MANIFESTATIONS OF AUTONOMIC REGULATION DISTURBANCES IN MILD CRANIO-BRAIN INJURY

MANIFESTATIONS OF AUTONOMIC REGULATION DISTURBANCES IN MILD CRANIO-BRAIN INJURY

Tsvetovsky S. B., Stupak V. V.

Novosibirsk Research Institute of Traumatology and Orthopedics named after Y. L. Tsivyan,
Novosibirsk, Russia

 According to the clinical guidelines approved at the XXXXIII Plenum of the Board of the Association of Neurosurgeons of Russia (St. Petersburg) on April 15, 2016, mild traumatic brain injury (TBI) includes concussion and contusion of the brain of mild severity [1].
Autonomic regulation disorders are very common, and often they present the single clinical manifestation of both acute and late periods of mild traumatic brain injury [2, 3, 4]. The severity and nature of autonomic dysregulation are associated with the severity of the injury and also depend on the adequacy of adaptive reactions. To conduct targeted pathogenetic therapy, it is necessary to differentiate the vagotonic and sympathicotonic orientation of vegetative-vascular disorders. It is also important to evaluate the contribution of sympathetic and parasympathetic influences to the overall picture of changes in autonomic tone and reactivity, reflecting autonomic dysregulation. Thus, there is a need to use objective methods to identify the nature and degree of dysregulation of autonomic functions in this group of patients. The task of objectifying the diagnosis of pathological changes in the vegetative status and monitoring the dynamics of states requires the use of quantitative methods. For a long time, such quantitative assessments of heart rate regulation as the Bayevsky stress index, the index of parasympathetic influences, the vegetative Kerdo index, based on a comparison of heart rate with diastolic pressure, and the Hildebrandt index, which is sensitive to functional mismatch in the regulation of the cardiac and respiratory systems, have been used for a long time [5]. However, in most cases, these indicators are not used in combination, and only stationary sections of the recording of rhythmograms are analyzed. In reactions to functional tests, only the ratios of the maximum and minimum duration of cardiointervals are considered; time characteristics and phases of reactions are not taken into account [6]. Judgments about the wave structure of the rhythm are based on a formal division of the high-frequency and low-frequency ranges of the duration of the waves or with a division into a larger number of “orders” [6, 7], and the waves with a duration of less than 15 seconds are unambiguously read as respiratory. Since relatively recently, the spectral characteristics of cardiorhythmograms have also been considered, with the calculation of the total spectral power [8, 9, 10]. This kind of analysis is used to identify group differences between patients with varying degrees of injury severity and is not very suitable for assessing the characteristics of the condition and tracking its dynamics in the particular patient. Integral spectral characteristics do not reflect differences in the structure of the rhythm.
The objective of the study - to obtain a comprehensive understanding of the features of autonomic regulation in patients with mild traumatic brain injury using a parallel analysis of heart rate, respiratory rate and blood pressure, with the calculation of a number of hemodynamic parameters.

MATERIAL AND METHODS

138 male patients with clinical manifestations of mild TBI aged 14 to 49 years were examined. Examinations were carried out on the day of admission, i.e., as close as possible to the time of injury, and after the rehabilitation period of 4 to 11 days. For comparison, 12 healthy subjects were examined.
The informed consent of the patients (or their close relatives, in case of limited ability of the patient to communicate) was obtained and complied with the ethical principles of the Declaration of Helsinki (2013), and the Rules of clinical practice in the Russian Federation (the Order of Health Ministry of RF, June 19, 2003, No. 266). The study was approved by the ethics committee of Novosibirsk Research Institute of Traumatology and Orthopedics named after Y. L. Tsivyan (the session protocol 007/22, July 27, 2022).
An active orthostatic test was used to detect deviations from the norm of vegetative tone and reactivity, as well as vegetative maintenance of activity. Additional information was recorded when using tests with breath holding and hyperventilation.
The equipment used provides ECG recording in the lead with the most pronounced R-wave, as well as pneumograms. In one variant, a module from a tracking system for intensive care units was used, which made it possible to record an ECG and, and, with rheographic method, a respiration signal using one pair of electrodes (CMSm12 unit, Medicor, Hungary). In the second variant, breathing was recorded using a temperature sensor using the respirotachometer module. Recording of the heart and respiration rhythms is carried out by accumulating arrays of readings of RR-intervals and time intervals between respirations. We also entered data on blood pressure values at the time of each cardiorhythmogram recording, and analyzed arrays of at least 220 cardiointervals.
When analyzing the records, rhythmograms are constructed − stepwise changing curves in which the height of each step is proportional to the duration of successive RR intervals. Graphical display of rhythmograms is necessary for their visual assessment when compared with quantitative analysis data and for identifying recording artifacts. It also makes it possible to analyze the temporal and amplitude characteristics of rhythm responses to orthostatic and other functional tests. To this end, by moving the special cursor around the screen, one can mark up to 6 points on the rhythmogram with fixing the value of the duration of the RR interval at each point, the distances between the points in time and the number of heartbeats that fell into this time interval, with the determination of the difference in durations neighboring marked intervals and in the corresponding values of the instantaneous heart rate (Fig. 1). Other permanent marks on the rhythmogram mark the RR intervals within which the front of the respiration signal arrives (Fig. 2). To assess the true severity of respiratory arrhythmia and distinguish it from the components of sinus arrhythmia not associated with respiration, the segments of rhythmograms are averaged over the respiration signal. For this purpose, the average values are calculated for the first RR intervals after the breath signal. Then for the second ones are calculated. The average curve of the respiratory wave is displayed graphically (Fig. 2), while at the end of the curve, the average values of RR-intervals formed by less than ten readings are discarded. Thus, with the variability of the respiratory rate, a reliable determination of changes in the heart rate, which are naturally associated with acts of breathing, is provided. The absolute (ms) and relative range of respiratory arrhythmia (as a percentage of the average duration of cardio intervals) are determined. The contribution of respiratory arrhythmia to the total variance of the heart rate is estimated by calculating the ratio of the average amplitude of the respiratory wave to the value of the total variance of the rhythm.

Figure 1 . Reactions of the heart rate to the transition to the orthostatic position: a) rhythmogram reflects the sympathetic vasoconstrictor reaction of resistive vessels, which determines the secondary slowing of the rhythm, a variant of the norm; b) rhythm response to orthostasis under conditions of high parasympathetic tone in the duct with adequate sympathetic reactivity; c) rhythm response to orthostasis with initially high sympathetic tone. In relation to tachycardia in the background of the reaction, they are reduced and delayed in time; d) insufficient vegetative provision. Sympathetic responses of increments in stroke volume and vascular tone are insufficient, there is no decrease in rhythm

Figure 2. An example of recording a cardiorhythmogram with the presence of pronounced respiratory periodicity and marks of respiratory acts. The results of the analysis of the respiratory rhythm (left part) and the characteristics of the respiratory arrhythmia of the heart rhythm (right). Two types of rhythm changes in time with breathing

 

The wave structure of the rhythm is also analyzed without regard to the acts of breathing. The characteristics of the distributions of the duration of the half-waves of the rhythm are calculated, during which the lengthening or shortening of cardio intervals occurs. In this case, the duration of half-waves is characterized by the number of cardiocycles. To determine the duration of half-waves during the transition to each subsequent interval, the arrhythmia index is calculated, which is the ratio of the difference between the subsequent and previous intervals to their sum, taking into account the sign of the difference. A half-wave is considered to be ongoing if this indicator does not change sign or becomes equal to zero, or changes sign, but does not exceed the threshold value. Thus, the response of the rhythm in areas with slightly varying durations of RR intervals is excluded. The ratio of the difference between the average values of the duration of half-waves to their sum gives an indicator of the asymmetry of the rhythm waves. The average values of the half-wave durations over time (seconds) and the asymmetry index for these values are also determined. Rhythm waves are also characterized by the average value of the amplitudes, that is, the difference in duration between the longest and shortest RR-intervals in a half-wave, the number of waves and their frequency in the analyzed segment of the cardiorhythmogram.
In addition to respiratory and slower rhythm waves, the rhythmograms of both healthy subjects and, especially, patients with autonomic dysregulation, may contain small variations in the duration of adjacent RR intervals. Visually, the structure of the rhythm, i.e., the dependence of subsequent cardiointervals in a row on the previous ones, can be assessed by the rhythmogram and by constructing scattergrams (Fig. 3, 4, 5). To quantify the structure of the rhythm, distributions of the arrhythmia index are constructed. The number of readings that fell into the region of positive values (when the RR interval lengthens compared to the previous one), into the region of negative values, and into the zero class is counted separately. The ratios of the number of positive and negative readings are calculated. The mean values of the values of positive and negative readings of the arrhythmia index are calculated separately, with the determination of the error of the mean.

Figure 3. Graphic display and quantitative characteristics of the wave structure of the rhythm. Rhythmogram with marks of the boundaries of half-waves, scattergram, histogram of the distribution of the arrhythmia index. Statistical characteristics of the distributions of RR intervals, arrhythmia index, rhythm waves. Histograms of half-wave distributions. Asymmetry of half-waves with a longer duration of the phases of the acceleration of the rhythm

 

Figure 4. Graphic display and quantitative characteristics of the rhythm structure. Initial sympathicotonia, hypersympathetic reaction to orthostasis. High value of the centralization index. Pronounced negative asymmetry of rhythm half-waves

Figure 5. A – slow-wave changes in rhythm, correlating with fluctuations in vascular tone, in the presence of signs of sympathicotonia and initial manifestations of dysrhythmia; B – rhythmogram with the presence of arrhythmic complexes. At a high heart rate, RR intervals are not correlated, the centralization index is low, and wave asymmetry indicators are positive

  

For stationary sections of the recording, such as at rest lying down and in a stationary state in orthostasis, the analysis of the heart and respiratory rhythms is carried out using statistical methods. Histograms are constructed, and the characteristics of the distributions of cardiointervals are calculated: mean, variance, mean error, asymmetry, etc. The average, maximum and minimum heart rate values are also measured. Diagnostically significant indices are calculated: tension index (TI), index of parasympathetic influences (IPI). The availability of data on blood pressure makes it possible to determine the vegetative Kerdo index, the assessment of the minute volume of blood circulation and the resistance of the peripheral vascular network. The assessment of the significance of differences in the characteristics of rhythm regulation during dynamic observations, including during functional tests, as well as differences from the average values of the corresponding parameters determined for a group of healthy subjects, was carried out using Student's t-test. The stress index according to Baevsky is defined as  , where Am - mode amplitude,i.e. number of cardiointervals in the class corresponding to the distribution mode, in percentage of total number of intervals in the analyzes massive; Mo – the value of the distribution mode of sizes of RR-intervals; D – the differencebetween the minimum and maximum size of the intervals.
Index of parasympathetic influences:  , where W – distribution width at the level of 1/4 of the value of the modeamplitude; M – average length of the cardiocycle; D and Am – the same as in theprevious formula. Kerdo vegetative index: , where Dd – diastolicpressure; HR – heart rate per minute. KVI = 0 in case of “vegetative balance” in the cardiovascular system. KVI is positive in case of predominance of sympathetic influences, and is negative in case of increased parasympathetic tone.
The minute volume of blood circulation was estimated by calculating: 1) pulse pressure: PAP = APsyst – APdyast; 2) mean pressure:  ; reduced pulse pressure: RPP = . The minute volume is MV = . Assessment of total peripheral vascular resistance:  .
The processing results are displayed on the screen and printed in the form of histograms, scattergrams and tables of numerical values. Histograms of time intervals between acts of breathing are constructed and displayed, the average respiratory rate is determined. The Hildebrandt index is calculated, which is sensitive to the functional mismatch between the regulation of the cardiac and respiratory systems. The index is calculated: HI = HR / RR, where RR – respiratory rate per minute. The norm range – 2.8-4.9.

RESULTS AND DISCUSSION

Due to common absence of data on the premorbid status of the victims and the heterogeneity of manifestations of dysregulation of autonomic functions, special attention was paid to monitoring the dynamics of indicators during treatment.
It was found that in people of normal constitution with mild craniocerebral injury, the severity of the clinical course of the disease more often correlates with an increase in signs that reflect an increase in sympathetic tone and reactivity, as well as vegetative support of activity, controlled by the nature of changes in indicators upon transition to an orthostatic position. In our study, positive values of the Kerdo index at rest were recorded in 81.9 %, inorthostasis – in 91.3 % of cases.
Sympathetic tone at rest is more often manifested by a shift towards tachycardia and less often by bradyforms with increased systolic blood pressure due to an increase in cardiac output. In orthostasis, a hypersympathetic increase in diastolic pressure with tachycardia is more often observed, due to the need to provide the proper minute volume in conditions of increased resistance of the peripheral vascular network. The same and even greater increase in heart rate in orthostasis is also observed with a significant prevalence of parasympathetic tone with a decrease in blood pressure. Here, however, tachycardia compensates for the decrease in cardiac output, which is reflected in the nature of the rhythmograms and estimates of the “strength” of the rhythm.
In this case, there is a mismatch in the regulation of the rhythm of the heart and respiration, leading to the output of CI values beyond the limits related to the norm (2.8-4.9), in the area corresponding to dystonia. The discrepancy between the rhythm of the heart and respiration with an increase in CI is most pronounced in orthostasis. At rest, 30 % of patients showed a moderate increase in respiratory rate due to the shallow depth of respiratory excursions in the supine position. When combined with a moderate increase in heart rate, HI is within normal limits. During the transition to orthostasis, the increase in the frequency of respiration in these cases is small or even negative, while the reaction of the heart rate is pronounced.
Vagotonia, sympathicotonia, vegetative balance and eutonia are reflected both in scope and in the phase of heart rate fluctuations in time with breathing. The phase of heart rate changes in connection with the act of breathing turned out to be a more visual and sensitive indicator of the consistency or dysregulation of intersystem relationships than the Hildebrandt index, since it is not a formal number, but a specific qualitative physiological parameter. Examples of various variants of rhythm changes in connection with respiratory acts are shown in Figure 2. With the predominance of parasympathetic influences, the average curve of respiratory arrhythmia shows a slowing of the rhythm with a subsequent return (tendency) to the average value (type 1). On the contrary, with sympathicotonia, there is an initial increase (type 2). With eutonia, the reaction is moderately bradycardic or biphasic: initial acceleration – slowdown. The sympathicotonic type of regulation at rest with a decrease in therelative range of respiratory arrhythmia below 2.2 % or a decrease in this indicator by more than 3 times upon transition to orthostasis are evidence of sympathicotonia and increased sympathetic reactivity and reflect changes caused by mild traumatic brain injury.
The indicator of asymmetry of rhythm waves is informative to identify the ratios of sympathetic and parasympathetic activity, their balance or going beyond the normal boundaries. With sympathetic tone in the wave period, the lengthening of cardiointervals occurs during a smaller number of cardiocycles than shortening, i.e., there are longer periods of increased heart rate (Fig. 4). The asymmetry index is negative. When analyzing survey data, a high correlation was noted between estimates of the total resistance of the vascular network and the degree of negative asymmetry of rhythm waves. For each individual subject, a shift towards negative asymmetry unambiguously took place in cases where the transition to the orthostatic position was associated with a decrease in minute volume with an increase in peripheral vascular resistance. Negative asymmetry of more than -10 at rest, its increase to more than -20 in orthostasis (or more than 4-fold increase) reflect increased sympathetic tension and pathologically enhanced autonomic activity. A dystonic increase in vascular tone and diastolic pressure, not accompanied by an adequate increase in stroke and minute volumes, is a sign of dysregulation with an actual lack of vegetative support for activity.
With pronounced clinical manifestations, the following changes in the structure of the rhythm, well distinguished on the rhythmogram, were closely correlated and are an undoubted sign of a mild brain injury: against the background of slow fluctuations of varying severity, there are small variations in the duration of adjacent RR intervals, forming sections of the recording in which almost every interval changes in side different from the previous one. Another degree of the same phenomenon is the presence of pronounced arrhythmic events against the background of correlated changes in cardiointervals that form the respiratory and “vascular” periodicals, or against the background of a rigid rhythm (Fig. 5b). The latter are combinations of an interval sharply elongated in relation to the background and a subsequent shortened one, or separate elongated and shortened intervals. Complexes of long and short intervals distinguish this phenomenon from extrasystole, in which a shortened pre-extrasystolic interval follows firstly, followed by a compensatory pause. In addition, the "range" of these complexes is much less than with extrasystole, no more than 20 %. Arrhythmic events are always combined with reduced resistance of the peripheral vascular network and low diastolic blood pressure. At the same time, systolic pressure is normal or elevated, the minute volume is increased, i.e., there are signs of a simultaneous increase in the multidirectional effects of regulation. Irregular arrhythmias occur when the automatism function of pacemakers, primarily the sinus node, is impaired [11]. The described combinations of fast irregular arrhythmias with slow-wave rhythms reflect a dystonic mismatch between the automatism function and the central level of regulation.
Due to the fact that tachycardia and rhythm fluctuations in orthostasis can be caused by various variants of dysregulation, registration and analysis of the transient reaction to orthostasis is important for differentiating states.
With normal reactions to orthostasis, a pronounced initial increase in heart rate (12-20 %) is recorded, which compensates for a decrease in venous return due to blood outflow into the volumetric vessels of the lower extremities, the normal tone of which is relatively low. This is followed by a normal sympathetic reaction of resistive vessels of the muscular type, leading to the restoration of venous return and a secondary decrease in rhythm. The high sympathetic reactivity of the vessels in the absence of a constantly maintained sympathetic tone is reflected in the biphasic nature of the transient process, when the secondary slowdown is large and is replaced again by an increase in the pulse until a stationary state for the orthostatic position is reached (Fig. 1a). The severity and duration of this phase of rhythm slowdown serve as a measure of vascular reactivity. Significant rhythm fluctuations in the last section of the transition process indicate the simultaneous activation of sympathetic and vagal influences and are correlates of dystonia in the proper sense of the word. With a high constant sympathetic tone, the primary increase in the pulse in this reaction is relatively small, the secondary decrease is prolonged in time, and the reaction is single-phase (Fig. 1c). With a decrease in vascular tone under conditions of the predominance of parasympathetic influences, the primary reaction is more pronounced in relation to the background, and there is practically no decrease in the pulse after it (Fig. 1d). These types of reactions are different from normal ones.
Quantitative characteristics of sympathetic vasoconstrictor hyperreactivity: the duration of the phase of the secondary decrease in the rhythm is less than 15 seconds, the duration of the RR-intervals at the peak of the decrease is 0.8-1.2 from the initial one, followed by a rapid increase by more than 18 %. High sympathetic tone: pulse rate at rest more than 85/min, prolongation of the primary acceleration phase up to 20 seconds or more, acceleration less than 15 %, prolongation of the pulse deceleration phase without rhythm fluctuations, a slight increase in the pulse rate in orthostasis relative to rest.
Dynamic observations are important for the diagnosis of mild TBI. Increased sympathetic tone and reactivity caused by the stressful impact of injury, in the absence of brain damage, normalize within 2 days after injury. Their long-term preservation is a diagnostically valuable feature. However, more than a quarter of patients with brain injury (28.3 % in our observations) showed a phasic course of the traumatic disease, which is expressed in the fact that the high sympathetic activity of the initial period is replaced by a sharp shift “to the parasympathetic side”. During the examination on the 4-8th day after admission, a picture of autonomic regulation is recorded, which differs significantly from the initial one and, in some respects, further deviates from the norm. There are symptoms of a decrease in vascular tone and reactivity, often with a decrease in blood pressure, and, as a result, tachycardia in orthostasis. Thus, the “recoil” phase is observed, replacing the increased sympathetic tone of the initial period and indicating that autonomic dysregulation lasts longer than the normalization of clinical symptoms.
A decrease in diastolic blood pressure in orthostasis relative to the supine position is a pathological reaction, especially in combination with a decrease in systolic pressure by more than 10 mm Hg. The decrease in the calculated estimate of the resistance of the peripheral vascular network by more than 20 % during the transition to orthostasis should definitely be attributed to the lack of vegetative support.
At rest and orthostasis, the presence of slow rhythm variations and its fluctuations with a period of 10-40 seconds, reflecting fluctuations in vascular tone, i.e. Traube-Goering waves (Fig. 5a), indicates a high probability of brain injury. The vegetative status is unstable in this case. Even with the initial mild vagotonia on the 3-5th day, shifts “toward the sympathetic side” of the chronotropic function, as well as blood pressure and vascular resistance at rest, with signs of insufficient reactivity and a decrease in the tone of resistive vessels in orthostasis, prevail. A sharp change in signs of vagotonia to similar sympathicotonic manifestations at rest and insufficiency of vegetative supply in the samples is a sign of the presence of a brain injury and a feature of its phase course.
The cases of more severe traumatic brain injuries showed a decrease in sympathetic tone, which is reflected in a decrease in blood pressure at rest, in the absence of a normal increase in diastolic blood pressure in orthostasis, and in signs of a decrease in vascular tone and reactivity from the very beginning of observation. The only parameter supported by sympathetic activity in such patients is a compensatory increase in heart rate in orthostasis. In some of these patients, in the orthostatic test, in the already stationary state for the vertical position, episodes of a relative slowing of the rhythm were observed, associated with dizziness and the inability to maintain the orthostatic position. It is obvious that the slowing of heart rate with low blood pressure and vascular tone leads to insufficient blood supply to the brain. Thus, these phenomena, as well as the presence of pronounced slow, irregular (non-respiratory) rhythm waves, reflect a traumatic effect on the vasomotor center of the brain.

CONCLUSION

The severity of clinical signs of injury often correlates with an increase in signs that reflect an increase in sympathetic tone and reactivity, as well as vegetative support of activity, controlled by the nature of changes in indicators when moving to an orthostatic position.
In most patients, repeated examinations within 3-5 days show a decrease in the severity of signs of the prevalence of sympathicotonic regulation of autonomic functions, and a tendency to return to the eutonic type. In a smaller part (28.3 %), a phasic course of the course of a traumatic disease is noted, which is expressed in the fact that the high sympathetic activity of the initial period is replaced by a sharp shift “to the parasympathetic side”, and with an initial mild vagotonia, shifts prevail on the 3-5th day to the sympathetic side" of chronotropic function, as well as blood pressure and vascular resistance at rest, with signs of insufficient reactivity and a decrease in the tone of resistive vessels in orthostasis. Activation of both divisions of the autonomic nervous system leads to multidirectional changes in tone and reactivity. A decrease in sympathetic tone, which is reflected in a decrease in blood pressure at rest, in the absence of a normal increase in diastolic blood pressure in orthostasis, in signs of a decrease in tone and vascular reactivity, was noted early in cases of more severe injuries. In such patients, there are gross changes in the structure of the rhythm, and "chaotic" arrhythmia. In some of these patients, in the orthostatic test, in the already stationary state for the vertical position, episodes of a relative slowing of the rhythm were observed, associated with dizziness and the inability to maintain the orthostatic position.
Thus, there are different mechanisms and symptoms of vegetative status disorders in patients with mild traumatic brain injury. The phases of the course of a traumatic disease, multidirectional changes, and low vegetative supply are associated with the severity of the injury.

Funding and conflict of interest information

The study was not sponsored.
The authors declare the absence of obvious and potential conflicts of interest related to the publication of this article.

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