in the scales scoring the level of consciousness (Glasgow, Four, Giocino), quick transfer of patients from the ICU to the neurorehabilitation unit (the significance of differences versus group 3 based on the χ 2 was P<0.016 and P<0.00004 versus group 4 ), minimum dependence of patients on the ventilator (the significance of differences versus group 3 based on the χ 2 was P<0.0017 and P<0.0002 versus group 4). Regression (improvement) of the level of consciousness by 1 level according to the Giocino scale (vegetative state -minimal consciousness -minimal consciousness «+» -clear consciousness) was observed in 29.6% of patients, indicating the recovery of brain functions (table 4).
A slightly lower increase in the level of consciousness, in comparison with the group 2, indicates an initially high level of this parameter in the group 1 (patients with a normal ANS function). Patients in this group presented the highest rates of the functional disability scale (DRS, M. , indicating the patients' recovery from coma to communication and social reintegration state. The value of this parameter (16-17 points) indicated the minimum level and reduction of disability in this group. MAS scoring of muscle hypertonicity (spasticity) in this group was 7.03±1.9 and 6.92±2.04 before and after the course of intensive therapy, respectively, which reflected the low level of pathological changes. The mortality in this group was minimal: 3.7% (death from peritonitis), which can be largely attributed to a random factor that does not depend on the general functional status of patients of the 1 st group (the difference in the mortality rate according to the χ 2 test versus the group 3 was P<0.03 and P<0.00001 with the group 4).
The 3 rd group (n=8, men -5, women -3, median age: 43.5±5.9 years) included patients with baseline (at admission) normal functional activity and development of sympathetic hyperactivity by day 30-60 of intensive therapy and rehabilitation (decrease in SDNN, rMSSD, pNN50, TP, an increase in SI), (table 2 and 3, fig. 2 and 3). The development of pathological changes reflected by electrophysiological parameters of HRV was accompanied by deterioration in the neurological and somatic status of patients (table 4). In this group, a decrease in the consciousness level according all scales (Glasgow, Four, Giocino) was registered, and the regression (improvement) of the consciousness level according to the Giocino scale was not observed in any patient in this group. Only 25% of patients in group 3 were transferred from the ICU to neurorehabilitation units with a lesser dependence on the constant vital sign monitoring. In patients of this group, the dependence on ventilator increased by 2-fold during their stay in intensive care units: from 37.5% to 62.5%, respectively. The mortality rate was 37.5%. There was a significant increase in disability rates according to the DRS; the MAS muscle hypertonicity scoring was a total of about 13 points, which is unreliably higher as compared to previous groups (table 4).
При анализе зависимости функциональных параметров АНС от неврологического статуса выявили некоторые закономерности, требующие интерпретации. При сравнении дисперсий в группах пациентов с показателями, характерными для нормы, симпатической или парасимпатической гиперактивности, и уровнями сознания по SDNN, rMSSD, pNN50, and TP values, high SI values), (table 2 and 3, fig. 2 and 3). The constant level of sympathetic hyperactivity was associated with poor neurological and somatic status of patients without dynamic changes (table 4). Consciousness level was determined by scales Glasgow, Four and Giocino, and the regression (improvement) of consciousness level according to the Giocino scale was not observed in any patient in this group. Only 13.3% of patients in group 3 were transferred from the ICU to neurorehabilitation units with a lesser dependence on the constant vital sign monitoring. Dependence on ventilators was observed in 61.5% and 66.6% of patients at admission and during their stay in intensive care units, respectively. The mortality rate in group 4 was 53.3%. According to the disability rating scale (DRS), the maximum values were observed (25.5 and 25.4 points at baseline and during the intensive therapy, respectively), indicating a complete lack of communication and social reintegration in this group of patients.
Muscle hypertonicity values were minimal as compared to the previous groups: a total of about 4.86 points (table 4).
Group 5 (n=7, men -5, women -2, median age: 30.7±8.7 years) included patients with parasympathetic ANS hyperactivity both at baseline and on day 30-60 of intensive therapy and rehabilitation (high SDNN, rMSSD, pNN50, TP levels and low SI), (table 2 and 3, fig. 2 and 3). In this group, the constant level of parasympathetic hyperactivity as determined by electrophysiological parameters of HRV indicated the depletion of functional activity of the ANS and was associated with a poor neurological and somatic status of patients without any dynamics (table 4). A low consciousness level according to Glasgow, Four and Giocino scales was registered in group 5, and the regression (improvement) of consciousness level according to the Giocino scale was not observed in any patient in this group. Only 42.8% of patients in this group were transferred from the ICU to neurorehabilitation units with a lesser dependence on the constant vital sign monitoring. In patients of this group, dependence on ventilator was observed in 28.5% of cases both at admission and during their stay in intensive care units. There was no mortality in this group. According to the disability rating scale (DRS), high values were observed (22-23 points), indicating a complete lack of communication and social reintegration in this group of patients as it was in group 4. The muscle hypertonicity index is the highest in comparison with the previous groups. In general, the 5th group of patients was characterized by both a decrease (absence) of the adaptive response of the ANS and a low rehabilitation potential in response to brain damage. High HRV values indicate a low activity or «depletion» of higher regulatory centers of the ANS, which reduces the adaptive capacity of the body. According to a number of clinical and experimental studies, parasympathetic hyperactivity is accompanied by fre-шкалам ком Глазго, Four, Giocino, мышечного тонуса по шкале MAS, количественной характеристики прогноза и уровня инвалидности по DRS получили достоверные отличия, таким образом различия средних величин в группах нельзя считать случайными. Статистические данные приведены в табл. 5.
The analysis of the dependence of the functional parameters of the ANS on the neurological status revealed some patterns that require interpretation. Comparison of the dispersion in the groups of patients with parameters typical for the normal values, sympathetic or parasympathetic hyperactivity, and levels of consciousness according to the Glasgow, Four, and Giocino coma scales, MAS muscle tone scoring, quantitative characteristics of the prognosis and the DRS level of disability demonstrated significant differences, so the differences in the average values in the groups cannot be considered accidental. Statistical data are presented in table 5.
Significant correlation between the parameters of the ANS functional activity and the level of consciousness had been revealed in the study. The level of consciousness was maximum in the groups of patients with normal functional activity of ANS and it was significantly improved with normalization of ANS parameters from values reflecting sympathetic or parasympathetic hyperactivity to normal ones. Previously found correlations between ANS impairment and increased intracranial pressure, impairments of mechanisms of autoregulation of cerebral circulation, immune response, activation of microglia and macrophages, damage of the blood-brain barrier and oxidative stress are among pathophysiological components of this dependence [22][23][24][25][26]. After a brain injury, 90% of patients present signs of autonomic dysfunction registered at the first week, and about 30% of them exhibited patterns of prolonged dysautonomia [28][29][30]. Development of quantitative predictors of the prognosis of the level of consciousness and targeted intensive therapy based on the parameters of HRV as the main method of determining the functional state of ANS continues to represent one of the modern research challenges [31][32][33].
Исследование дисбаланса АНС при гетеротопных повреждениях головного мозга (аноксия, травма, острые нарушения мозгового кровообращения, периоперационные нейрохирургические осложнения) актуальная задача современных научных исследований. Изучение взаимосвязи нарушения функционального статуса симпатиче-MAS scoring. A number of researchers [34][35][36][37][38][39][40][41] indicated the interdependence of the level of muscle tone and HRV parameters and ANS activity. Thus, in the case of sympathetic hyperactivity, the muscle hypertonicity (spasticity) revealed minimal manifestations, while parasympathetic hyperactivity was accompanied with the maximum manifestation of muscle hypertonicity. In our opinion, these data can be explained as follows: in the case of sympathetic hyperactivity, there is an increase in the activity of the central (hypothalamic) centers of the ANS and at the same time the activity of anatomically close central parts of the extrapyramidal system (central motor neuron) increases, which does not allow the development of pathological activity of the segmental apparatus of the spinal cord. On the contrary, in the case of parasympathetic hyperactivity, the activity of the central parts of the ANS is minimal, which may be due to the low activity of the central parts of the extrapyramidal system, and, as a consequence, there is a «disinhibition» of activity of the segmental apparatus of the spinal cord and the appearance of pronounced «spasticity». Data on the interdependence of the muscle tone and ANS need further study.
The study of ANS imbalance in heterotopic brain damage (anoxia, trauma, acute cerebral circulation disorders, perioperative neurosurgical complications) is an urgent task of modern scientific research. The studies of the relationship of disorders of the functional status of the sympathetic or parasympathetic nervous system in cerebral insufficiency, impairment of nutritional homeostasis, muscle dystonia, respiratory failure and weaning are the most important areas of scientific research of modern neuroresuscitation and rehabilitation.

Conclusion
Neuromonitoring of the functional state of the autonomic nervous system using the digital parameters of heart rate variability allows to identify the clinical groups of patients with significant differences in the level of consciousness and the prediction of the dynamics of consciousness, social reintegration status, muscle dystonia, and respiratory support.
Normal and abnormal parameters of the functional state of the ANS have a significant correlation with the assessment of consciousness levels using the Glasgow, Four, Giocino scales, DRS disability level, and muscle tone according to the modified Ashworth scale.
In the case of sympathetic hyperactivity, the dependence of patients on mechanical ventilation is more than 8 times higher than the dependence on ventilation in the normal functional activity of ANS.
Elimination of sympathetic hyperactivity is a reliable prognostic sign of improvement of patient's condition and regression of neurological symptoms.
form of sympathetic and parasympathetic hyperactivity during the intensive therapy and rehabilitation is a reliable indicator of its inefficiency.
The effectiveness of the intensive care and rehabilitation of patients with long-term impairment of consciousness, depending on the prosthetics of vital organs, can be objectively judged by neuromonitoring of the functional state of the autonomous nervous system. Устранение симпатической гиперактивностидостоверный прогностический признак улучшения состояния пациента и регресса неврологической симптоматики.