Cerebral Circulation and Metabolism of Patients with Cerebral Injury

Цель исследования — изучить изменения показателей церебральной макроциркуляции и метаболизма у пострадавших с сочетанной ЧМТ при инфузионном введении этилметилгидроксипиридина сукцината в дозах от 12,5 до 100 мг/час в зависимости от исходного паттерна мозгового кровотока. Материалы и методы. Обследовали 25 пациентов с тяжелой сочетанной ЧМТ, которым дополнительно к стандартному лечению внутривенно вводили этилметилгидроксипиридина сукцинат (ЭМГПС) в дозе 12,5 мг/час в течение 1 часа, после чего увеличивали дозу до 25 мг/час в течение 1 часа, затем до 50 мг/час в течение 1 часа, затем осуществляли инфузию в дозе 100 мг/час в течение 1 часа. Каждый час, перед увеличением дозы, измеряли показатели церебральной макроциркуляции. Методом транскраниальной допплерографии (ТДГ) изучали показатели линейной скорости кровотока (ЛСК): систолическую (Vmax), диастолическую (Vmin), среднюю скорость кровотока (Vm), пульсационный индекс (PI) и индекс сопротивления (RI), и оценивали содержание глюкозы, лактата, активность ЛДГ и значение рН венозной крови из яремной вены. Результаты. Инфузия ЭМГПС в дозе от 12,5/час до 100 мг/час при паттерне затрудненной перфузии и гипоперфузии сопровождалась благоприятными изменениями показателей ЛСК в виде увеличения церебральной перфузии. При паттерне мягкого ангиоспазма отмечали благоприятные изменения показателей ЛСК в виде снижения скоростных показателей, нормализации пульсового индекса и индекса сопротивления, что свидетельствовало о нормализации сосудистого тонуса и разрешения ангиоспазма. При паттерне гиперперфузии регистрировали благоприятные изменения показателей ЛСК в виде уменьшения явлений гиперемии и нормализации сосудистого тонуса. При паттерне выраженного ангиоспазма отмечали нормализацию сосудистого тонуса. Нормализация ЛСК сопровождалась нормализацией содержания лактата, активности ЛДГ и зничения рН венозной крови. Оптимальные результаты отмечали при инфузии в дозе 50—100 мг/час. Заключение. У пациентов с сочетанной ЧМТ применение ЭМГПС в виде инфузий в дозе 12,5—100 мг/час приводит к благоприятным изменениям показателей ЛСК и метаболизма в виде нормализации их значений при любом паттерне мозгового кровотока.

velocity parameters, normalization of the pulsation index and the resistance index which confirmed normalization of the vascular tone and vasospasm elimination.Positive changes in LBFV parameters in patients with a hyperperfusion pattern were noticed in the form of the reduction of hyperemia manifestations and normalization of the vascular tone.Patients with a severe vasospasm pattern presented normalization of the vascular tone.Normalization of LBFV parameters was accompanied by normalization of the lactate level, lactate dehydrogenase activity and the pH level in venous blood.Optimal values were found in infusions at a dose of 50-100 mg/h.

Conclusion.
Infusions of EMHPS at a dose of 12.5-100 mg/h to patients with concomitant cerebral trauma resulted in normalization of LBFV and metabolism parameters in patients with all kinds of CBF patterns.

Introduction
Treatment of patients with cerebral injury (CI) is considered to be one of the most important tasks of the emergency medicine [1][2][3][4][5].First of all, emergency care is needed to recover patients from shock, to ensure hemostasis and to decide on surgical intervention [6][7][8].
However, unfavorable results of the standard therapy encourage searching for treatment technologies that allow to minimize the risk of secondary ischemic brain injury [9][10][11].
However, research literature contains no information concerning the EMHPS effect on cerebral macrocirculation parameters depending on a source pattern and the route of administration: bolus dosing or the continuous infusion.
In this connection, the study of the effect of EMHPS infusions at a dose of 12.5-100 mg/h on linear blood flow velocity parameters, glucose and lactate levels, LDH activity and the acid-base balance in venous blood is of a practical interest.
The purpose of the study was to asses changes in cerebral macrocirculation and metabolism parameters in patients with concomitant cerebral injury during infusions of ethylmethylhydroxypyridine succinate at a dose of 12.5 to 100 mg/h depending on a source pattern of the cerebral blood flow.

Materials and Methods
The study included 25 patients with severe concomitant CI (table 1).There were 9 female and 16 male patients.The inclusion criteria were as follows: age between 21 and 60 years (the average age was 42.3 (28; 53) years)., moderate and severe CI combined with extracranial damage of long bones and/or thoracic and abdominal organs (with the consciousness depression of 4-13 points according to the Glasgow Coma Scale, GCS), the need in treatment in the ICU, patient's or patient's legal representative's consent for an EMHPS prescription.
16 of 25 patients were at a grave condition, 9 patients were classified as very grave (table 1).Traumatic and hemorrhagic shock developments were found in patients at a very grave condition, there were indications for the mechanical ventilation (MV) and the consciousness was impaired.
The standard treatment included analgesia and sedation, respiratory support as indicated, antibiotics, infusiontransfusion therapy to correct the water and electrolyte balance, arterial oxygen content, and oncotic pressure and to prevent disseminated intravascular coagulation syndrome, the enteral and parenteral nutrition, prevention of stress ulcers and correction of intracranial pressure (ICP).
In order to study the influence of EMHPS infusions at a dose of 12.5-100 mg/h on LBFV parameters and cerebral metabolism parameters, the enrolled patients received EMHPS infusions at a dose of 12.5 mg/h for 1 hour, then the dose was increased up to 25 mg/h within 1 hour, then up to 50 mg/h within 1 hour followed by an infusion at a dose of 100 mg/h for one hour.LBFV parameters were analyzed every hour before the increase of the dose as well as glucose and lactate levels, LDH activity and the pH level in venous blood from a jugular vein.
Transcranial Doppler was performed using an ultrasonic diagnostic system Sonomed 300V (Spectromed, Moscow, Russia) with a 2 MHz sensor.The standard method of R. Aaslid et al. [14] was used to probe the medial cerebral artery (MCA) and other vessels of the circle of Willis through the temporal «window».The systolic blood flow velocity (V max ), diastolic blood flow velocity (V min ), PI and RI were studied.When analyzing LBFV the following pa-Таблица 1. Характеристика обследованных больных.Table 1.Characteristics of Patients.
The statistical analysis of the findings was carried out using the Excel software after testing the values distribution for normality by the standard formulas (Shimko P. D., Vlasov M. P., 2003, Lakina G. F., 1990) [16,17].Mean values were presented as М±σ or Me (Р 25 ;Р 75 ).Significance of the presented data of nonparametric indices was assessed by Fischer test.A difference was considered significant at р 0,05.

Results and Discussion
The effect of changes of linear cerebral blood flow velocity, pulsation index and resistance index was recorded in cases of EMHPS infusions in an ascending dose of 12.5 -25 -50 -100 mg/h.
Table 2 shows the dynamics of parameters in patients with a hindered perfusion pattern.
As it appears from the data in table 2, one hour after the EMHPS infusion at a dose of 12.5 mg patients had PI decreased from 0.85 to 0.79 units which is a 7% decrease.After the infusion at a dose of 25 mg during another hour there were a 7% rise of V max , a 14.1% increase of V min , as well as a 5.5% decrease of RI as compared to the baseline.The EMHPS infusion at a dose of 50 mg for an hour led to a 21.2% rise of V max , a 36.7% increase of V min , as well as a 18% decrease of PI and a 11% drop of RI as compared to the baseline.The EMHPS infusion at a dose of 100 mg within the period of one hour resulted in a 42.5% rise of V max , a 60.4% increase of V min as well as a 14.1% decrease of PI and a 11.1% drop of RI as compared to the baseline.
The dynamics of observation didn't show any significant changes of the glucose level in blood which amounted to 5.5-5.7 mmol/l.The lactate level in blood went lower from 2.2±0.01 to 1.3±0.01mmol/l which was equal to a 40.1% decrease.The LDH activity dropped by 20.5% and the pH level increased from 7.29 to 7.38.
The dynamics of LBVF and metabolism parameters of patients with a mild vasospasm pattern is presented in table 2.
According to table 2, one hour after the EMHPS infusion at a dose of 12.5 mg a value of PI decrease from 0.93 to 0.83 units, jr a drop by 10.7%, became evident.After the EMHPS infusion at a dose of 25 mg during another hour, there was a 21.3% decrease of V max whereas RI dropped to 12 % compared to the baseline.The EMHPS infusion at a dose of 50 mg for an hour led to a 21.8% reduction of V max , a 10.9% decrease of V min and a 16.1% drop of PI with a decrease of RI to 10.3% comparing to their initial level.The EMHPS infusion at a dose of 100 mg within the period of one hour resulted in a 26.3% decrease of V max , a 19.3% drop of V min , as well as a 10.7% reduction of PI and a 8.6% decrease of RI comparing to their initial level.
1.9±0.01 to 1.5±0.01mmol/lwhich was equal to a 21% decrease.The LDH activity dropped by 17.1% and the pH level increased from 7.31 to 7.36.
The dynamics of LBVF and metabolism parameters of patients with a severe vasospasm pattern is presented in table 2.
According to table 2, one hour after the EMHPS infusion at a dose of 12.5 mg, no significant changes were recorded.After the infusion at a dose of 25 mg for 1 hour, there was a 10.5% decrease of V max , a 9.6% drop of V min as compared to the baseline.The EMHPS infusion at a dose of 50 mg for an hour led to a 20.1% Таблица 2. Динамика исследуемых показателей.Table 2.The dynamics of study parameters.

Parameters
Values of parameters upon the EMHPS infusion at a dose of 12.
Как следует из полученных результатов инфузия ЭМГПС в дозе от 12,5/час до 100 мг/час при паттерне затрудненной перфузии сопровождалась благоприятными изменениями показателей reduction of V max , a 11.8% decrease of V min , as well as a 11.7% drop of PI as compared to the baseline.The EMHPS infusion at a dose of 100 mg within the period of one hour resulted in a 22% decrease of V max , a 10.4% drop of V min , as well as a 12.1% reduction of PI comparing to their initial level.
The dynamics of observation didn't show any significant changes in the glucose blood level which amounted to 5.9-5.6 mmol/l.The lactate blood level decreased from 2.25±0.06 to 1.6±0.08mmol/l which was equal to a 28.8% decrease.The LDH activity dropped by 12.4% and the pH level amounted to 7.25-7.33.
Table 2 shows the dynamics of parameters of patients with a cerebral hypoperfusion pattern.
According to table 2, one hour after the EMHPS infusion at a dose of 12.5 mg a PI decrease from 0.85 to 0.79 units was recorded which is equal to a 7% drop.
After the infusion at a dose of 25 mg for 1 hour there was a 7% rise of V max , a 14.1% increase of V min , as well as a 5.5% decrease of RI as compared to the baseline.The EMHPS infusion at a dose of 50 mg for an hour led to a 21.2% rise of V max , a 36.7% increase of V min , as well as a 18% decrease of PI and a 11% drop of RI as compared to the baseline.The EMHPS infusion at a dose of 100 mg within the period of one hour resulted in a 42.5% rise of V max , a 60.4% increase of V min , as well as a 14.1% decrease of PI and a 11.1% drop of RI as compared to the baseline.
The dynamics of observation didn't show any significant changes in the glucose blood level which amounted to 5.5-5.7 mmol/l.The lactate blood level decreased from 2.1 to 1.5 mmol/l, the LDH activity dropped by 17.2% and the pH level amounted to 7.32-7.35.
The dynamics of LBVF and metabolism parameters of patients with a cerebral hyperperfusion pattern is reflected in table 2.
According to table 2, one hour after the EMHPS infusion at a dose of 12.5 mg no significant changes were recorded.After the infusion at a dose of 25 mg for 1 hour there was a 7.6% decrease of V max noticed as compared to the baseline.The EMHPS infusion at a dose of 50 mg for an hour led to a 11.3% reduction of V max as compared to the baseline.The EMHPS infusion at a dose of 100 mg within the period of one hour resulted in a 18.3% decrease of V max , a 17.2% drop of V min as compared to the baseline.PI and RI remained within reference limits.
The dynamics of observation did not show any significant changes of the glucose blood level which amounted to 5.9-5.7 mmol/l.The lactate blood level decreased from 1.9 to 1.6 mmol/l, the LDH activity dropped by 14.4% and the pH level amounted to 7.33-7.35.
Следовательно, у пациентов в остром периоде ЧМТ применение ЭМГПС в виде инфузий в дозе parameters of blood flow velocity was noticed with the increase of the dose.Such changes may be considered favorable in patients with initial hypoperfusion which was confirmed by the dynamics of the lactate level and ABB normalization.
The EMHPS infusions at a dose of 12.5 mg/h to 100 mg/h to patients with a mild vasospasm pattern had favorable changes in LBFV parameters including a decrease in velocity parameters, normalization of the pulsation index and the resistance index which confirmed normalization of the vascular tone and vasospasm elimination.The most significant decrease of velocity parameters was recorded during infusions at a dose of 25-100 mg/h.Such changes may be considered favorable in patients with a mild vasospasm, which was confirmed by the dynamics of the lactate level and normalization of pH level in venous blood.
Similarly, the EMHPS infusion at a dose of 12.5-100 mg/h in cases of a severe vasospasm pattern was followed by decreasing the LBFV parameters and normalization of the vascular tone, thus enhancing cerebral perfusion, even though vasospasm itself was not arrested.The most significant decrease of velocity parameters was recorded during infusions at a dose of 50-100 mg/h.The latter changes might be considered as favorable in patients with a severe vasospasm, which was confirmed by the dynamics of the lactate level, LDH activity and the pH level in venous blood.
The EMHPS infusion at a dose of 12.5 mg/h to 100 mg/h in cases of a hypoperfusion pattern was also followed by positive changes of LBFV parameters like cerebral perfusion enhancement and normalization of the vascular tone.Moreover, a distinct tendency towards the rise of linear indices of blood flow velocity was noticed with increasing the dose.Such changes may be considered favorable in patients with initial hypoperfusion which was confirmed by the dynamics of the lactate level and the pH level in venous blood.
Similarly, the EMHPS infusion at a dose of 12.5-100 mg/h in cases of a hyperperfusion pattern was followed by positive changes of LBFV parameters in the form of the reduction of hyperemia changes and normalization of the vascular tone.The most significant decrease of velocity parameters was recorded during infusions at a dose of 50-100 mg/h.The above changes may be considered favorable in patients with initial hyperperfusion which was confirmed by the dynamics of the lactate level, LDH activity and the pH level in venous blood.