POSTRESUSCITATION INSUFFICIENCY OF BLOOD CIRCULATION AND STATE OF ERYTHRON AFTER CLINICAL DEATH AS RESULT OF CHEST COMPRESSION
Kemerovo State Medical Academy,
Kemerovo, Russia
The results of our previous studies showed that regardless of duration and severity of dying the postresuscitation changes of systemic and regionary hemodynamics are associated with general consistent phasic characteristics with primary increase and following weakening of hemoperfusion intensity [1]. It was found that in conditions of posthypoxic disorder of vascular autoregulation [2] the time course of cerebral perfusion depends on intensity and duration of redistribution of cardiac output in favor of supradiaphragmatic segment of the body. Such changes determine postresuscitation mortality, which is at the highest level after elimination of clinical death as result of blood loss with simultaneous carbon monoxide poisoning [3]. At the same time, after technogenic disasters (underground explosions, undermine goave, road traffic accidents) disorder of life activity is associated with damaging action of another factor – chest compression. Therefore, it is important to ascertain the mechanisms of reperfusion disorders in early postresuscitation period of clinical death after chest compression.
Objective – to define some general regularities and pathogenetic significance of early postresuscitation changes in hemodynamics and erythron system after completion of clinical death as result of chest compression.
MATERIALS AND METHODS
The study included 61 cats and 280 rats under nembutal anesthesia (40-45 mg/kg, intraperitoneally) in concordance with the requirements of the orders #1179 by Ministry of Health of USSR, 10.10.1983, #267 by Ministry of Health of USSR, 19.06.2003, the Rules for Research with Experimental Animals, the Principles of European Convention (Strasbourg, 1986) and Helsinki Declaration of World Medical Association about Humane Treatment with Animals (1996).
Clinical death as result of chest compression (cats, n = 18; rats, n = 252) was modeled through chest compression with the cuff with air boost under manometric control until arrest of breathing and bleeding achievement. The pressure range in the cuff was 90-100 mm Hg. Hemodynamic control was realized according to systemic arterial pressure. From the first seconds of chest compression the sharp falling of systemic pressure happened, and after 10-15 sec its value approached the level of 7-10 mm Hg. After 2-2.5 min the animals did not show any attempts of independent breathing; the pupils extended, and the electrocardiogram was as the direct line. The animals were 5 minutes in state of clinical death. The researchers of the pathophysiology chair of Kemerovo State Medical Academy developed and experimentally tested the model (the patent of invention # 94028802/14 (028701), June, 25, 1996) in rats [4]. The animals were resuscitated by means of artificial lung ventilation and indirect heart massage. The resuscitation measures did not include stimulating agents, because of influence on hemodynamics and natural course of restorative processes.
In the basic state and during 3 hours of early postresuscitation period the main parameters of systemic and cerebral hemodynamics were estimated in the cats, and the main parameters of erythron in the rats. Cardiac output (CO, ml/kg/min) was estimated with thermodilution method [5]. At the same time, blood circulation (local thermal dilution) was registered in the posterior vena cava – subdiaphragmatic fraction (SubDF, ml/kg/min). Also supradiaphragmatic fraction (SupraDF) was calculated: SupraDF = CO – SubDF. Circulation centralization ratio (CCR, c.u.) was calculated [6]. Monitoring of arterial pressure (AP, mm Hg), heart rate (HR, beats per minute) and central venous pressure (CVP, mm H2O) was realized with the automatic diagnostic system Heart Scope-2 (Aqua, Moscow). Systolic volume (SV, ml/kg) and total peripheral resistance (TPR, dyn×s×cm-5) were calculated. Cerebral perfusion (CP) in cortex of frontal lobe (CP-F, ml/100g/min) and parietal lobe (CP-P, ml/100g/min) was estimated with hydrogen clearance [7]. Also estimation included hemoglobin level (hemoglobin-cyanide method), red blood cells count (in the counting chamber), reticulocytes (supravital staining), mean diameter of erythrocyte, hematocrit (centrifugation), mean contents and mean concentration of hemoglobin in one red blood cell. The mathematic indices (mean volume, thickness of red blood cells, sphericity index) were calculated according to I. Todorov (1968). Degrees of erythrocyte damage were estimated with level of free plasma hemoglobin with use of hemoglobin-cyanide method with the modification by L.D. Levin et al. (1993). The method by I.I. Hitelson and I.A. Terskov (1959) (the modification by I.A. Holend, 1992) was used for estimation of acid resistance of erythrocyte membranes. The level of free radical oxidation in cells was estimated indirectly by means of contents of sulfhydryl groups (ferricyanide method) and lipoprotein complex (Sudan black) in red blood cells of peripheral blood. Topography of erythrocyte surface was estimated with scanning electronic microscopy. Puncture samples of bone marrow were used for estimation of general amount of myelocariocytes (E.D. Goldberg, 1992), erythroblastic elements, leukoerythroblastic ratio, index of erythronormoblast maturation, partial erythroblastogram, actual mitotic index of cells of erythroid nucleus.
During the experiments (with cats and rats) we estimated the characteristics of early restoration of vital activity by means of the common tests. The value of neurologic deficiency in the cats was estimated with the modified 100-point scale by M.M. Todd et al. (Evtushenko A.Ya., 1989). As for the rats, we used the point system by S.P. Lysenkov and V.G. Korpachev (1982). The survival was assessed within 10 days after resuscitation.
The comparative analysis of postresuscitation changes in systemic and cerebral hemodynamics in cats was conducted with the series of experiments including clinical death after acute blood loss (n = 43). Postresuscitation state of erythron was compared to the data from the intact rats (n = 28).
The statistical analysis and calculations were conducted with Statistica 6.0 software [8]. For quantitative signs we calculated group values of summary statistics – mean arithmetic (M) and standard deviation (m). In case of normal distribution we used Student’s test. In case of absent normal distribution we used Mann-Whitney and Wilcoxon tests. χ2 test was used for intergroup comparison of qualitative values. Differences with p ≤ 0.05 were statistically significant. Correlation analysis was conducted with Origin Plot with calculation of Pearson’s coefficient of lineal correlation. The charts and diagrams were made with Microsoft Excel 2007.
RESULTS AND DISCUSSION
The period of dying from initiation of chest compression to arresting attempts of independent breathing and lost response of pupils to the light was 2.1 ± 0.1 min on average. Blood loss resulted in 3-fold increase of dying period (6.0 ± 0.37 min). The total period of hypoxia and ischemia, including time of chest compression and clinical death, was 7.1 ± 0.1 min. This period was 11.0 ± 0.22 min for blood loss including time of blood loss and clinical death. There were no statistically significant differences in restoration of vital activity (the first inhale, rhythmical breathing, pupillary response, lid reflex, pain sensitivity) in the animals with chest compression and acute blood loss.
The changes of cardiac output and cerebral perfusion were similar according to characteristics and direction in postresuscitation period of clinical death after chest compression. The same situation was in the cats with acute blood loss (table 1). Increase in efficiency of heart activity was moderate during the first 5 minutes and was associated with systolic volume in conditions of less intense increase in CVP in comparison with the animals after blood loss. On the minutes 3 and 5 systolic volume was 35 % and 14 % lower than in the animals after clinical death as result of acute single-step blood loss. On the minute 10 CO and systolic volume were higher than the basic values by contrast to the comparison group. Also CO increased because of total peripheral resistance (TPR) (within one hour before survival); its decrease was less intense within the first 10 min in comparison with the animals with acute blood loss. AP increased within 5 min of recirculation because of decreasing TPR and high activity of the heart. In the same time period cerebral hyperperfusion developed in both examined regions of the brain. It persisted within 10 min after survival. The same situation was in the comparison group, although increase in blood flow was two times lower. Therefore, cerebral hyperperfusion developed in conditions of increased cardiac output and arterial hypertension.
Table 1
| Cerebral perfusion and distribution of cardiac output in early postresuscitation period after clinical death as result of blood loss and chest compression (Ì ± m) |
| Note: * – Ð < 0.05 in comparison with the basic data; ** – P < 0.05 between the compared groups of the animals. SSH – death after acute single-step hemorrhage; , n = 43; CC – death after chest compression, n = 18. | ||||||||||||||||||
| CP-F – cerebral perfusion in frontal cortex; CP-P – cerebral perfusion in parietal lobe cortex; CO – cardiac output; SupraDF – supradiaphragmatic fraction of cardiac output; SubDF – subdiaphragmatic fraction of cardiac output; CCC – circulation centralization coefficient; TPR – total peripheral resistance. | ||||||||||||||||||
On 15th minute of survival CO decreased to the basic values and persisted at this level up to the end of the first hour by means of increased systolic volume. Arterial hypotension appeared as result of decreasing CO in conditions of low TPR. Bradycardia accompanied changes in CO and cerebral perfusion up to the end of the first hour of revival. In the end of the second hour CO decreased below the basic level, and, at the same time, cerebral perfusion decreased, and TPR and HR increased. Therefore, in the cats, which were resuscitated after clinical death as result of chest compression, the signs of cerebral hypoperfusion appeared one hour later than in the cats in the comparison group. The signs of cerebral hypoperfusion in both lobes appeared on 3rd hour of revival, when AP was restored almost to the basic level by means of intense increasing TPR (by 45 % on average). However decrease in cerebral perfusion in both lobes was less intense than in the comparison group. The value of blood loss was 71 %, whereas in the animals with blood loss – 58 % of the basic level.
The correlation analysis showed the lineal relationship (r = 0.98) between tissue perfusion in cortex of frontal and parietal lobes within 3 hours of early postresuscitation period. The changes of cerebral perfusion are tightly associated with restoration of cardiac output (r = 0.97).
Further analysis of hemodynamics showed that postresuscitation period of clinical death after chest compression had demonstrated the same direction in distribution of cardiac output as in the comparison group. At the same time, blood circulation decentralization with decreasing volumetric rate of perfusion in the supradiaphragmatic segment of the body developed later than in the comparison group. Therefore, as well as in the comparison group, moderate postresuscitation cerebral hyperperfusion was provided by sufficient increase in blood flow in the supradiaphragmatic segment of the body. Its maximal increase by 3 minutes was 192.0 ±12.3 % from the basic level (Fig. 1). However, postdiaphragmatic fraction of cardiac output did not increase and became below the basic level on the second hour of revival, as well as in the animals after clinical death as result of blood loss. Therefore, cardiac output redistributed in favor of the supradiaphragmatic segment, which indicated the increased coefficient of blood circulation centralization (BCC). Intensity of blood circulation centralization was the same as in the comparison group. Within the first hour circulation centralization persisted in the supradiaphragmatic segment of the body. It provided the same level of cerebral perfusion as the basic one. Within the second hour of revival supradiaphragmatic fraction of cardiac output was lower than the basic level. Circulation centralization disappeared and cerebral hypoperfusion developed. In the animals with clinical death after blood loss circulation decentralization and development of hypoperfusion in the supradiaphragmatic segment of the body (as well as cerebral hypoperfusion) appeared within the first hour of revival. The correlation analysis showed the direct lineal relationship between changes of cerebral perfusion in both lobes and time course of SupraDF (r = 0.98).
Figure
The postresuscitation changes in supradiaphragmatic fraction (SupraDF) of cardiac output in the animals after clinical death as result of blood loss and chest compression. The light markers – statistically significant differences in comparison with the basic data; * – statistically significant differences between the groups.
The table 2 includes the results of resuscitation for the cats after clinical death as result of chest compression. The postresuscitation mortality was 17 % in this group as compared with 33 % in the animals with clinical death after blood loss. At the same time, among 18 cats with five minutes of clinical death as result of chest compression, 15 cats survived and were observed during 15 days, and 3 cats were lost.
| Table 2 | |||||||||||||||
| The results of resuscitation and life expectancy of the animals (cats) in postresuscitation period after clinical death as result of acute blood loss and chest compression | |||||||||||||||
| Note: SSH – death after single-step hemorrhage; CC – death after chest compression; * – P ≤ 0.05 according to χ2 test with SH group. |
Apparent neurologic deficiency was absent in all survived cats on 10th day of observation in contrast to the survived animals with clinical death after blood loss. In this group neurologic deficiency was absent only in 13 cats, and it was 12.1 ± 0.6 points in 16 cats.
Intense cerebral hyperperfusion with significant increase in supradiaphragmatic fraction of CO was in 3 lost animals in contrast to the survived animals. It was during 26.0 ± 2.1 min after revival at maximal increase in volumetric blood flow in brain cortex and in the supradiaphragmatic segment of the body (2.2 ± 0.05 times higher as compared to the basic values). Duration of cerebral hyperperfusion and increasing supraDF was moderate in 15 survived animals. It was 11.3 ± 0.8 min, with maximal increase of 1.5 ± 0.05 times in comparison with the basic values.
Therefore, in the animals with clinical death from chest compression the postresuscitation mortality reduced almost two times. It happened as result of elimination of less severe and continuous terminal state. Exclusion of blood loss from the process of dying, and exclusion of reinfusion during revival removed the number of the injuring factors, which additionally burden the course of terminal state and exhaust the compensatory mechanisms [9-13].
Absent blood loss (resulting in the situation when circulation integrates deposited red blood cells and interstitial fluid) and absent intraarterial inflating of the discharged blood determined less intense increase in TPR and CVP after completion of clinical death after chest compression. Therefore, recirculation was accompanied by less intense diastolic filling of the heart resulting in less intense increase in systolic volume and cardiac output than in the animals after clinical death as result of blood loss. In conditions of the response of early postresuscitation centralization of blood circulation the redistribution of moderately increased CO in favor of the supradiaphragmatic segment provided adaptive 1.5-fold increase in cerebral perfusion, which took place during 10 minutes after revival.
The following decrease in cardiac output with development of hypoperfusion on the second hour of revival happened after discharge of venous bed. As result, CVP stabilized at the basic level on 3rd hour of the study. It is possible that in the animals with clinical death after chest compression development of systemic hyperperfusion of moderate intensity and duration limits excessive extravasation of fluid and its accumulation in the interstitium and cellular sector [14], and it slows down development of hypoperfusion.
The appropriate level of supradiaphragmatic perfusion was provided by persistent (in the first hour of revival) basic level of cardiac output, and the response of early postresuscitation centralization of circulation provided appropriate level of supradiaphragmatic blood flow, which delayed development of cerebral hypoperfusion in conditions of disorder of autoregulation of tone of cerebral vessels. The evident signs of autoregulation appeared only in the end of the second hour of revival.
The postresuscitation changes in erythron system were characterized by development of hemolytic anemia [15, 16] that was confirmed by increasing amount of free hemoglobin from 10th minute after revival: 0.5 ± 0.3 g/l in comparison with the basic data – 0.35 ± 0.02 g/l (p ≤ 0.05). The changes in erythron system were accompanied by development of hypoxia of mixed genesis; the hematic component supplemented circulatory disorders. One of the main pathogenetic factors of hemolysis of red blood cells was hypoxia as result of dying and clinical death. Oxygen deficiency resulted in the number of metabolic disorders including activation of processes of lipid peroxile oxidation [17-19]. As result, the levels of lipoproteins and sulfhydryl groups of red blood cells decreased that resulted in altering permeability of erythrocyte membrane, potassium loss in the cells, accumulation of natrium and calcium ions. Osmotic pressure increased in red blood cells, and their shape (spherocytes, domed cells etc.) and deformation capacity changed. Decreasing contents of sulfhydryl groups in red blood cells indicates decreasing peroxile resistance.
In postresuscitation period fulfillment of red blood cells was by means of activation of erythropoiesis (table 3): increasing amount of nucleated erythroid cells in the bone marrow, increasing amount of reticulocytes and polychromatophils in peripheral blood. Within the first 24 hours the number of erythroid precursors in bone marrow and reticulocytes in the blood increased by 20 % on average in comparison with the controls (p > 0.05). Such progressive increase persisted up to 5th day of the experimental study (137 % of the normal level). On the day 14 after revival the animals in the experimental and control groups did not show any differences in the number of erythroid cells in bone marrow, level of hemoglobin, amount of red blood cells and reticulocytes.
Table 3
| The dynamic changes in bone marrow compartment of erythron in rats in postresuscitation period (Ì ± m) | ||||||||||
| Note: * - Ð < 0.05 in comparison with the basic data. The amount of animals in each group, n = 6. | |||||||
Therefore, time of dying during chest compression was significantly lower than in blood loss. It gives positive influence on the course of restorative processes after recirculation. The postresuscitation changes in systemic and cerebral hemodynamics show the same features than in the animals with clinical death after blood loss. Moreover, moderate increase in cardiac output (sufficient for adaptive redistribution in favor of the supradiaphragmatic segment) provides the level of cerebral perfusion favorable for neurologic recovery and delays reduction of blood flow. During recirculation period the identified disorders of erythron system indicate development of anemia of hemolytic origin. Restoration of normal amount of red blood cells takes place within the first two weeks of postresuscitation period as result of activation of erythropoiesis. On day 14 the general amount of erythroid cells of bone marrow restores completely, the levels of red blood cells, reticulocytes and hemoglobin normalize.
The results of the study should be considered for conduction of intensive care and after completion of terminal state as result of chest compression (underground explosives, undermine goave, road traffic accidents). Ultimately, timely postresuscitation correction of hemodynamics and morphofunctional state of erythron is oriented to restoration and normalizing gas transport function that is one of the determinant factors of resuscitation outcomes.
CONCLUSION
1. In postresuscitation period of chest compression the hemodynamic changes were characterized by staged pattern, and the disorders in erythron system were manifested in view of hemolytic anemia. System hyperperfusion of moderate intensity and duration developed. The hypoperfusion stage appeared by the second hour that was significantly later than in the animals dying from blood loss.
2. In early postresuscitation period the changes of cerebral perfusion were conditioned by time course of cardiac output and features of its distribution. Development of moderate cerebral hyperperfusion was associated with appropriate increase in cardiac output and intensity of its redistribution into the supradiaphragmatic segment of the body. Delayed development of cerebral hypoperfusion related to late decrease in cardiac output and blood circulation decentralization.
3. Development of primarily moderate hyperperfusion and formation of late hypoperfusion of the brain were accompanied by quite fast correction of consequences of ischemia; it was confirmed by improving neurologic recovery and increasing survival in the animals with clinical death after chest compression.
4. In the lost animals restoration of vital activity after completion of clinical death as result of chest compression happened in conditions of development of extremely intense systemic and cerebral hyperperfusion.