INTERCOMMUNICATION OF INDEXES OF CARDIOVASCULAR SYSTEM AND ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH TRAUMATIC SHOCK

Omsk Emergency Aid Station,

 Kabanov City Clinical Hospital #1,

City Clinical Hospital of Emergency Medical Aid #1,

Omsk State Medical Academy, Omsk, Russia

At the present time the term traumatic shock is considered as an injury complicated by blood loss and pain syndrome, which condition vascular spasm, systemic perfusion of organs and tissues, circulatory hypoxia and severe disorders of vascular endothelium [1]. Therefore, the objective of the study is researching an associativity of parameters of central hemodynamics and vascular endothelial function at the background of its morphological assessment in patients with traumatic shock.

MATERIALS AND METHODS

We conducted the simple blind prospective clinical cohort randomized (the envelope method) study including 50 patients (mean age 29.5 ± 3.8) with traumatic shock of degree 3. The patients were distributed into two groups according to a type of infusion therapy at prehospital and hospital stages. Road traffic injuries were the cause of traumatic shock in all patients. The causes of acute blood loss were closed and open fractures of the femoral and/or fibular and shin bones in combination with fractures of pelvic bones and closed abdominal injury with injuries to the internal organs (traumatic ruptures of the liver, the spleen and the omentum). The inclusion criteria were: 1) patients’ age of 18-40; 2) acute beginning of a disease; 3) admission to a medical facility within 2 hours after onset of a disease. The exclusion criteria were: 1) concurrent sub- and decompensated chronical pathology of kidneys, the liver, the heart and the lungs; 2) history of oncologic pathology; 3) previous hormonal therapy and chemical therapy; 4) diabetes mellitus of types 1 and 2; 5) terminal state; 6) participation in other study, 7) allergic responses to introduction of colloid solutions of hemodynamic type on the basis of 6 % HEC and 4 % MG. Traumatic shock was diagnosed at prehospital stage (before infusion therapy) in the presence of previous injuries and on the basis of the following signs: level of consciousness (9 points and less according to Glasgow Coma Scale), paleness and coldness of the skin, mean arterial pressure (35 mm Hg and less) and shock index (2.9 and more). At prehospital stage all patients received multimodal analgesia (narcotic and non-narcotic analgetics), infusion therapy through a catheter in the central (subclavian or jugular) vein, and inotropic and vascular support with dopamine (5 mg/kg of body mass/min). After tracheal intubation all patients received artificial lung ventilation with Chirolog Paravent PAT (Chirana, Slovakia). The first group (25 patients) received infusion therapy 0.9 % natrium chloride crystalloid solution and 4 % modified gelatin (MG) colloid solution. The second group (25 patients) received infusion therapy with balanced crystalloid solution (isotonic sterofundine) and 4 % MG colloid solution. Crystalloids/colloids ratio was 1:3 in the patients of the groups 1 and 2. The blood loss volume at prehospital and hospital stages was estimated with the data of clinical symptoms and estimation of external blood loss [1]. The total blood loss was 3,447.7 ± 231.1 ml in the group 1, and 3,431.6 ± 212.3 ml in the group 2. The total volume of infusion-transfusion media was 9,987.4 ± 11.5 ml in the group 1, and 9,979.6 ± 109.5 ml in the group 2. The volume of infused colloid solutions in the group 1 was 3,246.3 ± 97.1 ml, in the group 2 – 3,301.2 ± 92.8 ml. The volume of infused crystalloid solutions was 1,265.2 ± 48.6 ml in the group 1, and 1,245 ± 56.7 ml in the group 2. During the first 24 hours replacement therapy for anemia and consumption coagulopathy was realized with the general criteria with use of transfusion of fresh frozen single-group plasma and red blood cells [2]. The time from initiation of anti-shock measures to admission to the hospital was 56.9 ± 0.4 min in the group 1, and 56.7 ± 0.5 min in the group 2. At hospital stage all patients with traumatic shock were immediately transferred to the surgery room for performing emergent surgical care, where anti-shock therapy (which was initiated at prehospital stage) was continued and the diagnostic examinations were realized (X-ray examination of the chest, abdominal cavity, the cranium, pelvic bones, injured extremities; abdominal ultrasonic examination, laparoscopy, biochemical data, hemostasis parameters, total blood and urine analysis, blood group and Rh factor determination). Surgical treatment was realized with total intravenous anesthesia (fentanyl + ketamine + seduxen) with muscle relaxants in conditions of ALV with air-oxygen mixture. Surgical treatment was performed for all patients (n = 50, 100 %). Its volume depended on location and severity of an injury. The patients of the first group received treatment after 8.6 ± 1.1 minutes, the patients of the second group – after 8.8 ± 1.3 minutes. After that the patients were admitted to the intensive care unit for infusion-transfusion, antibacterial respiratory and symptomatic therapy. Inotropic and vascular support with use of dopamine was performed for the patients of the first group within 48.1 ± 2.4 hours, for the patients of the second group – 47.3 ± 2.1 hours. After admission to ICU the parameters of cardiovascular system were estimated (stroke volume (SV, ml), cardiac output (CO, l), total peripheral vascular resistance (TPVR, dyn×s×cm^-5), total blood volume (TBV, l), volume of circulating erythrocytes (VCE, l)) by means of non-invasive tetrapolar rheography and impedancemetry. The hemodynamic monitor ICARD (Chirana, Slovakia) was used for estimation of systolic (SAP, mm Hg), diastolic (DAP, mm Hg) and mean arterial pressure (MAP, mm Hg), and heart rate (HR, min^-1). The standardized methods were used for estimating hematocrit (%), levels of red blood cells (10¹²/l), hemoglobin (g/l), APTT (sec.), lactate (mmol/l), endothelin-1 (fmol/l) and von Willebrand factor (%) in the serum of venous blood. The examinations were made upon admission to the ICU, as well as 12 and 24 hours after it. For morphological study the biopsy samples were taken from the injured and resected omentum. The samples were fixed in 10 % neutral formaline and after entry into spirits they were placed into the paraffin blocks. The slices of 3-5 mcm were stained with haematoxylin and eosin according to van Gison and Weyhert. Histologic and histochemical estimation of the samples was made. The systemic statistical analysis of clinical, laboratory and instrumental examinations was performed by several stages with use of the analysis of variance and Statistica 6 software (StatSoft, USA, 1999) with obligatory determination of statistical significance (p < 0.05) [3]. The degree of connection between the variables was estimated with Pearson’s parametric correlation analysis with obligatory estimation of reliability, which was confirmed with p < 0.05 [3]. The study was conducted on the basis of the approval from the bioethical committee of Kabanov City Clinical Hospital #1 and City Clinical Hospital of Emergency medical Aid #1. The study corresponds to the ethical standards corresponding to Helsinki Declaration – The Ethical Principles for Medical Research with Human Subjects 2000 and the Rules for Clinical Practice in Russian Federation confirmed by The Order of Health Ministry of Russia from19.06.2005, #266.              

RESULTS

Despite of prehospital and hospital (intrasurgical) anti-shock therapy, the state of the patients in the groups 1 and 2 was extremely severe after admission to the ICU. It was confirmed by volemic status, systemic hemodynamics, hemostasis, hematocrit, count of red blood cells and hemoglobin level (tables 1, 2). After admission the hemodynamic type of blood circulation was registered in all patients. It was confirmed by MBV, which was supported by means of the compensatory mechanisms – intense tachycardia and significant increasing TPVR (tables 1, 2). The cause of low cardiac output was hypovolemia conditioned by massive acute blood loss and development of endothelial insufficiency, which was confirmed by the parameters of vascular endothelial dysfunction (tables 1, 2). The intensity of circulatory disorders was supported by levels of lactate and diuresis (tables 1, 2). Besides, the intense disorders of hemostasis system were conditioned by hypovolemia, endothelial dysfunction, metabolic acidosis and deficiency of clotting factors at the background of acute massive blood loss. It was supported by APTT (tables 1, 2). There were no statistically significant differences between the values of central hemodynamics, hemostasis, vascular endothelial function, hematologic and biochemical parameters (tables 1, 2) in the patients of the groups 1 and 2 after admission to the ICU. It means that the values were equivalent. Infusion-transfusion therapy as a part of intensive care made almost the same effective influence on hemostasis parameters, functions of vascular endothelium, volemic and hemodynamic status in the patients of both groups (tables 1, 2) during the whole period of follow-up. Actually, the realized comparative intergroup analysis identified the positive statistically significant dynamics in the patients of the groups 1, 2: systolic and mean arterial pressure, SV, CO, TPVR, TBV, VCP, VCE, diuresis, lactate, APTT, endothelin-1, von Willebrand factor, hematocrit, red blood cells and hemoglobin (the tables 1, 2). At the same time, the intergroup analysis (the tables 1, 2) did not show any reliable differences in the above-mentioned parameters in the patients of the groups 1 and 2 during the whole period of observation. It testified almost equivalent efficiency of realized infusion-transfusion therapy regarding to correction of hemocirculatory and hemostasiological disorders and endothelial dysfunction.  

Table 2
Dynamics of parameters of systemic hemodynamics, function of vascular endothelium, diuresis, hematologic and biochemical indices in patients with traumatic shock of group II,  Me (QL; QA) – median (higher and lower quartiles)

                        

 DISCUSSION

It is certainly that absolute hypovolemia is a leading pathogenetic factor, which defines severity of general state and characteristics of hemodynamic disorders in patients with traumatic shock of degree 3 [1]. It induced development of circulatory, hemostasiological insufficiency and also endothelial insufficiency, which was confirmed by increased plasma levels of endothelin-1 and von Willebrand factor (tables 1, 2). Besides, dysfunction of vascular endothelium was confirmed by the data of morphologic examinations of the vessels in the omentum (Figures 1, 2). The morphologic examinations found the similar changes: red blood cell aggregation, clot formation and stasis. The existing morphological picture was common for evident disorders of circulation, hemostasis, transcapillary exchange and endothelial insufficiency [4] in conditions of critical state.

Figure 1 The patient M. (group I). Sludging of red blood cells and clotting. Adiemorrhysis.Hematoxylin and eosine staining according to van Gieson and Weigert.Magnification x200.	Figure 2 The patient S. (group II). Sludging of red blood cells and clotting.Adiemorrhysis.Hematoxylin and eosine staining according to van Gieson and Weigert. Magnification x 200.

In its turn, increased levels of von Willebrand factor and its activity were not only an accelerator of platelet adhesion to the subendothelium through binding of the superficial receptor of platelets Ib, but also stimulation of platelet-thrombocytic interactions through association of glycoprotein IIb/IIIa [5], and also the indicator of endothelial injury in critically ill patients [6]. Platelet adhesion is mostly intensive in the vessels of macro- and microcirculation that defines development of disorders in hemostasis system and non-respiratory pulmonary function [4].

The high serum levels of endothelin-1 in the patients with severe traumatic shock were directly conditioned by a mechanic injury and acute cardiovascular insufficiency as result of blood loss, because the main activators of endothelin-1 synthesis are activation of sympathoadrenal system, ischemia and hypoxia [5]. These factors activate mRNA transcription, synthesis of endothelin precursors, their turning into endothelin-1 and its secretion within several minutes [6]. At the same time, catecholamines, angiotensin II, high density lipoproteins, growth factors, thrombin, thromboxane À₂, Ñà²⁺, ionophore and phorbol ester activate intracellular mechanisms for endothelin-1 synthesis without participation with plasmalemma receptors through direct influence on protein kinase C and Ñà²⁺ release from sarcoplasmic reticulum [5]. Moreover, endothelin-1 creates not only immediate constrictor influence on the vascular wall [6] (that was confirmed by high TPVR [tables 1, 2]), but also causes anti-natriuretic action [4]. Besides, endothelin-1 worsens the course and induces development of acute cardiac insufficiency through the direct toxic influence on the cardiac muscle, causes pulmonary hypertension and creates prothrombogenic activity [6, 7].

Therefore, the conducted correlation analysis identified some reliable relationships between endothelin-1 and von Willebrand factor in the patients of the groups 1 and 2 (r = -0.88, ð < 0.02; r = -0.84, ð < 0.02). It was related to the fact that traumatic shock (which is characterized with injuries, systemic hypoperfusion, tissue-organ hypoxia and release of inflammatory mediators) conditions severe metabolic disorders and favors development and sustention of endothelial dysfunction [8]. Besides, significant disorders in function and structure of the endothelium causes not only rapid activation of renin-angiotensin system, that gives the properties of an traumatic agent in regard to different organs and systems [6], but it also causes stimulating the processes of oxidant stress, which conditions development of unprogrammed cell apoptosis [5].

Moreover, the correlation analysis identified the statistically significant correlation relationships between SV and endothelin-1 (r = -0.45, ð < 0.05; r = -0.41, ð < 0.05), total blood volume and endothelin-1 (r = -0.57, ð < 0.04; r = -0.49, ð < 0.05), TBV and von Willebrand factor (r = -0.68, ð < 0.03; r = -0.58, ð < 0.04), TPVR and endothelin-1 (r = 0.61, ð < 0.04; r = 0.6, ð < 0.04), which testified the relationship between vascular endothelial dysfunction and the parameters of cardiovascular system. It is noteworthy that the relationships between TBV and the parameters reflecting endothelial dysfunction indirectly supposed the presence of relative hypovolemia in the patients with traumatic shock of degree 3. In its turn, it allowed bearing the evidence of the fact that the strategy and the tactics of infusion-transfusion therapy for traumatic shock of degree 3 should be based on the point that hypovolemia has the double component – absolute and relative genesis.

 

CONCLUSION:

1. Already after their admission to ICU the patients with traumatic shock of third degree demonstrate presence of endothelial dysfunction, which is confirmed not only by increased plasma levels of endothelin-1 and von Willebrand factor, but also by the morphological data.
2. The patients with traumatic shock of 3rd degree show the reliable relationship between the parameters of vascular endothelial dysfunction and TBV.
3. Traumatic shock of 3rd degree is both hypovolemic and redistributive according to its genesis.
4. The strategy and tactics of infusion-transfusion therapy for patients with traumatic shock of 3rd degree are to be realized with consideration of this important feature at prehospital and hospital stages.