Novokuznetsk State Institute of Postgraduate Medicine,

Novokuznetsk, Russia

 

Microcirculation disorders accompany any nosologic process in the body. Metabolic and transport processes of the body at the organic, tissue and cellular level are realized directly in the microcirculation system, which includes both microvascular bed, where the main function of cardiovascular system flows, transcapillary change arises and is maintained, dynamic relationships between all blood components and endothelium are realized, and necessary homeostasis is provided [1, 2].   

The main objective of intensive care for severely injured patients is restoration of appropriate tissue perfusion. However the anesthesiologist-intensivist estimate improvements in microcirculation by means of subjective evidence about absence of skin marbling, rash blanching at pressure symptom and presence of diuresis, whereas stabilization of central hemodynamics with achievement of oriented levels for the main parameters are the marks for immediate correction and only give indirect reflection of capillary flow state [3, 4, 5]. That is why the direct examination of microcirculation system is useful in treatment of such category of patients.

Severity of a traumatic injury is characterized with not only and not just the fact of an injury (a primary injury), but to a greater degree with a secondary injury that finally determines the general severity of state. Development and course of traumatic disease are under influence by characteristics and location of a primary injury, despite of versatile manifestation of a severe injury. As for polytrauma pathogenesis, the main importance is related to direct consequences of an injury such as blood loss, hypoxia, strong pathologic nociceptive impulsion that almost in all cases are accompanied by appearance of disorders of hemodynamics and oxygen transport. Hypoperfusion in critically ill patients result in endothelial injuries and causes pathologic changes in the blood that worsen microcirculation system functioning [4, 5, 6]. A severe cerebral injury as result of severe traumatic brain injury (TBI) initiates multiple pathologic processes in cerebral tissues (resulting in microcirculation slowdown, hypercoagulation, diapedesis, local vasospasm, increasing blood viscosity, microcirculation blockade) and at the level of the body. Also such processes cause injuries in organs and tissues which are intact at the moment of development of acute cerebral syndrome [7]. Discharge of catecholamines, activation of endotheliocytes, monocytes, neutrophils, systems of coagulation and complement initiate adhesive processes and synthesis of proinflammatory factors, free radicals and proteases and result in activation of thrombocytes [7, 8, 9]. However there is only scarce data about direct examination of disorders in microcirculation system and differences according to various location of a primary injury. The data is only in view of some individual reports and are insufficiently described in the modern literature.      

The above mentioned facts have founded the basis for stating the objective of the study.

Objective – to compare the changes in microcirculation in critical conditions caused by isolated severe brain injuries and polytrauma to develop a differentiated approach to intensive care.

 

MATERIALS AND METHODS

The study included 138 patients with severe injuries treated in the departments of anesthesiology and intensive care, Novokuznetsk City Clinical Hospital #29, and in the intensive care unit, Novokuznetsk City Clinical Hospital #1. The control points of the study were the days 1, 3, 5 and 7 after the injuries.  The study excluded the patients who died during the observation period, and the patients with concurrent decompensated pathologies. All patients were transported to the hospital within 1-3 hours after the injuries. The injuries were diagnosed on the basis of clinical, laboratory, instrumental and radiologic data, which were collected during complex examination by the multi-specialized team.   

The patients were distributed into two groups: the main group (82 patients), which received common intensive care, and the intervention group (56 patients), which received common therapy and some medical measures for correction of microcirculatory disorders in the earliest terms. Inside the main and intervention groups the patients were distributed into 2 subgroups according to the characteristics and location of traumatic injuries.      

The subgroup 1 included 34 patients with TBI in the main group, the mean age of 44.8 ± 1.8, GCS – 6.9 ± 1, APACHE II – 19.1 ± 3.2.

The subgroup 1a included 20 patients with TBI, the mean age of 43.6 ± 2.2, GCS – 7.1 ± 0.9, APACHE II – 18.6 ± 3.3.   

As for the injury patterns, the first place was taken by cerebral compression due to meningeal hematoma (epi- and subdural) in combination with severe cerebral contusion. The second place was taken by cerebral compression due to intracerebral and multiple hematomas in combination with severe cerebral contusion. Surgical treatment of isolated TBI resided in resection cranial trepanation with hematoma removal and draining of regions of crushing/contusion of the brain. Anesthesiology was realized according to ataralgesia at the background of oxygen ventilation. The mean blood loss was 550 ± 50 ml in the subgroup 1, 480 ± 50 ml in the subgroup 1a. The volume of infusion therapy was 1,850.5 ± 100 ml and 1,880 ± 60 ml correspondingly. Hydration was realized mainly with saline solution (0.9 % NaCl). In case of intense hypovolemia and a tendency to hypotension, the infusion was supplemented with colloid solutions (hydroxyethyl starch 130/0.4 or modified gelatin) with the dosage not above 50 ml/kg. Some patients (6 patients in the subgroup 1, 4 patients in the subgroup 1a) with unstable hemodynamics required vasopressor support with dopamine (6-12 µg/kg/min).            

The subgroup 2 included 48 patients with polytrauma in the main group, the mean age of 42 ± 2.8, ISS – 31.6 ± 2.5, APACHE II – 20.7 ± 1.4. The subgroup 2a included 36 patients with polytrauma in the intervention group, the mean age of 42.5 ± 3, ISS – 31.4 ± 2.8, APACHE II – 20.3 ± 1.2.    

The injuries in 2 or more anatomic functional regions were registered in the patients with polytrauma in the main and intervention groups. The location of the traumatic injuries was as indicated below. The leading place was taken by the combination of skeletal trauma and a blunt abdominal injury with internal organ injuries. The second place was taken by the extensive skeletal injury with mild TBI. The third position was the skeletal injury with closed blunt abdominal and thoracic injuries with internal organ injuries. The combination of a skeletal injury and a blunt thoracic injury with internal organ injuries was in the smallest proportion of the cases. Also an additional exclusion criterion in the subgroups was severe traumatic brain injury and development of purulent septic complications in the observation period. Surgical treatment of polytrauma included fracture stabilization: external fixation devices, skeletal traction and metal osteosynthesis. In cases of the combination of a skeletal injury and suspected abdominal injuries we conducted laparoscopy with switch to middle laparotomy (if necessary). The full volume of surgical assistance was realized (splenectomy, liver rupture suturing, intestinal perforation suturing etc.). Pleural cavity draining was conducted for the combination of skeletal injuries and chest injuries which were complicated by pneumo- and/or hemothorax. Anesthetic measures included endotracheal narcosis with premixed nitrous oxide at the background of central narcotic analgesia (33.3 %) and total intravenous anesthesia at the background of artificial ventilation with oxygen (66.7 %). After completion of surgical treatment the patients were transferred to the intensive care unit. The mean value of intrasurgical blood loss was 850 ± 45 ml in the subgroup 2, 780 ± 50 ml in the subgroup 2a. The volume of infusion therapy was 3,250 ± 150 ml and 3,680 ± 140 ml in the subgroups 2 and 2a correspondingly. The infusion media were crystalloid solutions (0.9 % NaCl, Ringer's solution, 5 % glucose). In necessary cases colloids were supplemented at the dosage of 50 ml/kg (hydroxyethyl starch 130/0.4 or modified gelatin). Due to significant blood loss (decreasing hemoglobin below 60-70 g/l) intrasurgical hemotransfusion was conducted for 10 patients in the subgroup 2 and for 8 patients in the subgroup 2a. Hemodynamics was unstable in 6 patients in the subgroup 2 and in 6 patients in the subgroup 2a. As result, vasopressor support was used (noradrenaline, 0.05-2 µg/kg/min, dopamine, 5-15 µg/kg/min, mesaton, 2-10 µg/kg/min, adrenaline, 2-15 µg/kg/min, separately or in combinations).                                  

Therefore, the patients of the reviewed groups were similar according to the age, patterns of diseases and the basic severity.

All patients received intensive care measures including infusion-transfusion therapy, vasoactive drugs for persistent unstable hemodynamics (dopamine, 5-15 µg/kg/min, mesaton, 2-10 µg/kg/min, adrenaline, 2-15 µg/kg/min, separately or in combinations), respiratory support according to the concept of safe artificial lung ventilation, antibiotics including the drugs of wide range, nutritive support with enteral, mixed or full parenteral mode. In case of renal dysfunction (estimated with RIFLE) the patients received renal replacement therapy with venovenous hemofiltration mode/hemodiafiltration or daily prolonged hemodialysis.       

Besides the common clinical, laboratory and instrumental methods of examination the patients of both groups received monitoring of microcirculation (at least 3 times per a day). Cutaneous laser doppler flowmetry (LDF) was used for the same purpose. It was performed with the laser analyzer for capillary blood flow (LAKK-02) of domestic production (LASMA, Russia). The device allows complex estimation of microcirculation in various categories of patients [11, 12]. The examinations were performed each day within 7 days. The examined region included the external lower one-third of the shoulder on both hands. This region was chosen due to poor presence of arteriolovenular anastomoses (i.e. it gives the most precise estimation of blood flow) [10, 11]. The duration of the examination was 3 minutes. The following values were registered: the mean value of microcirculation (it shows a degree of perfusion in volume units of tissue per a time unit; it is measured in perfusion units); mean square deviation of amplitude of perfusion variations from mean arithmetic value (it characterizes temporary variability of perfusion and reflects mean modulation of blood flow in all frequency bands); variation coefficients (VC), which indicates the percent contribution of active factors of regulation in general modulation of tissue blood flow. After wavelet transformation of amplitude spectrum the analysis of standard patterns of the rhythms of blood flow variations was conducted: neurogenic and myogenic components.

Simultaneously with registration of microcirculatory blood flow state the sampling of the blood was performed for laboratory examinations of structural functional state of endothelium. The serum levels of endothelin-1 (ET-1) were estimated with the immunoenzyme method with the tools from Biomedica (Austria). Production of nitric oxide (NO) and von Willebrand factor (vWF) was estimated with the test systems from R&D Systems (USA) and Technoclone (Austria) and the tools for enzymoimmunoassay (a reader, a washer, a shaker-incubator) from BioRad (USA).

          The control group for estimation of normal microcirculation included 35 almost healthy volunteers who had been recognized as work capable individuals after the annual preventive examination. The mean age of the controls was 42.1 ± 1.2.

Microsoft Excel and Microsoft Word (Microsoft Office 2010) and Graph Pad In Statversion 3.06 Graph Pad Software 2003 (Sigma, USA) were used for statistical analysis. Descriptive statistics was used for systematization, visual presentation in view of diagrams and tables, and quantitative description. Kolmogorov-Smirnov test was used for estimation of normality of the sample. Student’s test was used for statistical estimation in normal distribution. In case of non-normal data distribution, the statistical significance was estimated with Mann-Whitney test, intragroup differences – with Wilcoxon test. The prepared data was presented as mean (M) and error in mean (m) for each value [12]. P value < 0.05 was statistically significant.                

 

RESULTS AND DISCUSSION

The table 1 demonstrates the values of microcirculation in the subgroups 1, 2 and in the control group.

According to the presented data, during all days the patients with isolated TBI demonstrated the mean level of perfusion within the range of the control values. It was associated with absent differences in microcirculation values. The blood flow was stable in microcirculatory bed. It was testified by absent differences in standard deviation. The variation coefficients (VC) were reliably low from the first day of the study. It characterized the low response of microcirculatory bed to initiation of active regulators of vascular tone. Within the days 3-5 the values of this parameter were reliably decreased in comparison with the registered values on the 1st day in the subgroup 1. As for neurogenic tone (NT) and myogenic tone (MT), we found their reliable increase beginning from the 1st day. On 5th day the significant decrease in the values was observed in comparison with the control group and, as result, in the subgroup 1 from the 1st day. The values of NT and MT were within the normal range on 7th day.

The patients with polytrauma demonstrated low peripheral perfusion from the 1st day of the study. It was testified by the value of microcirculation, which was significantly lower in comparison with the values in the control group. In the 2nd subgroup perfusion was within the normal range at the background of intensive care from 3rd day to the end of the study. The standard deviation was reliably lower in comparison with the control data within all days of the study. Such fact testified the decreasing variability in flow of formed elements through microcirculatory bed and indirectly witnessed predominance of vasoconstrictive mechanisms of regulation of vascular tone. In its turn, the value of variation coefficient was significantly lower the normal range only on 1st and 3rd days of the follow-up, whereas on 5th and 7th days activity of modulators of microvascular bed increased and it resulted in increasing peripheral perfusion with persistent low variability of red blood cell flow through the microvessels. As for neurogenic and myogenic tones, any statistically reliable differences were absent.                

After comparison of the data about microcirculation in polytrauma the following facts were found: within 3 days after the injuries the patients of the subgroup 2 demonstrated significant decrease in peripheral perfusion in comparison with the patients of the subgroup 1. It was confirmed by the statistically significant values of microcirculation in the indicated time interval. The variability of microflow was without differences in both subgroups (no difference in SD). The same results were found in regard to neurogenic and myogenic tones. In the subgroup of the patients with polytrauma the variation coefficient was high only on 3rd day of the study without any differences at any other time.   

The table 2 shows the levels of the markers of structural functional state of endothelium in the subgroups 1 and 2.

The statistically significant level of endothelin (without significant changes up to the end of the study) was found in regard to the markers of structural functional state of endothelium in both groups beginning from 1st day of the study. NO was within the normal levels within all days. Activity of von Willebrand factor was within the normal range within 3 days, with its significant increase on 5th day with persistence up to the end of the study.

Therefore, the differences between disorders of microcirculation in polytrauma and isolated traumatic brain injury resided in the early basic posttraumatic decrease in peripheral tissue perfusion with the identical response to the injury from the side of the modulators of microcirculatory bed and the endothelial response in view of intense vasoconstrictive activity in internal covering of vessels.       

 The identified disorders of microcirculation resulted in initiation of a curative algorithm, which allowed correction of microcirculation disorders in the maximally earliest terms in the intervention group. It is necessary to note that the common components of intensive care for the critically ill patients in the main and intervention groups did not have any critical distinctions. The main objectives of the offered curative program were normalization of tissue perfusion, decreasing heterogeneity in capillary bed for achievement of adequate oxygen delivery and restoration of cellular metabolism. The main agents with positive influence on microcirculatory bed were reamberin (400-800 ml per day), perftoranum (2-3 ml/kg/per day) separately or in combination, depending on primary pathology, which resulted in development of critical state, and depending on the level of peripheral tissue perfusion. The choice of these drugs was conditioned by the following fact: amber acid, which is the basis of reamberin, influences on cellular metabolism, promotes disappearance of tissue acidosis (by means of correction of hypoxia), improves and restores the processes in microvascular bed [13]; perftoranum improves rheological properties of the blood and restores functioning of spastic capillaries, with improvement of microflow and decrease in heterogeneity of microcirculatory bed [14].

As a part of intensive care for isolated TBI, the use of the medical algorithm for correction of microcirculation disorders was used for 20 patients. The results are presented in the table 3. It is necessary to note that use of reamberin for TBI is limited because of contraindications in the form of cerebral edema. Helical computer tomography was conducted before making a decision about infusion of this drug in the subgroup 1a. After confirming the absence of intense cerebral edema the decision about administration of the drug was made for 80 % of the cases (16 patients with isolated TBI). In other cases only infusion of perftoranum (3 ml/kg/per day for 3 days) was initiated. It is necessary to note that in 4 cases of refusal from reamberin the main level of peripheral perfusion was below 3.5 perfusion units, and it resulted in lethal outcomes. According to the indicated data, there was no statistically significant difference in tissue microperfusion in the subgroup 1a in comparison with the controls and the subgroup 1, i.e. the values of microperfusion were within the control range. Also there were no statistically significant differences in relation to standard deviation. In other words, the flow of the formed elements through microvascular bed was stable in the subgroups 1 and 1a. From 3rd day to the end of the study the variation coefficient was significantly higher in the subgroup of the patients with isolated TBI, where special correction for microcirculation disorders was made. Moreover, on 7th day of the study the variation coefficient in this subgroup was within the reference values. It indicated the improvement in the processes of regulation of microvascular tone. At the background of targeted correction of microcirculation disorders in the program of intensive care for the patients with isolated TBI we registered some improvements in the active modulators of tissue perfusion in view of early stabilization of neurogenic influences (the value of NT within the reference values from 3rd day of the study) and local mechanisms of regulation of vascular tone. The values of MT were within the references on 5th day. At the same time, the patients with isolated TBI without administration of differentiated correction of microcirculation disorders demonstrated the significant variations of NT and MT with trends to increase and decrease of the values. Therefore, use of differentiated correction of microcirculation disorders in the program of intensive care for isolated TBI resulted in improving microperfusion by means of influence on the active modulators of microvascular regulation. In combination with absent difference in peripheral perfusion of tissues it testified higher functional reserve of microcirculatory bed in the patients of the subgroup 1a.

The table 4 shows the summary data of microcirculation in the patients with polytrauma at the background of administration of targeted differentiated correction of microcirculation disorders with use of the program of intensive care (the subgroup 2a of the intervention group) in comparison with the patients of the subgroup 2 in the main group and the controls.  

At the background of combined administration of infused reamberin and perftoranum, the reviewed category of the patients with polytrauma demonstrated statistically significant increase in microcirculation values on 5th day of the study. The standard deviations in the subgroup 2a were within the references on 3rd day of the study and persisted at the same level up to the end of the study, whereas the value of the examined parameter in the subgroup 2 was at the low level. The variation coefficient was within the references in the subgroup 2a on 3rd day, with the statistically significant differences from the patients of the subgroup 2. After consideration of the dynamic changes in the active modulators of microcirculation we did not find any differences in NT in the main and intervention groups. It characterized the stable state of neurogenic regulation of vascular tone in polytrauma. Beginning from the third day of the study we could observe a reliable increase in MT in the subgroup 2a of the intervention group in comparison with the control group and the subgroup 2 of the main group. Increasing MT was found in the main group on 5th day. By 7th day the statistically significant difference between the reviewed subgroups was found. MT value was higher in the intervention group. Therefore, administration of targeted differentiated correction of microcirculation disorders in the patients with polytrauma was accompanied by improving peripheral perfusion of tissues by means of improvement in regulatory influences from the active modulators of microcirculation. Moreover, restoration of microhemodynamics was faster in the subgroup of the intervention group in comparison with the main group.                                         

 

CONCLUSION

Severe traumatic injuries result in microcirculation disorders with some variations depending on characteristics and location of a primary injury. Polytrauma is accompanied by basic decrease in tissue perfusion in comparison with an isolated traumatic brain injury in identical responses from the modulators of vascular tone and endothelium. Early targeted differentiated correction of microcirculation disorders as a part of intensive care for severe traumatic injuries has positive influence on microcirculation by means of improvement in its regulation. Direct non-invasive monitoring of microcirculation with administration of laser doppler flowmetry allows early identification of tissue perfusion disorders and determination of the main cause in different types of traumatic injuries.