Using Heart Rate Variability Monitoring for Dexmedetomidine Dosing in Neurointensive Care Patients

Aim: to validate the use of heart rate variability monitoring during dexmedetomidine administration in patients with brain injury of various etiologies.Material and methods. The study included 25 patients (14 male, 11 female, mean age 58.2±1.81 years) 20 and more days after traumatic brain injury (TBI) (n=9; 36%), acute stroke (n=4; 16%), anoxic brain injury (n=6; 24%), subarachnoid hemorrhage (SAH) (n=6; 24%). Dexmedetomidine was prescribed because of sympathetic hyperactivity as diagnosed by heart rate variability (HRV). The following indices were measured: SI (stress index, in normalized units [nu]), SDNN (standard deviation of all normal sinus RR intervals over 24 h, in ms), RMSSD (root-mean-square of successive normal sinus RR interval difference, in ms), pNN 50% (the percentage of successive normal sinus RR intervals >50 ms), TP (total power of the frequency spectrum, in ms2). HRV parameters were determined prior to dexmedetomidine infusion (baseline), on days 1–3, 4–5, 9–10, 15–20 of drug administration. Sympathetic hyperactivity was diagnosed by determining following values: SDNN < 13.31 ms, RMSSD < 5.78 ms, pNN 50% < 0.110%, SI > 900 nu, and TP < 200 ms2. Normal reference ranges for HRV parameters were as follows: SDNN (13.31–41.4 ms), RMSSD (5.78–42.3 ms), pNN5 0% (0.110–8.1%), SI (80–900 nu), and TP (200–2000 ms2).Results. The starting dose of dexmedetomidine for sympathetic hyperactivity was 0.12–0.24 µg/kg/hr (mean dose 0.16±0.01; total 200 µg/day). According to digital HRV data, the effective dose ED50 of dexmedetomidine was 0.26±0.03 µg/kg/hour (353.8±35.1 µg total per day) that was achieved on day 9–10 of drug administration.Conclusion. Electrophysiological neuromonitoring of the autonomic nervous system function increases the efficacy of dexmedetomidine administration in patients with brain injury of various etiologies.


Introduction
The current indications for the use of dexmedetomidine are given in the Russian Registry of Medicines and include sedation in adult patients in the intensive care unit with the required depth, which does not exceed awakening in response to vocal stimulation (corresponding to a range from 0 to -3 points on the RASS [Richmond Agitation-Sedation Scale]). The use of the drug requires careful selection and titration of the dose because it is commonly (in 10% of cases and more) accompanied by adverse reactions such as hypotension, bradycardia, bradypnoea, etc. [1][2][3][4]. It should be noted that the use of the RASS scale is largely subjective and in some patients with a low level of consciousness (vegetative state, minimal consciousness state) the approved clinical criteria cannot be used to select the optimal dose of dexmedetomidine. These and other factors prompt the search for objective criteria for drug dosing based on the evaluation of reproducible physiological parameters [5,6]. It is currently important to select clear indications for dexmedetomidine dose selection in intensive care.
The aim of the study was to validate the use of heart rate variability monitoring during dexmedetomidine administration in patients with brain injury of various etiologies.
The study was performed in accordance with the Declaration of Helsinki, the Constitution of the Russian Federation (Article 21), the Basic Law on the Health Protection of the Citizens of the Russian Federation, orders and instructions of the Russian Ministry of Health. The study protocol was reviewed by the ethical committee, which determined that the research risks were minimized and reasonable in relation to the anticipated benefits, and complete adequate information was provided to the subjects or their officially approved representatives.
The age distribution of patients enrolled in the study is shown in Fig. 1.
The indication for intravenous infusion of dexmedetomidine (Orion Pharma, Finland) included heart rate variability (HRV) values typical for the sympathetic hyperactivity. The aim of dexmedetomidine dose titration was to achieve normal HRV values. The parasympathetic hyperactivity detection served as a rationale for a drug dose reduction or withdrawal (5minute cardiac intervals recording on Polispectr-8 EX device, Neurosoft company, Russia, was used).
Group 1 consisted of patients with electrophysiological guidance of dexmedetomidine administration according to HRV data (n=17, 11 males and 6 females), of them 7 had prior TBI, 5 had SAH, 3 suffered from stroke, and 2 patients experienced consequences of brain anoxic injury. The mean age of patients was 45.7±3.46 years. Group 2 included patients administered with dexmedetomidine according to the standard clinical criteria (procedural sedation during ventilation) (n=8, 3 males and 5 females), of them 2 had prior TBI, 1 had SAH, 1 suffered from stroke, and 4 had brain anoxic injury. The mean age of patients in this group was 38.5±5.72 years.
To compare the efficacy of dexmedetomidine administration, the frequency rate of side effects (hypotension, bradycardia, bradypnea, no effect, drug withdrawal) in the groups was assessed. We evaluated patients' condition changes with dexmedetomidine administration guided by HRV parameters based on the following variables: level of consciousness according to FOUR and CRS-R (Coma Recovery Scale-Revised) scales, frequency rate of patients' recovery from vegetative state, patients' dependence on ventilation.
Statistical data analysis was performed using Med-Calc Software, version 18.10.2. Differences were considered statistically significant if P 0.05. The «null» hypothesis was tested using Pearson's χ 2 test and Anova analysis of variance.

Results and Discussion
All the patients from group 1 had electrophysiological HRV parameters typical for sympathetic hyperactivity (SDNN < 13.31 ms, RMSSD < 5.78 ms, pNN50% < 0.110%, SI > 900 nu, TP <200 ms 2 ). The mean values for the time domain and spectral HRV analysis prior to and during dexmedetomidine administration are given in Table 1.
The changes in SDNN and RMSSD values, being the main markers of time domain HRV analysis and indicating the presence or suppression of sympathetic hyperactivity during intravenous continuous infusion of dexmedetomidine, are presented in Fig. 2.
The rise in SDNN and rMSSD values was statistically significant starting from day 9-10 of dexmedetomidine administration. These trends persisted up to 20-30 days from the start of dexmedetomidine intravenous infusion, indicating the achievement of sustained sympathetic block.
The changes in SDNN, an essential electrophysiological HRV parameter, in relation to the rate and duration of the continuous dexmedetomidine infusion, are shown in Fig. 3.
The rise in SDNN was related to the dose and duration (days) of dexmedetomidine administration. Analysis of gradual dose-effect relationship curves showed that the most dramatic rise in SDNN was seen in the first 3 days of dexmedetomidine infusion. Later on, the SDNN increase persisted and associated with an increase in the dose of the drug and elimination of sympathetic hyperactivity.
When analyzing the incidence of side effects in the groups 1 and 2, we obtained the results summarized in Table 2.
The mean duration of continuous dexmedetomidine infusion in Group 1 patients was 26.07±7.63 days (ranging from 4 to 42 days), in Group 2 -5.8±1.55 days (ranging from 1 to 9 days). This difference is due to the frequent development of side effects and lack of clinical efficacy of dexmedetomidine in Group 2 patients compared to Group 1. Thus, hypotension (systolic BP less than 90 mm Hg) in Group 1 was observed in only 2 patients (11.7%) compared to Group 2, where arterial hypotension developed in 6 patients (75%), (P 0.001). Sinus bradycardia (heart rate less than 60 min -1 ) in Group 1 was observed in 1 patient (5.8%) compared to Group 2, where sinus bradycardia developed in 6 patients (75%) (P 0.001). Decrease in respiratory rate to 10 min -1 or less in Group 1 was observed in 1 patient (5.8%) compared to Group 2, where bradypnea developed in 3 patients (37.5%) (P 0.05). Failure to achieve the clinical endpoint (elimination of sympathetic hyperactivity signs such as agitation, hypertension, tachycardia, tachypnea, desynchronization with ventilator) was observed in 1 patient (5.8%) in the group 1 and in 4 patients (50%) from group 2.
The following parameters showed significant differences in Group 1 patients prior to and on days 30-60 th day of dexmedetomidine administration: increased level of consciousness according to FOUR and CRS-R scales, reduced number of patients in vegetative state, decreased dependence on ventilator with restoration of spontaneous breathing (P<0.05, Table 3).
Autonomic nervous system dysfunction with increased sympathetic drive is the leading factor underlying both acute and chronic critical illness in brain injury and many other conditions [8]. Persistent sympathetic overactivity in patients post traumatic brain injury, cerebral circulation disorders of vascular and other origins provokes increased blood flow abnormalities, secondary brain inflammation and prevents restoration of nutritional status and respiratory function along with increasing the risk of tachyarrhythmias and heart failure [9,10]. Hence, the use of drugs eliminating autonomic dysfunction constitutes a new direction in intensive care medicine. Dexmedetomidine as a central alpha-2 receptor agonist has both experimentally and clinically proven effect on the correction of autonomic nervous system imbalance [11][12][13][14][15][16][17][18][19][20].

Conclusion
Electrophysiological digital parameters of heart rate variability reflecting sympathetic hyperactivity are the guiding parameters to start the intravenous dexmedetomidine therapy.
Electrophysiological assessment of autonomic function using heart rate variability parameters is an informative way of selecting and titrating the dose of dexmedetomidine.
The level of sympathetic hyperactivity serves as an indication for starting dexmedetomidine therapy. Reaching the normal values of autonomic function parameters is the target, while parasympathetic hyperactivity serves as a rationale for discontinuing the drug or reducing the dose of dexmedetomidine.
Electrophysiological neuromonitoring of autonomous nervous system as the main regulator of the body homeostasis increases the efficacy of dexmedetomidine in patients with brain injury of different etiologies.
Author contribution. Yuri Yu. Kiryachkov, DM, developed the aims, suggested the methodology of the study and was responsible for the statistical data analysis. Marina V. Petrova, DM, professor, refined the presentation of material and authored the «Discussion» section of the paper. Bagautdin G. Muslimov performed the literature search and contributed to categorization of materials. Oleg V. Gridnev, DM, professor, selected the patients for the study participation.