- Email: [email protected]
Microcirculation and hemorrhagic shock
Microcirculation and Hemorrhagic Shock HENGO HALJAMiiE,
MD, PhD
Blood loss is followed by compensatory cardiovascular readjustments that favor the maintenance of blood flow to central vital organs rather than to peripheral tissues. The microcirculatory changes that occur in skeletal muscle in shock states are of major importance, since skeletal muscle is not only the largest cell mass of the body but also one of the major target organs for neurohumorally mediated compensatory vascular readjustments. lntravital microscopic studies show that the microvascular blood flow in skeletal muscle is intermittent in the early posthemorrhagic period. This probably reflects an interplay between OLadrenergic vasoconsfffctor and p-adrenergic vasodilator activities, which serves to enhance a compensatory mobilization of interstitial fluid into the vascular compartment. A period of complete microcirculatory arrest is then seen, followed by reperfusion engaging only 30% to 50% of the capillaries that were seen perfused in resting skeletal muscle. The microvascular blood flow in shock is further characterized by a pronounced heterogeneity in distribution. Many capillaries remain constantly unperfused, while in others a slow, intermittent blood flow is seen. Obstruction of many capillaries by white blood cells and their slow passage through other capillaries seem to be the main reasons for the maldistribution of capillary blood flow in shock. Red blood cell aggregates obstructing capillary blood flow are not seen. The heterogeneous tissue perfusion is accompanied by local variations in cellular hypoxic injury, as is evidenced by multifocal measurements of tissue oxygen tension and by cellular transmembrane potential registrations. The blood-tissue exchange of substances is impaired because of the reduction in capillary surface area and changes within the interstitial compartment. Therefore, shock-induced metabolic changes in skeletal muscle remain mainly local and are not at all, or only to a limited extent, reflected in central blood. Following volume treatment the heterogeneity in capillary perfusion persists, since white blood cells often remain trapped in capillaries and obstruct blood flow. Treatment of shock with hypertonic solutions, ATP-MgC12. or steroids could be beneficial by enhancing the mobilization of trapped white blood cells. Microcirculatory disturbances and their local metabolic consequences in skeletal muscle of critically ill patients can be monitored in the intensive care unit by the use of microelectrodes for contin-
From the Department Gbteborg, Sweden.
of Anesthesia,
Sahlgren’s
Hospital,
Presented at the First International Conference on the Basic Mechanisms and Clinical Management of Shock, Merrillville, Indiana, September 10-l 1, 1982, and accepted for publication at that time. Address reprint requests to Dr. Haljamae: Department of Anesthesia, Sahlgren’s Hospital, S-413 45 Gdteborg, Sweden, Key Words: Blood-tissue exchange, hemorrhagic shock, leukocytes, shock treatment, skeletal muscle metabolism, skeletal muscle microcirculation, tissue pH, tissue PO,, transmembrane potential, vital microscopy. 100
uous or intermittent measurements of tissue gas tensions (PO*, PcuJ, tissue pli, and tissue potassium levels.
Hemorrhagic shock may be characterized as a failure of the circulation to meet the metabolic demands of the body tissues. The basic defect is a disturbance in the distribution of blood flow within the microvasculature, resulting in a changed cellular supply-to-demand ratio of oxygen. The distribution of blood flow to individual vascular beds is determined by neurohumoral factors and by local autoregulatory mechanisms. The compensatory cardiovascular readjustments following blood loss, however, favor the maintenance of blood flow to central vital organs at the expense of blood flow peripheral tissues. The blood flow and oxygen supply to the brain are thus favored during hypovolemia.’ The oxygen supply to the liver is considerably reduced,1-3 but less than that to peripheral tissues such as skin and skeletal muscle,4 which are the major target organs for neurohumorally mediated compensatory vascular readjustments. The metabolic and cellular functional disturbances that occur in hypoperfused tissues following severe hemorrhage have been studied in detail.‘-I5 The knowledge of the underlying microcirculatory disturbances is, however, still rather limited, since there is a lack of representative high-resolution intravital microscopic studies on cellular tissues. Most of the available information on circulatory changes within the terminal vascular bed during shock is thus based on studies of connective tissues such as the mesentery, the hamster cheek pouch, or the human conjunctivae, which are all easy to study in the vital microscope. General information on structural and functional characteristics of the microvasculature can be obtained from such studies, but the changes observed during shock in these relatively acellular tissues may not be representative for those occurring in cellular tissues, which have much higher basal metabolic demands. Technical and preparative improvements during recent years have, however, made cellular tissues such as skeletal muscle available for high-resolution intravital microscopic studies. 16-22The importance of absolute control of the external environment for the representativity of the exposed tissue, especially during studies of shock-induced microcirculatory changes, has also been recognized.21-23 The present survey will be mainly confined to the interplay between microcirculatory, interstitial, and cellular metabolic changes in
HALJAMAE
skeletal muscle during hemorrhagic lowing treatment.
shock and fol-
DISTRIBUTION OF BLOOD FLOW WITHIN THE MICROVASCULATURE DURING SHOCK The capillaries in skeletal muscle are not continuously perfused under resting conditions. There is an intermittent blood flow through groups of capillaries supplied by the same terminal arterioles.22~23The cyclic on-and-off type of flow probably reflects a coupling between blood flow distribution and local metabolic needs within the tissue,24,25 and it involves 90% of all the capillaries in skeletal muscle. It is also accompanied by cyclic variations (frequency 0.5 to 2 per minute) in local tissue oxygen tension26 and in hydrostatic pressure within the capillaries.27 Blood loss results in intense vasoconstriction in the arteries and arterioles of skeletal muscle, leading to complete circulatory standstill within the tissue.22.23 This initial phase of vasoconstriction is short. Usually, intermittent tissue perfusion reappears within a minute, and at the same time variations in vasoconstriction of pre- as well as postcapillary vessels are seen. This intermittent tissue flow may reflect an interplay between a-adrenergic vasoconstrictor and padrenergic vasodilator activities. P-Adrenergic vascular mechanisms seem to be of importance for the early compensatory mobilization of interstitial tissue fluid into the vascular compartment after blood 10ss.*~**~The P-adrenergic stimulation of precapillary vessels will increase the capillary surface area available for fluid absorption, and that of postcapillary vessels will lower capillary hydrostatic pressure by changing the pre- to postcapillary resistance ratio. Both these factors govern transcapillary refill. This initial “compensatory phase” is soon followed by a new period of intense vasoconstriction. Complete microcirculatory arrest ensues and may last for 5 to 20 minutes. When tissue perfusion reappears, the on-and-off type of flow, characteristic for resting skeletal muscle, has usually disappeared. The number of perfused capillaries has decreased by 50% to 70% compared with the prehemorrhagic resting condition. The distribution of the flow within skeletal muscle during shock is very heterogeneous, and three levels of “patchiness” between flow and no-flow have been distinguished. **Y*~ Occasionally, transverse arterioles remain intensely constricted, leaving no blood flow into a whole transverse muscle segment. Unperfused terminal arterioles are commonly seen, but their supply areas are usually not completely deprived of blood flow, since some perfusion is obtained from adjacent arterioles via capillary interconnections. The most pronounced heterogeneity in tissue perfusion, however, is seen within the capillary bed. Some cap-
n MICROCIRCULATION
illaries remain constantly perfused, with flow rates exceeding those seen during resting conditions. Other capillaries are intermittently perfused at irregular intervals. The passage of white blood cells (WBCs), which are much stiffer than red blood cells (RBCs) and also larger, through the capillaries seems to be the major reason for this variability in blood flo~.**~*~**~~~~~~~ Many capillaries remain constantly unperfused, and there is evidence that this may be due to WBC plugging. Quantitative evaluations of changes in capillary blood flow velocities during shock have been very difficult to perform because of this extreme variability within, as well as between, different capillaries. However, the volume flow through the tissue seems to be reduced by 50 to 70% compared with that seen in resting skeletal muscle. In the postcapillary vessels, the blood flow in shock is sluggish, and increasing numbers of WBCs are seen to adhere to venular walls. In some intravital microscopic studies, it has been suggested that such a tilling of venules with blood corpuscles could obstruct blood flow and induce tissue edema.31*32 In other studies, however, no significant interference with blood flow, not even during late shock, has been found.22,23
BLOOD CELL RHEOLOGY AND HETEROGENEOUS TISSUE PERFUSION DURING SHOCK White
Blood
Cells
It has been known for many years that WBCs may temporarily obstruct blood flow during their passage through narrow capillaries even under normal pressure/33 In recent studies by Bagge and co-workers,33-35 the rheology of WBCs has been characterized in detail. It is now becoming more and more obvious that WBCs, by affecting the distribution of the blood flow within the capillary bed, may play a major role in the pathophysiology of shock. 12.22,23*27~30~31,36*37 White blood cells are spherical, and the average diameter, for polymorphonuclear granulocytes, is about 8 to 9 pm, and for lymphocytes, about 6 pm in circulating blood.32 Internal capillary diameters in skeletal muscle vary between 2.8 and 8 Frn, the average being 5.3 Fm.38 The arteriolar end of the capillary is usually narrower (-4.5 km) than the venular end (-5.6 Fm). Thus, WBCs have to become considerably deformed when they enter most capillaries, and their shape is approximately that of an elongated cylinder during the passage through narrow capillaries. In vitro, intravital, and electron microscopic studies of WBC behavior in capillaries 34 have shown that WBCs are viscoelastic and, furthermore, that they become deformed at constant volume during their passage through capillaries. Since undeformed WBCs have a membrane reserve (up to 70%), large deformations are 101
AMERICAN
JOURNAL
OF EMERGENCY
MEDICINE
n Volume 2, Number 1
FIGURE 1. In vitro view of white blood cell (w) temporarily trapped in a capillary at a narrow section caused by the bulging nucleus of an endothelial cell (e) and the nucleus of a pericyte (p). The cylindrical shape of the white blood cell after adjustment to the capillary dimensions is clearly seen. Some plasma seems to pass beyond the white blood cell so that red blood cells are seen to accumulate behind the white blood cell and form a temporary rouleaux formation (r). Arrow denotes flow direction. (Courtesy of Dr. Bagge, University of Goteborg. Sweden.)
possible at constant volume without stretching of the cell membrane. The adaptation of WBCs to the narrow arteriolar orifices of capillaries seems critical even under resting blood flow conditions. They are often seen trapped at the entrance of capillaries, and the transformation from spheres to cylinders may require a few seconds or sometimes even some minutes.33.34 They are also halted at narrow sections along the capillary. Figure 1 shows a trapped WBC in a capillary at a narrowing caused by the bulging nucleus of an endothelial cell and an adjacent pericyte. The figure shows well the appearance of a deformed WBC when it has adjusted to the dimensions of the capillary. It has not been possible to establish whether a trapped WBC can sIowly move out of such a wedge position by active movements. The deformation of WBCs in the capillaries requires energy. The major driving force is probably the hydrostatic pressure within the capillary, which during resting conditions is about 30 mm Hg at the arteriolar end and 8 to 10 mm Hg lower at the venular end.27s39 Blood viscosity, and the surface characteristics and dimension of WBCs as well as of capillaries, are all factors important to the amount of energy that is needed for the capillary passage of the cells. At high flow rates, the WBCs seem to be mainly carried in the axial blood stream in the arterioles and are therefore possibly shunted through the microvasculature via large capillaries, i.e., via “thoroughfare channels.” Thus, normally relatively few of them engage small capillary side branches. When the flow rate decreases, more WBCs reach the marginal blood stream, and they are therefore more readily distributed to the capillary network. During shock, the flow rate in the microvascular bed is low and the capillary hydrostatic pressure is decreased by 30 to 40%. 27 These changes might ex102
plain why more WBCs become trapped when the subject is in shock. Compensatory mechanisms, such as hemodilution and reduction of blood viscosity due to transcapillary fluid reabsorption, do not seem efficient enough to overcome the decrease in hydrostatic driving pressure during shock. Shock-induced changes in viscoelastic properties of WBCs could be another factor of importance for trapping of WBCs in capillaries. However, no qualitative differences in stiffness of WBCs before and after shock have been demonstrated in vitro.30 This does not exclude the possibility that changes in the viscoelastic properties of WBCs occur in vim, since the WBCs that are affected may be the ones seen trapped in the microvasculature. In many of the capillaries that remain open, the flow rate is usually high and the blood can probably not be utilized efficiently for cellular nutrition. It may therefore represent a shunting of blood through the tissue, which is in agreement with the decreasing arterio-venous oxygen tension gradient usually seen during shock conditions. It may thus be concluded that recent intravital microscopic studies of the microcirculation in skeletal muscle during hemorrhagic shock indicate that blocking of capillaries by WBCs can be an important reason for the pronounced maldistribution of blood flow within the microvasculature. Red BloodCells Red blood cells (RBCs) also have to be deformed during their passage through capillaries, since the average diameter of RBCs (7.5 pm) exceeds that of most capillaries.24 Their deformation is determined by the intrinsic deformability of the cell and the shear stress acting on the cell surface.40 Red blood cells have a favourable surface-area-to-volume ratio, which allows
HALJAMiiE
FIGURE 2. Disturbances in blood-tissue exchange processes during shock. Left, During resting conditions there is an adequate blood supply to the tissues, aerobic tissue metabolism, and undisturbed bloodtissue exchange of substances. Right, (1) Shock reduces the capillary surface area available for exchange processes; (2) the density of the interstitial ground substance increases because of mobilization of fluid from the interstitium; (3) the resulting impairment of blood-tissue exchange processes causes tissue hypoxia: (4) metabolites accumulate locally and (5) affect cellular energy production: (6) the cell can no longer keep up a normal transcellular potassium gradient; (7) the transmembrane potential level decreases; (8) because of the impaired blood-tissue exchange metabolites, hydrogen ions, potassium, and so on accumulate in the interstitium and may interfere with the function of the vascular smooth muscle cells, so that (9) the irreversible phase of shock ensues when, at reflow, fluid is lost into the interstitium. (From HaljamPe H, et al. Pathophysiology of shock. Pathol Res Pratt 1979:165:200-211.)
n MICROCIRCULATION
RESTING CONDITION I HYPOVOLEMIC
SHOCK
CELLS
INTERS
VASCUL
pronounced deformations at constant volume and surface area.41 Three-dimensional observations of RBC deformation in capillaries indicate that it occurs primarily by a folding of the disc about the longitudinal axis of the capillary.42q43 Although the mechanical properties of the RBCs are important determiners of blood flow, RBCs seem to deform very easily during normal conditions and are not seen to obstruct capillary blood flow. The flow of RBCs through tissues is further enhanced by a low functional hematocrit in the capillaries because of faster passage of RBCs than of plasma through the capillary bed.‘4 Recent studies have demonstrated significant alterations in the homeostasis of RBCs during shock.44-47 There is an increase in intracellular sodium and a decrease in intracellular potassium caused by changes in membrane permeability and in active sodium transport. The water content of RBCs is also increased. This may affect the surface-to-volume ratio and thereby the deformability of RBCS.~~ In studies with the vital microscope, no capillary obstruction by individual RBCs has been described during shock.22.23,36 However, RBCs are often seen to accumulate behind slowly moving or arrested WBCs, as shown in Figure 1. A slow passage of plasma past trapped WBCs may explain the buildup of such rouleaux formations. When the WBCs move on and reach the venules, these rouleaux formations break up immediately. These RBC aggregates adjacent to WBCs may thus explain the presence of a slowly circulating RBC volume during shock, 49 but they do not seem to be of importance for the distribution of the blood flow within the microvasculature.
MICROCIRCULATORYCHANGES AN0 TISSUE METABOLISM DURINGSHOCK Tissue oxygen tension in skeletal muscle decreases considerably following blood 10ss.~,~~~~ The intravital microscopic observations of a very heterogeneous distribution of the remaining blood flow within the microvasculature suggests the presence of marked local variations in tissue oxygen tension as well. Direct mapping of oxygen pressure fields in skeletal muscle following hemorrhage verifies such a variation.51y52 It seems logical to assume that the observed WBC plugging of capillaries is the main reason for these local variations in tissue oxygen tension. Differences in blood supply to oxidative muscles could, however, also contribute, since the blood flow to red muscle fibers seems less affected than that to white ones during shock.53 Hemorrhagic shock results in a pronounced tissue anaerobiosis in skeletal muscle (Fig. 2). Increased tissue levels of lactate and hydrogen ions are seen, and the production and utilization of high-energy phosphagens is disturbed. 9,10,12Muscle cells can no longer keep up a normal transmembrane gradient of electrolytes, and as a consequence the membrane potential level decreases from a normal resting level of - 90 mV to as low as - 60 to - 70 mV.5,6+12*13 The reduction of the transmembrane potential level of muscle cells seems intimately related to the severity of a hypoxic injury.‘3,54-56 Transmembrane potential measurements have therefore been used to reveal local variations in cell injury within skeletal muscle during hypovolemic shock.57 When thin microelectrodes are slowly ad103
AMERICAN
JOURNAL
OF EMERGENCY
MEDICINE
n Volume 2, Number 1
vanced through muscle tissue, the transmembrane potential level of each penetrated muscle cell is obtained. In resting skeletal muscle there is only a small variation in the membrane potential level between adjacent muscle fibers. During shock, however, large differences are seen, ranging from normal level to values as low as -60 mV. These observations of cellular functional disturbances during shock are therefore well in agreement with intravital microscopic observations of blood flow distribution. This heterogeneity in blood flow distribution and in consequent cellular injury could represent a sophisticated defense mechanism of the body that serves to limit the tissue injury in a critical situation. Since the remaining blood flow to the tissue during shock is too low to supply all the cells with sufficient amounts of oxygen, some cells are sacrificed so that others may survive.
MICROCIRCULATORY CHANGES AND BLOODTISSUE EXCHANGE DURING SHOCK The exchange of substances between blood and tissue cells is dependent on blood flow, capillary surface area, capillary permeability, concentration gradients, and transport through the interstitial tissue and across cell membranes. The intravital microscopic studies, referred to above, clearly show that the blood flow and the capillary surface area available for exchange processes are both markedly reduced in skeletal muscle following blood loss. “Hidden acidosis”58 and “hidden cellular electrolyte changes”5~‘2~59during shock have also been demonstrated. “Hidden” means that local tissue changes are not at all, or only partly, reflected in central blood. Today it is well recognized that the levels of (for instance) lactate, hydrogen ions, and potassium in the interstitial fluid are all significantly higher than the corresponding blood levels during shock.‘? It is still unclear, however, whether the observed disturbance in blood flow to the tissues is the main reason for the impaired blood-tissue exchange, or whether changes within the interstitial tissue are also of importance.5q’2 Shires and co-worker@ studied the equilibration of radiosulfate for measurement of the extracellular space during shock and found a reduction of the functional extracellular space. The equilibration of radiosulfate depends not only on blood flow distribution but also on diffusion through the interstitium. Appelgren and Lewis6i separated these two components by studying the local tissue clearance of injected radioactive iodide and xenon. The clearance of xenon is flow-limited, and that of iodide is diffusion-limited. They found that diffusion was considerably more limited than blood flow in skeletal muscle during shock. A similar transport defect within the interstitial tissue was advocated by Koven et al,62 and this is in agreement with our earlier studies on interstitial electrolyte changes during shock.5.S9,63 The impaired diffusion
through the interstitium in shock states seems to be caused by an increase in interstitial colloidal density due to the compensatory mobilization of fluid from the interstitium into the circulation. 12*@ Present data thus suggest that microcirculatory as well as interstitial factors are both of importance for the impaired bloodtissue exchange of substances during hemorrhagic shock. The pathophysiologic events within the tissue are summarized in Figure Z.t* These changes in bloodtissue exchange processes may be looked upon as part of an important defense mechanism, since metabolites and other potentially toxic substances from hypoxic cells in peripheral tissues are prevented from reaching central blood and thereby disturbing the function of vital organs. In late shock, however, such an interstitial accumulation of metabolites, hydrogen ions, potassium, etc. may initiate the decompensatory phase because of local interference with the function of vascular smooth muscle cells.5*12*65
MICROCIRCULATORY EFFECTS OF SHOCK TREATMENT The aim of shock therapy is to restore an adequate nutritive blood flow to tissues so that cellular metabolism and function are normalized. The hemodynamic and metabolic effects of treatment with various types of fluids have been studied extensively. However, the microcirculatory effects are not known in detail. Most indirect studies indicate that disturbances in tissue perfusion may persist for prolonged periods of time following treatment, since defects in peripheral indicator mixing and in oxygen utilization often can be demonstrated.27*59*66-70Factors such as tissue edema, microembolus-induced closure of capillaries, and swelling of endothelial cells have been considered of importance for the impaired reperfusion. Direct intravital microscopic studies of the effects of fluid administration on the microcirculation in skeletal muscle of subjects in shock have also shown that the distribution of blood flow remains heterogeneous in spite of the fact that near-normal arterial blood pressure is reached.” Many capillaries remain blocked by WBCs, and the postinfusion increase in blood flow is mainly restricted to previously perfused capillaries. There are, however, differences in the microcirculatory effects depending on the type and amount of fluid given.” Treatment of hemorrhagic shock by restoring only the shed volume of blood does not seem to restitute normal flow pattern within the tissue. The volume flow increases, but this is mainly due to increased flow velocities in previously perfused capillaries. Many capillaries thus remain blocked by WBCs, and temporary rouleaux formations at trapped WBCs, as shown in Figure 1, are still commonly seen. After resuscitation with crystalloids, a postinfusion hyperemia is seen, but the maldistribution of blood flow within the capillary bed persists. Crystalloids also
HALJAMAE
seem to induce a pronounced edema in skeletal muscle when given in small volumes (two times lost blood volume) after prolonged hemorrhagic shock.71 Colloid given as dextran 70 following shock seems to mobilize trapped WBCs better and reduces the defect in tissue perfusion more than do whole blood or crystalloids. The beneficial effects of dextran on blood viscosity could perhaps explain enhanced WBC mobilization.‘* From such experimental studies,‘l however, no decisive conclusions can be drawn regarding the ideal shock treatment for efficient restitution of microvascular blood flow. There is still a lack of information on the microcirculatory, cellular metabolic, and cellular functional effects of the adminstration of optimal combinations of fluids supplemented by proper pharmacologic modulation of the activity of the symphathetic nervous system and of vascular tone. In studies with the vital microscope, edema formation in skeletal muscle following shock treatment is often seen.71 Swelling of the interstitial tissue, endothelial cells, and WBCs could explain a poor capillary reperfusion in the postinfusion period. Regimens for reduction of tissue swelling as part of the initial treatment may therefore be of value. This could, for instance, be obtained by giving hypertonic solutions or by supplying the cells with energy in order to rapidly normalize membrane transport function and thereby cellular volume control. Prevention of tissue damage during shock and ischemia by infusion of hypertonic solutions has repeatedly been reported. Brooks and co-workers73 showed in 1963 that recovery from hemorrhagic shock occurred more rapidly in dogs treated with 1.8% saline, 2.74% sodium bicarbonate, or 10% glucose than in dogs treated with isotonic solutions. It was assumed that the hypertonicity reduced postischemic cellular swelling. Since then, the use of hypertonic solutions for situations such as tissue preservation is commonly accepted.74 Hypertonic glucose, saline, mannitol, or imidazole solutions for shock treatment have all been shown to reduce tissue perfusion defects and increase surviva1.70~75-77On the basis of the concepts presented here on pathophysiologic changes during shock (Fig. 2), initial treatment with hypertonic solutions seems valuable, since loss of fluid at reperfusion into a hyperosmotic interstitium is prevented, and swelling of endothelial cells as well as WBCs may be reduced. The passage of WBCs through capillaries may be further enhanced by the direct vasodilatory action of hypertonic solutions on the microvasculature.78 Correction of shock-induced tissue abnormalities by intravenous administration of ATP-MgC12 has been considered of value in the treatment of shock.79,80 The exact mechanism for the ATP-mediated beneficial effects are not known. The ATP may improve tissue perfusion by its vasodilatory actions and/or provide energy for restitution of membrane function in hypoxic cells. Both effects could be of importance for release
n MICROCIRCULATION
of trapped WBCs from the microvascuiature. Steroids may be of importance for the restitution of adequate tissue perfusion following shock by stabilizing cell membranes and by blocking the local inflammatory response to tissue anoxia. Intravital microscopic studies indicate that extravasation of WBCs is common in the late stages of shock.22*23Such a migration of WBCs is prevented by steroids.81 Other beneficial effects of steroids, such as reduction of peripheral vascular resistance8*yg3 and increase in tissue oxygen availabilitys4 may also favor reperfusion of blocked capillaries.
CLINICAL MONITORING OF SHOCK-INDUCED MICROCIRCULATORY CHANGES The cellular metabolic consequences of the microcirculatory deterioration in peripheral tissues during shock are only partially reflected in central blood (Fig. 2). Skeletal muscle, being the largest cell mass of the body and suffering a severe reduction in blood flow, is the major source of lactate.85 Information on local changes in skeletal muscle and on blood-tissue gradients is therefore of considerable value in the clinical management of critically ill patients. The overall tissue perfusion defect can be estimated by measuring cardiovascular, respiratory, and blood parameters from which oxygen transport and consumption can be calculated.67,86 Direct measurements of the oxygen tension in the tissue and of the blood-tissue gradient by the use of microelectrodes seem to provide a more valuable index of tissue perfusion.50-52~87*88 The severity of the concomitant tissue metabolic and cellular functional disturbances can be evaluated from measurements of blood-tissue pH and potassium gradients.89-95 Clinical experience with the use of various types of microelectrodes for monitoring of shock-induced microcirculatory changes is increasing. Within a few years it may be part of the routine monitoring of all critically ill patients. The author thanks Dr. Bagge, of the Laboratory of Experimental Biology, Department of Anatomy, University of Gdteborg, Sweden, for valuable discussions and for supplying Figure 1.
REFERENCES 1. Gerratana FJ, Saranchak HJ, Owens G. Cerebral and hepatic blood flow measured during shock using the mass spectrometer. J Surg Res 1976;20:489-492. 2. Silver IA. Ion fluxes in hypoxic tissues. Microvasc Res 1977;13:409-420. 3. Lovelace DR, Short BL, Rink RD. Hepatic oxygen supply in reversible and irreversible hemorrhagic shock. J Surg Res 1979;26:120-128. 4. Brantigan JW, Ziegler EC, Hynes KM, et al. Tissue gases during hypovolemic shock. J Appl Physiol 1974;37:117122. 5. Haljamtie H. “Hidden” cellular electrolyte responses to hemorrhagic shock and their significance. Rev Surg 1970;27:315-324.
AMERICAN
JOURNAL
OF EMERGENCY
MEDICINE
n Volume
6. Cunningham JN Jr, Shires GT, Wagner Y. Cellular transport defects in hemorrhagic shock. Surgery 1971;70:215-222. 7. Baue AE, Wurth MA, Chaudry IH, et al. Impairment of cell membrane transport during shock and after treatment. Ann Surg 1973;178:412-421. 8. Chaudry IH, Sayeed MM, Baue AE. Depletion and restoration of tissue ATP in hemorrhagic shock. Arch Surg 1974;108:208-211. 9. Baue AE, Chaudry IH, Wurth MA, et al. Cellular alterations with shock and ischemia. Angiology 1974;25:31-42. IO. Schumer W, Erve PR. Cellular metabolism in shock. Circ Shock 1975;2:109-127. 11. Chaudry IH, Sayeed MM, Baue AE. Alterations in high-energy phosphates in hemorrhagic shock as related to tissue and organ function. Surgery 1976;79:666-668, 12. Haljamae H, Amundson B, Bagge U, et al. Pathophysiology of shock. Pathol Res Pratt 1979;165:200-211. 13. lllner H, Shires GT. The effect of hemorrhagic shock on potassium tranport in skeletal muscle. Surg Gynecol Obstet 1980;150:17-25. 14. Holliday RL, lllner HP, Shires GT. Liver cell membrane alterations during hemorrhagic shock in the rat. J Surg Res 1981;31:506-515. 15. Sayeed MM, Adler RJ, Chaudry IH, et al. Effects of hemorrhagic shock on hepatic transmembrane potentials and intracellular electrolytes, in vivo. Am J Physiol 1981;240:R211-R219. 16. Branemark P-l, Eriksson E. Method for studying qualitative and quantitative changes of blood flow in skeletal muscle. Acta Physiol Stand 1972;84:284-288. 17. Baez S. An open cremaster muscle prepartation for the study of blood vessels by in vivo microscopy. Microvasc Res 1973;5:384-394. 18. Hutchins PM, Goldstone J, Wells R. Effects of hemorrhagic shock on the microvasculature of skeletal muscle. Microvast Res 1973;5:131-140. 19. Myrhage R, Hudlicka 0. The microvascular bed and capillary surface area in rat extensor hallucis proprius muscle (EHP). Microvasc Res 1976;11:315-323. 20. Fronek K, Zweifach BW. Microvascular blood flow in cat tenuissimus muscle. Microvasc Res 1977;14:181-189. 21. Amundson B, Bagge U, Haljamae H. Control of tissue environment during vital microscopy of the microcirculation in the m. tenuissimus in cat. Acta Physiol Stand 1980;108:139-146. 22. Amundson B, Jennische E, Haljamae H. Correlative analysis of microcirculatory and cellular metabolic events in skeletal muscle during hemorrhagic shock. Acta Physiol Stand 1980;108:147-158. 23. Amundson B. Skeletal muscle microcirculation and metabolism in hemorrhagic shock (doctoral thesis). Medical Faculty, University of Goteborg, Sweden, 1979. 24. Gaethgens P. Hemodynamics of the microcirculation. Physical characteristics of blood flow in the microvasculature. In Meessen H (ed). Handbuch der Allgemeinen Pathologie
25. 26. 27.
28.
ill/7. Microcirculation. Berlin, Heidelberg: SpringerVerlag, 1977:231-287. Johnson PC. The myogenic response and the microcirculation. Microvasc Res 1977;13:1-18. Kunze K. Spontaneous oscillations in Pop in muscle tissue. Adv Exp Med Biol 1976;75:631-637. Zweifach BW. Mechanisms of blood flow and fluid exchange in microvessels: Hemorrhagic hypotension model. Anesthesiology 1974;41:157-168. Lundvall J, Hillman J. Fluid transfer from skeletal muscle to blood during hemorrhage: Importance of beta-adrenergic vascular mechanisms. Acta Physiol Stand 1978;102:450458.
2, Number
1
29. Hillman J. Further studies on beta-adrenergic control of transcapillary fluid absorption from skeletal muscle to blood during hemorrhage. Acta Physiol Stand 1981; 112;281-286. 30. Bagge U, Amundson B, Lauritzen C. White blood cell deformability and plugging of skeletal muscle capillaries in hemorrhagic shock. Acta Physiol Stand 1980;180:159163. 31. Eriksson E, Lisander B. Low flow states in microvessels of skeletal muscle in cat. Acta Physiol Stand 1972;86:202210. 32. Eriksson E, Ericsson LE. Intra- and extravascular morphology in skeletal muscle at low flow states. Bibl Anat 1973;12:308-314. 33. Bagge U, Brdnmark P-l. White blood cell rheology. An intravital study in man. Adv Microcirc 1977;7:1-17. 34. Bagge U, Johansson BR, Olofsson J. Deformation of white blood cells in capillaries: A combined intravital and electron microscopic study in the mesentery of rabbits. Adv Microcirc 1977;7:18-28. 35. Bagge U, Skalak R, Attefors R. Granulocyte rheology. Experimental studies in an in vitro micro-flow system. Adv Microcirc 1977;7:29-48. 36. Bagge U, Amundson B, Braide M. A method to observe and quantitate leukocyte interference with low flow in the skeletal muscle microcirculation. Bibl Anat 1981;20:557560. 37. Wilson JW. Leukocyte sequestration and morphological augmentation in the pulmonary network following hemorrhagic shock and related forms of stress. Adv Microcirc 1972;4:197-232. 38. Eriksson E, Myrhage R. Microvascular dimensions and blood flow in skeletal muscle. Acta Physiol Stand 1972;86:211-222. 39. Zweifach BW. Microcirculation. Am Rev Physiol 1973; 35:117-150. 40. Chien S. Determinants of blood viscosity and red cell deformation. Stand J Clin Lab Invest 1981;41 (Suppl 156):712. 41. Schmid-Schonbein H, Gaehtgens P. What is red cell deformability? Stand J Clin Lab Invest 1981;41(Suppl 156):13-26. 42. Bagge U, Branemark P-l, Karlsson R, et al. Three-dimensional observations of red blood cell deformation in capillaries. Blood Cells 1980;6:231-237. 43. Bagge U, Brat-remark P-l. Red cell shapes in capillaries. Stand J Clin Lab Invest 1981;41(Suppl 156):59-61. 44. Cunningham JN Jr, Shires GT, Wagner Y. Changes in intracellular sodium and potassium content of red blood cells in trauma and shock. Am J Surg 1971;122:650-654. 45. Day 8, Friedman SM. Red cell sodium and potassium in hemorrhagic shock measured by lithium substitution analysis. J Trauma 1980;20:52-54. 46. lllner HP, Cunningham JN Jr, Shires GT. Red blood cell sodium content and permeability changes in hemorrhagic shock. Am J Surg 1982;143:349-355. 47. Kreis DJ Jr, Chaudry JH, Schleck S, et al. Red cell sodium, potassium and ATP levels during hemorrhagic shock. J Surg Res 1981;31:225-231. 48. LaCelIe PL, Smith BD. Biochemical factors influencing erythrocyte deformability and capillary entrance phenomena. Stand J Clin Lab Invest 1981;41(Suppl 156):145-149. 49. Gibson JG, Seligman AM, Peacock WC, et al. The circulating red cell and plasma volume and the distribution of blood in large and minute vessels in experimental shock in dogs, measured by radioactive isotopes of iron and iodine. J Clin Invest 1947;26:126-144. 50. Niinikoski J. Tissue oxygenation in hypovolemic shock. Ann
HALJAMAE
Clin Res 1977;9:151-156. 51. Kessler M, Hoper J, Krumme BA. Monitoring of tissue perfusion and cellular function. Anesthesiology 1976;45: 184-197. 52. Lund N, Cdman S, Lewis DH. Skeletal muscle oxygen pressure fields in rats: A study of the normal state and the effects of local anesthetics, local trauma and hemorrhage. Acta Anaesththesiol Stand 1980;24:155-160. 53. Jennische E, Amundson 8, Haljamae H. Metabolic responses in feline “red” and “white” skeletal muscle to shock and ischemia. Acta Physiol Stand 1979;106:39-45. 54. Jennische E, Medegard KAI, Haljamae H. Transmembrane potential changes as an indicator of cellular metabolic deterioration in skeletal muscle during shock. Eur Surg Res 1979;10:125-133. 55. Jennische E, Enger E, Medegard A, et al. Correlation between tissue pH, cellular transmembrane potentials, and cellular energy metabolism during shock and during ischemia. Circ Shock 1978;5:251-260. 56. Jennische E, Hagberg H, Haljamle H. Extracellular potassium concentration and membrane potential in rabbit gastrocnemius muscle during tourniquet ischemia. Pflugers Arch 1982;392:335-339. 57. Haljamae H, Jennische E, Medegard A. Transmembrane potential measurements as an indicator of heterogeneous distribution of nutritive blood flow in skeletal muscle during shock. Acta Physiol Stand 1977;101:458-464. 58. Bergen& S-E, Carlsten A, Gelin L-E, et al. “Hidden acidosis” in experimental shock. Ann Surg 1969;169:227-232. 59. Hagberg S, Haljamae H, Rockert H. Shock reactions in skeletal muscle: Ill. The electrolyte content of tissue fluid and blood plasma before and after induced hemorrhagic shock. Ann Surg 1968;168:243-248. 60. Middleton ES, Mathews R, Shires GT. Radiosulphate as a measure of the extracellular fluid in acute hemorrhage. Ann Surg 1969;170:174-186. 61. Appelgren KL, Lewis DH. Capillary flow and capillary transport in dog skeletal muscle in hemorrhagic shock. Eur Surg Res 1972;4:29-45. 62. Koven IH, MacMillan N, Lo S, et al. Correction by hyaluronidase of the interstitial tissue transport defect during shock: A new approach to therapy. J Trauma 1975; 15:992-997. 63. Haljamae H. Effects of hemorrhagic shock and treatment with hypothermia on the potassium content and transport of single mammalian skeletal muscle cells. Acta Physiol Stand 1970;78:189-200. 64. Haljamae H. Anatomy of the interstitial tissue. Lymphology 1978;11:128-132. 65. Zweifach BW, Fronek A. The interplay of central and peripheral factors in irreversible hemorrhagic shock. Prog Cardiovasc Dis 1975;18:147-180. 66. Shires T, Coln D, Carrico J, et al. Fluid therapy in hemorrhagic shock. Arch Surg 1964;88:688-693. 67. Shoemaker WC, Reinhard JM. Tissue perfusion defects in shock and trauma states. Surg Gynecol Obstet 1973; 137:980-986. 68. Wright CJ. Regional effects of hypovolemia and resuscitation with whole blood, saline or plasma. J Surg Res 1975;18:9-16. 69. Small A, Homer LD. An explanation of impaired solute mixing in extracellular fluid after hemorrhagic shock. Am J Physiol 1979;236:H440-H446. 70. Shah DM, Newell JC, SabaTM. Defects in peripheral oxygen utilization following trauma and shock. Arch Surg 1981;116:1277-1281. 71. Amundson 8, Jennische E, Haljamae H. Skeletal muscle microcirculatory and cellular metabolic effects of whole blood, Ringer’s acetate, and dextran 70 infusions in hem-
n MICROCIRCULATION
orrhagic shock. Circ Shock 1980;7:111-120. 72. Gruber UF, Messmer K. Colloids for blood volume support. Prog Surg 1977;15:49-76. 73. Brooks DK, Williams WG, Manley RW, et al. Osmolar and electrolyte changes in haemorrhagic shock: Hypertonic solutions in prevention of tissue damage. Lancet 1963;1:521-527. 74. Collings GM, Hartly LCJ, Clunie GJA. Kidney preservation for transportation. Br J Surg 1972;59:187-189. 75. Fritz SD, Fills CT, Lurie D. The effect of hypertonic glucose upon survival in hemorrhagic shock utilizing a re-stress model in sheep. J Trauma 1976;16:284-288. 76. De Felippe J Jr, Timoner J, Kelasco IT, et al. Treatment of refractory hypovolemic shock by 7.5% sodium cloride injections. Lancet 1980;2:1102-1104. 77. Kelasco IT, Pontieri V, Rocha-e-Silva M Jr, et al. Hyperosmotic NaCl and severe hemorrhagic shock. Am J Physiol 1980;239:H664-H673. 78. Duling BR, Staples E. Microvascular effects of hypertonic solutions in the hamster. Microvasc Res 1976;11:51-56. 79. Chaudry IH, Baue AE. The use of substrates and energy in the treatment of shock. Adv Shock Res 1980;3:27-46. 80. Chaudry IH, Clemens MG, Baue AE. Alterations in cell function with ischemia and shock and their correction. Arch Surg 1981;116:1309-1317. 81. Fauci AS. Glucocorticoid therapy: Mechanisms of action and clinical considerations. Ann Surg 1976;84:304-315. 82. Motsay GJ, Alho A, Jaegert T, et al. Effects of corticosteroids on the circulation in shock: Experimental and clinical results. Fed Proc 1970;29:1861-1873. 83. Altura BM, Altura BT. Peripheral vascular actions of glucocorticoids and their relationship to protection in circulatory shock. J Pharmacol Exp Ther 1974:190:300-315. 84. Bryan-Brown CW, Back S, Makabali G, et al. Consumable oxygen: Availability of oxygen in relation to oxyhemoglobin dissociation. Crit Care Med 1973;1:17-21. 85. Daniel AM, Shizgal HM, MacLean LD. The anatomic and metabolic source of lactate in shock. Surg Gynecol Obstet 1978;147:697-700. 86. Shoemaker WC, Launder WJ, Castagna J, et al. Method for estimation of perfusion defect in shock. J Surg Res 1976;20:77-84. 87. Niinikoski J, Halkola L. Skeletal muscle Pas: Indicator of peripheral tissue perfusion in hemorrhagrc shock. Adv Exp Med Biol 1978;94:585-592. 88. Schonleben K, Hauss JP, Spiegel U, et al. Monitoring of tissue Pop in patients during intensive care. Adv Exp Med Biol 1978;94:593-598. 89. Couch NP, Dmochowski JR, Van de Water JM, et al. Muscle surface pH as an index of peripheral perfusion in man. Ann Surg 1971;173:173-183. 90. Filler RM, Das JB, Espinosa HM. Clinical Experience with continuous muscle pH monitoring as an index of tissue perfusion and oxygenation and acid-base status. Surgery 1972;72:23-33. 91. Laks H, Dmochowski JR, Couch NP. The relationship between muscle surface pH and oxygen transport. Ann Surg 1976;183;193-198. 92. Harrison DK, Walker WF. Tissue pH electrodes for clinical applications. J Med Eng Technol 1980;4:3-7. 93. Treasure T. The application of potassium selective electrodes in the intensive care unit. Intensive Care Med 1978;4:83-89. 94. Linton RAF, Lim M, Band DM. Continuous intravascular monitoring of plasma potassium using potassium-selective electrode catheters. Crit Care Med 1982;10:337-340. 95. McKinley BA, Houtchens BA, Janata J. Continuous monitoring of interstitial fluid potassium during hemorrhagic shock in dogs. Crit Care Med 1981;9:845-851.
MD, PhD
Blood loss is followed by compensatory cardiovascular readjustments that favor the maintenance of blood flow to central vital organs rather than to peripheral tissues. The microcirculatory changes that occur in skeletal muscle in shock states are of major importance, since skeletal muscle is not only the largest cell mass of the body but also one of the major target organs for neurohumorally mediated compensatory vascular readjustments. lntravital microscopic studies show that the microvascular blood flow in skeletal muscle is intermittent in the early posthemorrhagic period. This probably reflects an interplay between OLadrenergic vasoconsfffctor and p-adrenergic vasodilator activities, which serves to enhance a compensatory mobilization of interstitial fluid into the vascular compartment. A period of complete microcirculatory arrest is then seen, followed by reperfusion engaging only 30% to 50% of the capillaries that were seen perfused in resting skeletal muscle. The microvascular blood flow in shock is further characterized by a pronounced heterogeneity in distribution. Many capillaries remain constantly unperfused, while in others a slow, intermittent blood flow is seen. Obstruction of many capillaries by white blood cells and their slow passage through other capillaries seem to be the main reasons for the maldistribution of capillary blood flow in shock. Red blood cell aggregates obstructing capillary blood flow are not seen. The heterogeneous tissue perfusion is accompanied by local variations in cellular hypoxic injury, as is evidenced by multifocal measurements of tissue oxygen tension and by cellular transmembrane potential registrations. The blood-tissue exchange of substances is impaired because of the reduction in capillary surface area and changes within the interstitial compartment. Therefore, shock-induced metabolic changes in skeletal muscle remain mainly local and are not at all, or only to a limited extent, reflected in central blood. Following volume treatment the heterogeneity in capillary perfusion persists, since white blood cells often remain trapped in capillaries and obstruct blood flow. Treatment of shock with hypertonic solutions, ATP-MgC12. or steroids could be beneficial by enhancing the mobilization of trapped white blood cells. Microcirculatory disturbances and their local metabolic consequences in skeletal muscle of critically ill patients can be monitored in the intensive care unit by the use of microelectrodes for contin-
From the Department Gbteborg, Sweden.
of Anesthesia,
Sahlgren’s
Hospital,
Presented at the First International Conference on the Basic Mechanisms and Clinical Management of Shock, Merrillville, Indiana, September 10-l 1, 1982, and accepted for publication at that time. Address reprint requests to Dr. Haljamae: Department of Anesthesia, Sahlgren’s Hospital, S-413 45 Gdteborg, Sweden, Key Words: Blood-tissue exchange, hemorrhagic shock, leukocytes, shock treatment, skeletal muscle metabolism, skeletal muscle microcirculation, tissue pH, tissue PO,, transmembrane potential, vital microscopy. 100
uous or intermittent measurements of tissue gas tensions (PO*, PcuJ, tissue pli, and tissue potassium levels.
Hemorrhagic shock may be characterized as a failure of the circulation to meet the metabolic demands of the body tissues. The basic defect is a disturbance in the distribution of blood flow within the microvasculature, resulting in a changed cellular supply-to-demand ratio of oxygen. The distribution of blood flow to individual vascular beds is determined by neurohumoral factors and by local autoregulatory mechanisms. The compensatory cardiovascular readjustments following blood loss, however, favor the maintenance of blood flow to central vital organs at the expense of blood flow peripheral tissues. The blood flow and oxygen supply to the brain are thus favored during hypovolemia.’ The oxygen supply to the liver is considerably reduced,1-3 but less than that to peripheral tissues such as skin and skeletal muscle,4 which are the major target organs for neurohumorally mediated compensatory vascular readjustments. The metabolic and cellular functional disturbances that occur in hypoperfused tissues following severe hemorrhage have been studied in detail.‘-I5 The knowledge of the underlying microcirculatory disturbances is, however, still rather limited, since there is a lack of representative high-resolution intravital microscopic studies on cellular tissues. Most of the available information on circulatory changes within the terminal vascular bed during shock is thus based on studies of connective tissues such as the mesentery, the hamster cheek pouch, or the human conjunctivae, which are all easy to study in the vital microscope. General information on structural and functional characteristics of the microvasculature can be obtained from such studies, but the changes observed during shock in these relatively acellular tissues may not be representative for those occurring in cellular tissues, which have much higher basal metabolic demands. Technical and preparative improvements during recent years have, however, made cellular tissues such as skeletal muscle available for high-resolution intravital microscopic studies. 16-22The importance of absolute control of the external environment for the representativity of the exposed tissue, especially during studies of shock-induced microcirculatory changes, has also been recognized.21-23 The present survey will be mainly confined to the interplay between microcirculatory, interstitial, and cellular metabolic changes in
HALJAMAE
skeletal muscle during hemorrhagic lowing treatment.
shock and fol-
DISTRIBUTION OF BLOOD FLOW WITHIN THE MICROVASCULATURE DURING SHOCK The capillaries in skeletal muscle are not continuously perfused under resting conditions. There is an intermittent blood flow through groups of capillaries supplied by the same terminal arterioles.22~23The cyclic on-and-off type of flow probably reflects a coupling between blood flow distribution and local metabolic needs within the tissue,24,25 and it involves 90% of all the capillaries in skeletal muscle. It is also accompanied by cyclic variations (frequency 0.5 to 2 per minute) in local tissue oxygen tension26 and in hydrostatic pressure within the capillaries.27 Blood loss results in intense vasoconstriction in the arteries and arterioles of skeletal muscle, leading to complete circulatory standstill within the tissue.22.23 This initial phase of vasoconstriction is short. Usually, intermittent tissue perfusion reappears within a minute, and at the same time variations in vasoconstriction of pre- as well as postcapillary vessels are seen. This intermittent tissue flow may reflect an interplay between a-adrenergic vasoconstrictor and padrenergic vasodilator activities. P-Adrenergic vascular mechanisms seem to be of importance for the early compensatory mobilization of interstitial tissue fluid into the vascular compartment after blood 10ss.*~**~The P-adrenergic stimulation of precapillary vessels will increase the capillary surface area available for fluid absorption, and that of postcapillary vessels will lower capillary hydrostatic pressure by changing the pre- to postcapillary resistance ratio. Both these factors govern transcapillary refill. This initial “compensatory phase” is soon followed by a new period of intense vasoconstriction. Complete microcirculatory arrest ensues and may last for 5 to 20 minutes. When tissue perfusion reappears, the on-and-off type of flow, characteristic for resting skeletal muscle, has usually disappeared. The number of perfused capillaries has decreased by 50% to 70% compared with the prehemorrhagic resting condition. The distribution of the flow within skeletal muscle during shock is very heterogeneous, and three levels of “patchiness” between flow and no-flow have been distinguished. **Y*~ Occasionally, transverse arterioles remain intensely constricted, leaving no blood flow into a whole transverse muscle segment. Unperfused terminal arterioles are commonly seen, but their supply areas are usually not completely deprived of blood flow, since some perfusion is obtained from adjacent arterioles via capillary interconnections. The most pronounced heterogeneity in tissue perfusion, however, is seen within the capillary bed. Some cap-
n MICROCIRCULATION
illaries remain constantly perfused, with flow rates exceeding those seen during resting conditions. Other capillaries are intermittently perfused at irregular intervals. The passage of white blood cells (WBCs), which are much stiffer than red blood cells (RBCs) and also larger, through the capillaries seems to be the major reason for this variability in blood flo~.**~*~**~~~~~~~ Many capillaries remain constantly unperfused, and there is evidence that this may be due to WBC plugging. Quantitative evaluations of changes in capillary blood flow velocities during shock have been very difficult to perform because of this extreme variability within, as well as between, different capillaries. However, the volume flow through the tissue seems to be reduced by 50 to 70% compared with that seen in resting skeletal muscle. In the postcapillary vessels, the blood flow in shock is sluggish, and increasing numbers of WBCs are seen to adhere to venular walls. In some intravital microscopic studies, it has been suggested that such a tilling of venules with blood corpuscles could obstruct blood flow and induce tissue edema.31*32 In other studies, however, no significant interference with blood flow, not even during late shock, has been found.22,23
BLOOD CELL RHEOLOGY AND HETEROGENEOUS TISSUE PERFUSION DURING SHOCK White
Blood
Cells
It has been known for many years that WBCs may temporarily obstruct blood flow during their passage through narrow capillaries even under normal pressure/33 In recent studies by Bagge and co-workers,33-35 the rheology of WBCs has been characterized in detail. It is now becoming more and more obvious that WBCs, by affecting the distribution of the blood flow within the capillary bed, may play a major role in the pathophysiology of shock. 12.22,23*27~30~31,36*37 White blood cells are spherical, and the average diameter, for polymorphonuclear granulocytes, is about 8 to 9 pm, and for lymphocytes, about 6 pm in circulating blood.32 Internal capillary diameters in skeletal muscle vary between 2.8 and 8 Frn, the average being 5.3 Fm.38 The arteriolar end of the capillary is usually narrower (-4.5 km) than the venular end (-5.6 Fm). Thus, WBCs have to become considerably deformed when they enter most capillaries, and their shape is approximately that of an elongated cylinder during the passage through narrow capillaries. In vitro, intravital, and electron microscopic studies of WBC behavior in capillaries 34 have shown that WBCs are viscoelastic and, furthermore, that they become deformed at constant volume during their passage through capillaries. Since undeformed WBCs have a membrane reserve (up to 70%), large deformations are 101
AMERICAN
JOURNAL
OF EMERGENCY
MEDICINE
n Volume 2, Number 1
FIGURE 1. In vitro view of white blood cell (w) temporarily trapped in a capillary at a narrow section caused by the bulging nucleus of an endothelial cell (e) and the nucleus of a pericyte (p). The cylindrical shape of the white blood cell after adjustment to the capillary dimensions is clearly seen. Some plasma seems to pass beyond the white blood cell so that red blood cells are seen to accumulate behind the white blood cell and form a temporary rouleaux formation (r). Arrow denotes flow direction. (Courtesy of Dr. Bagge, University of Goteborg. Sweden.)
possible at constant volume without stretching of the cell membrane. The adaptation of WBCs to the narrow arteriolar orifices of capillaries seems critical even under resting blood flow conditions. They are often seen trapped at the entrance of capillaries, and the transformation from spheres to cylinders may require a few seconds or sometimes even some minutes.33.34 They are also halted at narrow sections along the capillary. Figure 1 shows a trapped WBC in a capillary at a narrowing caused by the bulging nucleus of an endothelial cell and an adjacent pericyte. The figure shows well the appearance of a deformed WBC when it has adjusted to the dimensions of the capillary. It has not been possible to establish whether a trapped WBC can sIowly move out of such a wedge position by active movements. The deformation of WBCs in the capillaries requires energy. The major driving force is probably the hydrostatic pressure within the capillary, which during resting conditions is about 30 mm Hg at the arteriolar end and 8 to 10 mm Hg lower at the venular end.27s39 Blood viscosity, and the surface characteristics and dimension of WBCs as well as of capillaries, are all factors important to the amount of energy that is needed for the capillary passage of the cells. At high flow rates, the WBCs seem to be mainly carried in the axial blood stream in the arterioles and are therefore possibly shunted through the microvasculature via large capillaries, i.e., via “thoroughfare channels.” Thus, normally relatively few of them engage small capillary side branches. When the flow rate decreases, more WBCs reach the marginal blood stream, and they are therefore more readily distributed to the capillary network. During shock, the flow rate in the microvascular bed is low and the capillary hydrostatic pressure is decreased by 30 to 40%. 27 These changes might ex102
plain why more WBCs become trapped when the subject is in shock. Compensatory mechanisms, such as hemodilution and reduction of blood viscosity due to transcapillary fluid reabsorption, do not seem efficient enough to overcome the decrease in hydrostatic driving pressure during shock. Shock-induced changes in viscoelastic properties of WBCs could be another factor of importance for trapping of WBCs in capillaries. However, no qualitative differences in stiffness of WBCs before and after shock have been demonstrated in vitro.30 This does not exclude the possibility that changes in the viscoelastic properties of WBCs occur in vim, since the WBCs that are affected may be the ones seen trapped in the microvasculature. In many of the capillaries that remain open, the flow rate is usually high and the blood can probably not be utilized efficiently for cellular nutrition. It may therefore represent a shunting of blood through the tissue, which is in agreement with the decreasing arterio-venous oxygen tension gradient usually seen during shock conditions. It may thus be concluded that recent intravital microscopic studies of the microcirculation in skeletal muscle during hemorrhagic shock indicate that blocking of capillaries by WBCs can be an important reason for the pronounced maldistribution of blood flow within the microvasculature. Red BloodCells Red blood cells (RBCs) also have to be deformed during their passage through capillaries, since the average diameter of RBCs (7.5 pm) exceeds that of most capillaries.24 Their deformation is determined by the intrinsic deformability of the cell and the shear stress acting on the cell surface.40 Red blood cells have a favourable surface-area-to-volume ratio, which allows
HALJAMiiE
FIGURE 2. Disturbances in blood-tissue exchange processes during shock. Left, During resting conditions there is an adequate blood supply to the tissues, aerobic tissue metabolism, and undisturbed bloodtissue exchange of substances. Right, (1) Shock reduces the capillary surface area available for exchange processes; (2) the density of the interstitial ground substance increases because of mobilization of fluid from the interstitium; (3) the resulting impairment of blood-tissue exchange processes causes tissue hypoxia: (4) metabolites accumulate locally and (5) affect cellular energy production: (6) the cell can no longer keep up a normal transcellular potassium gradient; (7) the transmembrane potential level decreases; (8) because of the impaired blood-tissue exchange metabolites, hydrogen ions, potassium, and so on accumulate in the interstitium and may interfere with the function of the vascular smooth muscle cells, so that (9) the irreversible phase of shock ensues when, at reflow, fluid is lost into the interstitium. (From HaljamPe H, et al. Pathophysiology of shock. Pathol Res Pratt 1979:165:200-211.)
n MICROCIRCULATION
RESTING CONDITION I HYPOVOLEMIC
SHOCK
CELLS
INTERS
VASCUL
pronounced deformations at constant volume and surface area.41 Three-dimensional observations of RBC deformation in capillaries indicate that it occurs primarily by a folding of the disc about the longitudinal axis of the capillary.42q43 Although the mechanical properties of the RBCs are important determiners of blood flow, RBCs seem to deform very easily during normal conditions and are not seen to obstruct capillary blood flow. The flow of RBCs through tissues is further enhanced by a low functional hematocrit in the capillaries because of faster passage of RBCs than of plasma through the capillary bed.‘4 Recent studies have demonstrated significant alterations in the homeostasis of RBCs during shock.44-47 There is an increase in intracellular sodium and a decrease in intracellular potassium caused by changes in membrane permeability and in active sodium transport. The water content of RBCs is also increased. This may affect the surface-to-volume ratio and thereby the deformability of RBCS.~~ In studies with the vital microscope, no capillary obstruction by individual RBCs has been described during shock.22.23,36 However, RBCs are often seen to accumulate behind slowly moving or arrested WBCs, as shown in Figure 1. A slow passage of plasma past trapped WBCs may explain the buildup of such rouleaux formations. When the WBCs move on and reach the venules, these rouleaux formations break up immediately. These RBC aggregates adjacent to WBCs may thus explain the presence of a slowly circulating RBC volume during shock, 49 but they do not seem to be of importance for the distribution of the blood flow within the microvasculature.
MICROCIRCULATORYCHANGES AN0 TISSUE METABOLISM DURINGSHOCK Tissue oxygen tension in skeletal muscle decreases considerably following blood 10ss.~,~~~~ The intravital microscopic observations of a very heterogeneous distribution of the remaining blood flow within the microvasculature suggests the presence of marked local variations in tissue oxygen tension as well. Direct mapping of oxygen pressure fields in skeletal muscle following hemorrhage verifies such a variation.51y52 It seems logical to assume that the observed WBC plugging of capillaries is the main reason for these local variations in tissue oxygen tension. Differences in blood supply to oxidative muscles could, however, also contribute, since the blood flow to red muscle fibers seems less affected than that to white ones during shock.53 Hemorrhagic shock results in a pronounced tissue anaerobiosis in skeletal muscle (Fig. 2). Increased tissue levels of lactate and hydrogen ions are seen, and the production and utilization of high-energy phosphagens is disturbed. 9,10,12Muscle cells can no longer keep up a normal transmembrane gradient of electrolytes, and as a consequence the membrane potential level decreases from a normal resting level of - 90 mV to as low as - 60 to - 70 mV.5,6+12*13 The reduction of the transmembrane potential level of muscle cells seems intimately related to the severity of a hypoxic injury.‘3,54-56 Transmembrane potential measurements have therefore been used to reveal local variations in cell injury within skeletal muscle during hypovolemic shock.57 When thin microelectrodes are slowly ad103
AMERICAN
JOURNAL
OF EMERGENCY
MEDICINE
n Volume 2, Number 1
vanced through muscle tissue, the transmembrane potential level of each penetrated muscle cell is obtained. In resting skeletal muscle there is only a small variation in the membrane potential level between adjacent muscle fibers. During shock, however, large differences are seen, ranging from normal level to values as low as -60 mV. These observations of cellular functional disturbances during shock are therefore well in agreement with intravital microscopic observations of blood flow distribution. This heterogeneity in blood flow distribution and in consequent cellular injury could represent a sophisticated defense mechanism of the body that serves to limit the tissue injury in a critical situation. Since the remaining blood flow to the tissue during shock is too low to supply all the cells with sufficient amounts of oxygen, some cells are sacrificed so that others may survive.
MICROCIRCULATORY CHANGES AND BLOODTISSUE EXCHANGE DURING SHOCK The exchange of substances between blood and tissue cells is dependent on blood flow, capillary surface area, capillary permeability, concentration gradients, and transport through the interstitial tissue and across cell membranes. The intravital microscopic studies, referred to above, clearly show that the blood flow and the capillary surface area available for exchange processes are both markedly reduced in skeletal muscle following blood loss. “Hidden acidosis”58 and “hidden cellular electrolyte changes”5~‘2~59during shock have also been demonstrated. “Hidden” means that local tissue changes are not at all, or only partly, reflected in central blood. Today it is well recognized that the levels of (for instance) lactate, hydrogen ions, and potassium in the interstitial fluid are all significantly higher than the corresponding blood levels during shock.‘? It is still unclear, however, whether the observed disturbance in blood flow to the tissues is the main reason for the impaired blood-tissue exchange, or whether changes within the interstitial tissue are also of importance.5q’2 Shires and co-worker@ studied the equilibration of radiosulfate for measurement of the extracellular space during shock and found a reduction of the functional extracellular space. The equilibration of radiosulfate depends not only on blood flow distribution but also on diffusion through the interstitium. Appelgren and Lewis6i separated these two components by studying the local tissue clearance of injected radioactive iodide and xenon. The clearance of xenon is flow-limited, and that of iodide is diffusion-limited. They found that diffusion was considerably more limited than blood flow in skeletal muscle during shock. A similar transport defect within the interstitial tissue was advocated by Koven et al,62 and this is in agreement with our earlier studies on interstitial electrolyte changes during shock.5.S9,63 The impaired diffusion
through the interstitium in shock states seems to be caused by an increase in interstitial colloidal density due to the compensatory mobilization of fluid from the interstitium into the circulation. 12*@ Present data thus suggest that microcirculatory as well as interstitial factors are both of importance for the impaired bloodtissue exchange of substances during hemorrhagic shock. The pathophysiologic events within the tissue are summarized in Figure Z.t* These changes in bloodtissue exchange processes may be looked upon as part of an important defense mechanism, since metabolites and other potentially toxic substances from hypoxic cells in peripheral tissues are prevented from reaching central blood and thereby disturbing the function of vital organs. In late shock, however, such an interstitial accumulation of metabolites, hydrogen ions, potassium, etc. may initiate the decompensatory phase because of local interference with the function of vascular smooth muscle cells.5*12*65
MICROCIRCULATORY EFFECTS OF SHOCK TREATMENT The aim of shock therapy is to restore an adequate nutritive blood flow to tissues so that cellular metabolism and function are normalized. The hemodynamic and metabolic effects of treatment with various types of fluids have been studied extensively. However, the microcirculatory effects are not known in detail. Most indirect studies indicate that disturbances in tissue perfusion may persist for prolonged periods of time following treatment, since defects in peripheral indicator mixing and in oxygen utilization often can be demonstrated.27*59*66-70Factors such as tissue edema, microembolus-induced closure of capillaries, and swelling of endothelial cells have been considered of importance for the impaired reperfusion. Direct intravital microscopic studies of the effects of fluid administration on the microcirculation in skeletal muscle of subjects in shock have also shown that the distribution of blood flow remains heterogeneous in spite of the fact that near-normal arterial blood pressure is reached.” Many capillaries remain blocked by WBCs, and the postinfusion increase in blood flow is mainly restricted to previously perfused capillaries. There are, however, differences in the microcirculatory effects depending on the type and amount of fluid given.” Treatment of hemorrhagic shock by restoring only the shed volume of blood does not seem to restitute normal flow pattern within the tissue. The volume flow increases, but this is mainly due to increased flow velocities in previously perfused capillaries. Many capillaries thus remain blocked by WBCs, and temporary rouleaux formations at trapped WBCs, as shown in Figure 1, are still commonly seen. After resuscitation with crystalloids, a postinfusion hyperemia is seen, but the maldistribution of blood flow within the capillary bed persists. Crystalloids also
HALJAMAE
seem to induce a pronounced edema in skeletal muscle when given in small volumes (two times lost blood volume) after prolonged hemorrhagic shock.71 Colloid given as dextran 70 following shock seems to mobilize trapped WBCs better and reduces the defect in tissue perfusion more than do whole blood or crystalloids. The beneficial effects of dextran on blood viscosity could perhaps explain enhanced WBC mobilization.‘* From such experimental studies,‘l however, no decisive conclusions can be drawn regarding the ideal shock treatment for efficient restitution of microvascular blood flow. There is still a lack of information on the microcirculatory, cellular metabolic, and cellular functional effects of the adminstration of optimal combinations of fluids supplemented by proper pharmacologic modulation of the activity of the symphathetic nervous system and of vascular tone. In studies with the vital microscope, edema formation in skeletal muscle following shock treatment is often seen.71 Swelling of the interstitial tissue, endothelial cells, and WBCs could explain a poor capillary reperfusion in the postinfusion period. Regimens for reduction of tissue swelling as part of the initial treatment may therefore be of value. This could, for instance, be obtained by giving hypertonic solutions or by supplying the cells with energy in order to rapidly normalize membrane transport function and thereby cellular volume control. Prevention of tissue damage during shock and ischemia by infusion of hypertonic solutions has repeatedly been reported. Brooks and co-workers73 showed in 1963 that recovery from hemorrhagic shock occurred more rapidly in dogs treated with 1.8% saline, 2.74% sodium bicarbonate, or 10% glucose than in dogs treated with isotonic solutions. It was assumed that the hypertonicity reduced postischemic cellular swelling. Since then, the use of hypertonic solutions for situations such as tissue preservation is commonly accepted.74 Hypertonic glucose, saline, mannitol, or imidazole solutions for shock treatment have all been shown to reduce tissue perfusion defects and increase surviva1.70~75-77On the basis of the concepts presented here on pathophysiologic changes during shock (Fig. 2), initial treatment with hypertonic solutions seems valuable, since loss of fluid at reperfusion into a hyperosmotic interstitium is prevented, and swelling of endothelial cells as well as WBCs may be reduced. The passage of WBCs through capillaries may be further enhanced by the direct vasodilatory action of hypertonic solutions on the microvasculature.78 Correction of shock-induced tissue abnormalities by intravenous administration of ATP-MgC12 has been considered of value in the treatment of shock.79,80 The exact mechanism for the ATP-mediated beneficial effects are not known. The ATP may improve tissue perfusion by its vasodilatory actions and/or provide energy for restitution of membrane function in hypoxic cells. Both effects could be of importance for release
n MICROCIRCULATION
of trapped WBCs from the microvascuiature. Steroids may be of importance for the restitution of adequate tissue perfusion following shock by stabilizing cell membranes and by blocking the local inflammatory response to tissue anoxia. Intravital microscopic studies indicate that extravasation of WBCs is common in the late stages of shock.22*23Such a migration of WBCs is prevented by steroids.81 Other beneficial effects of steroids, such as reduction of peripheral vascular resistance8*yg3 and increase in tissue oxygen availabilitys4 may also favor reperfusion of blocked capillaries.
CLINICAL MONITORING OF SHOCK-INDUCED MICROCIRCULATORY CHANGES The cellular metabolic consequences of the microcirculatory deterioration in peripheral tissues during shock are only partially reflected in central blood (Fig. 2). Skeletal muscle, being the largest cell mass of the body and suffering a severe reduction in blood flow, is the major source of lactate.85 Information on local changes in skeletal muscle and on blood-tissue gradients is therefore of considerable value in the clinical management of critically ill patients. The overall tissue perfusion defect can be estimated by measuring cardiovascular, respiratory, and blood parameters from which oxygen transport and consumption can be calculated.67,86 Direct measurements of the oxygen tension in the tissue and of the blood-tissue gradient by the use of microelectrodes seem to provide a more valuable index of tissue perfusion.50-52~87*88 The severity of the concomitant tissue metabolic and cellular functional disturbances can be evaluated from measurements of blood-tissue pH and potassium gradients.89-95 Clinical experience with the use of various types of microelectrodes for monitoring of shock-induced microcirculatory changes is increasing. Within a few years it may be part of the routine monitoring of all critically ill patients. The author thanks Dr. Bagge, of the Laboratory of Experimental Biology, Department of Anatomy, University of Gdteborg, Sweden, for valuable discussions and for supplying Figure 1.
REFERENCES 1. Gerratana FJ, Saranchak HJ, Owens G. Cerebral and hepatic blood flow measured during shock using the mass spectrometer. J Surg Res 1976;20:489-492. 2. Silver IA. Ion fluxes in hypoxic tissues. Microvasc Res 1977;13:409-420. 3. Lovelace DR, Short BL, Rink RD. Hepatic oxygen supply in reversible and irreversible hemorrhagic shock. J Surg Res 1979;26:120-128. 4. Brantigan JW, Ziegler EC, Hynes KM, et al. Tissue gases during hypovolemic shock. J Appl Physiol 1974;37:117122. 5. Haljamtie H. “Hidden” cellular electrolyte responses to hemorrhagic shock and their significance. Rev Surg 1970;27:315-324.
AMERICAN
JOURNAL
OF EMERGENCY
MEDICINE
n Volume
6. Cunningham JN Jr, Shires GT, Wagner Y. Cellular transport defects in hemorrhagic shock. Surgery 1971;70:215-222. 7. Baue AE, Wurth MA, Chaudry IH, et al. Impairment of cell membrane transport during shock and after treatment. Ann Surg 1973;178:412-421. 8. Chaudry IH, Sayeed MM, Baue AE. Depletion and restoration of tissue ATP in hemorrhagic shock. Arch Surg 1974;108:208-211. 9. Baue AE, Chaudry IH, Wurth MA, et al. Cellular alterations with shock and ischemia. Angiology 1974;25:31-42. IO. Schumer W, Erve PR. Cellular metabolism in shock. Circ Shock 1975;2:109-127. 11. Chaudry IH, Sayeed MM, Baue AE. Alterations in high-energy phosphates in hemorrhagic shock as related to tissue and organ function. Surgery 1976;79:666-668, 12. Haljamae H, Amundson B, Bagge U, et al. Pathophysiology of shock. Pathol Res Pratt 1979;165:200-211. 13. lllner H, Shires GT. The effect of hemorrhagic shock on potassium tranport in skeletal muscle. Surg Gynecol Obstet 1980;150:17-25. 14. Holliday RL, lllner HP, Shires GT. Liver cell membrane alterations during hemorrhagic shock in the rat. J Surg Res 1981;31:506-515. 15. Sayeed MM, Adler RJ, Chaudry IH, et al. Effects of hemorrhagic shock on hepatic transmembrane potentials and intracellular electrolytes, in vivo. Am J Physiol 1981;240:R211-R219. 16. Branemark P-l, Eriksson E. Method for studying qualitative and quantitative changes of blood flow in skeletal muscle. Acta Physiol Stand 1972;84:284-288. 17. Baez S. An open cremaster muscle prepartation for the study of blood vessels by in vivo microscopy. Microvasc Res 1973;5:384-394. 18. Hutchins PM, Goldstone J, Wells R. Effects of hemorrhagic shock on the microvasculature of skeletal muscle. Microvast Res 1973;5:131-140. 19. Myrhage R, Hudlicka 0. The microvascular bed and capillary surface area in rat extensor hallucis proprius muscle (EHP). Microvasc Res 1976;11:315-323. 20. Fronek K, Zweifach BW. Microvascular blood flow in cat tenuissimus muscle. Microvasc Res 1977;14:181-189. 21. Amundson B, Bagge U, Haljamae H. Control of tissue environment during vital microscopy of the microcirculation in the m. tenuissimus in cat. Acta Physiol Stand 1980;108:139-146. 22. Amundson B, Jennische E, Haljamae H. Correlative analysis of microcirculatory and cellular metabolic events in skeletal muscle during hemorrhagic shock. Acta Physiol Stand 1980;108:147-158. 23. Amundson B. Skeletal muscle microcirculation and metabolism in hemorrhagic shock (doctoral thesis). Medical Faculty, University of Goteborg, Sweden, 1979. 24. Gaethgens P. Hemodynamics of the microcirculation. Physical characteristics of blood flow in the microvasculature. In Meessen H (ed). Handbuch der Allgemeinen Pathologie
25. 26. 27.
28.
ill/7. Microcirculation. Berlin, Heidelberg: SpringerVerlag, 1977:231-287. Johnson PC. The myogenic response and the microcirculation. Microvasc Res 1977;13:1-18. Kunze K. Spontaneous oscillations in Pop in muscle tissue. Adv Exp Med Biol 1976;75:631-637. Zweifach BW. Mechanisms of blood flow and fluid exchange in microvessels: Hemorrhagic hypotension model. Anesthesiology 1974;41:157-168. Lundvall J, Hillman J. Fluid transfer from skeletal muscle to blood during hemorrhage: Importance of beta-adrenergic vascular mechanisms. Acta Physiol Stand 1978;102:450458.
2, Number
1
29. Hillman J. Further studies on beta-adrenergic control of transcapillary fluid absorption from skeletal muscle to blood during hemorrhage. Acta Physiol Stand 1981; 112;281-286. 30. Bagge U, Amundson B, Lauritzen C. White blood cell deformability and plugging of skeletal muscle capillaries in hemorrhagic shock. Acta Physiol Stand 1980;180:159163. 31. Eriksson E, Lisander B. Low flow states in microvessels of skeletal muscle in cat. Acta Physiol Stand 1972;86:202210. 32. Eriksson E, Ericsson LE. Intra- and extravascular morphology in skeletal muscle at low flow states. Bibl Anat 1973;12:308-314. 33. Bagge U, Brdnmark P-l. White blood cell rheology. An intravital study in man. Adv Microcirc 1977;7:1-17. 34. Bagge U, Johansson BR, Olofsson J. Deformation of white blood cells in capillaries: A combined intravital and electron microscopic study in the mesentery of rabbits. Adv Microcirc 1977;7:18-28. 35. Bagge U, Skalak R, Attefors R. Granulocyte rheology. Experimental studies in an in vitro micro-flow system. Adv Microcirc 1977;7:29-48. 36. Bagge U, Amundson B, Braide M. A method to observe and quantitate leukocyte interference with low flow in the skeletal muscle microcirculation. Bibl Anat 1981;20:557560. 37. Wilson JW. Leukocyte sequestration and morphological augmentation in the pulmonary network following hemorrhagic shock and related forms of stress. Adv Microcirc 1972;4:197-232. 38. Eriksson E, Myrhage R. Microvascular dimensions and blood flow in skeletal muscle. Acta Physiol Stand 1972;86:211-222. 39. Zweifach BW. Microcirculation. Am Rev Physiol 1973; 35:117-150. 40. Chien S. Determinants of blood viscosity and red cell deformation. Stand J Clin Lab Invest 1981;41 (Suppl 156):712. 41. Schmid-Schonbein H, Gaehtgens P. What is red cell deformability? Stand J Clin Lab Invest 1981;41(Suppl 156):13-26. 42. Bagge U, Branemark P-l, Karlsson R, et al. Three-dimensional observations of red blood cell deformation in capillaries. Blood Cells 1980;6:231-237. 43. Bagge U, Brat-remark P-l. Red cell shapes in capillaries. Stand J Clin Lab Invest 1981;41(Suppl 156):59-61. 44. Cunningham JN Jr, Shires GT, Wagner Y. Changes in intracellular sodium and potassium content of red blood cells in trauma and shock. Am J Surg 1971;122:650-654. 45. Day 8, Friedman SM. Red cell sodium and potassium in hemorrhagic shock measured by lithium substitution analysis. J Trauma 1980;20:52-54. 46. lllner HP, Cunningham JN Jr, Shires GT. Red blood cell sodium content and permeability changes in hemorrhagic shock. Am J Surg 1982;143:349-355. 47. Kreis DJ Jr, Chaudry JH, Schleck S, et al. Red cell sodium, potassium and ATP levels during hemorrhagic shock. J Surg Res 1981;31:225-231. 48. LaCelIe PL, Smith BD. Biochemical factors influencing erythrocyte deformability and capillary entrance phenomena. Stand J Clin Lab Invest 1981;41(Suppl 156):145-149. 49. Gibson JG, Seligman AM, Peacock WC, et al. The circulating red cell and plasma volume and the distribution of blood in large and minute vessels in experimental shock in dogs, measured by radioactive isotopes of iron and iodine. J Clin Invest 1947;26:126-144. 50. Niinikoski J. Tissue oxygenation in hypovolemic shock. Ann
HALJAMAE
Clin Res 1977;9:151-156. 51. Kessler M, Hoper J, Krumme BA. Monitoring of tissue perfusion and cellular function. Anesthesiology 1976;45: 184-197. 52. Lund N, Cdman S, Lewis DH. Skeletal muscle oxygen pressure fields in rats: A study of the normal state and the effects of local anesthetics, local trauma and hemorrhage. Acta Anaesththesiol Stand 1980;24:155-160. 53. Jennische E, Amundson 8, Haljamae H. Metabolic responses in feline “red” and “white” skeletal muscle to shock and ischemia. Acta Physiol Stand 1979;106:39-45. 54. Jennische E, Medegard KAI, Haljamae H. Transmembrane potential changes as an indicator of cellular metabolic deterioration in skeletal muscle during shock. Eur Surg Res 1979;10:125-133. 55. Jennische E, Enger E, Medegard A, et al. Correlation between tissue pH, cellular transmembrane potentials, and cellular energy metabolism during shock and during ischemia. Circ Shock 1978;5:251-260. 56. Jennische E, Hagberg H, Haljamle H. Extracellular potassium concentration and membrane potential in rabbit gastrocnemius muscle during tourniquet ischemia. Pflugers Arch 1982;392:335-339. 57. Haljamae H, Jennische E, Medegard A. Transmembrane potential measurements as an indicator of heterogeneous distribution of nutritive blood flow in skeletal muscle during shock. Acta Physiol Stand 1977;101:458-464. 58. Bergen& S-E, Carlsten A, Gelin L-E, et al. “Hidden acidosis” in experimental shock. Ann Surg 1969;169:227-232. 59. Hagberg S, Haljamae H, Rockert H. Shock reactions in skeletal muscle: Ill. The electrolyte content of tissue fluid and blood plasma before and after induced hemorrhagic shock. Ann Surg 1968;168:243-248. 60. Middleton ES, Mathews R, Shires GT. Radiosulphate as a measure of the extracellular fluid in acute hemorrhage. Ann Surg 1969;170:174-186. 61. Appelgren KL, Lewis DH. Capillary flow and capillary transport in dog skeletal muscle in hemorrhagic shock. Eur Surg Res 1972;4:29-45. 62. Koven IH, MacMillan N, Lo S, et al. Correction by hyaluronidase of the interstitial tissue transport defect during shock: A new approach to therapy. J Trauma 1975; 15:992-997. 63. Haljamae H. Effects of hemorrhagic shock and treatment with hypothermia on the potassium content and transport of single mammalian skeletal muscle cells. Acta Physiol Stand 1970;78:189-200. 64. Haljamae H. Anatomy of the interstitial tissue. Lymphology 1978;11:128-132. 65. Zweifach BW, Fronek A. The interplay of central and peripheral factors in irreversible hemorrhagic shock. Prog Cardiovasc Dis 1975;18:147-180. 66. Shires T, Coln D, Carrico J, et al. Fluid therapy in hemorrhagic shock. Arch Surg 1964;88:688-693. 67. Shoemaker WC, Reinhard JM. Tissue perfusion defects in shock and trauma states. Surg Gynecol Obstet 1973; 137:980-986. 68. Wright CJ. Regional effects of hypovolemia and resuscitation with whole blood, saline or plasma. J Surg Res 1975;18:9-16. 69. Small A, Homer LD. An explanation of impaired solute mixing in extracellular fluid after hemorrhagic shock. Am J Physiol 1979;236:H440-H446. 70. Shah DM, Newell JC, SabaTM. Defects in peripheral oxygen utilization following trauma and shock. Arch Surg 1981;116:1277-1281. 71. Amundson 8, Jennische E, Haljamae H. Skeletal muscle microcirculatory and cellular metabolic effects of whole blood, Ringer’s acetate, and dextran 70 infusions in hem-
n MICROCIRCULATION
orrhagic shock. Circ Shock 1980;7:111-120. 72. Gruber UF, Messmer K. Colloids for blood volume support. Prog Surg 1977;15:49-76. 73. Brooks DK, Williams WG, Manley RW, et al. Osmolar and electrolyte changes in haemorrhagic shock: Hypertonic solutions in prevention of tissue damage. Lancet 1963;1:521-527. 74. Collings GM, Hartly LCJ, Clunie GJA. Kidney preservation for transportation. Br J Surg 1972;59:187-189. 75. Fritz SD, Fills CT, Lurie D. The effect of hypertonic glucose upon survival in hemorrhagic shock utilizing a re-stress model in sheep. J Trauma 1976;16:284-288. 76. De Felippe J Jr, Timoner J, Kelasco IT, et al. Treatment of refractory hypovolemic shock by 7.5% sodium cloride injections. Lancet 1980;2:1102-1104. 77. Kelasco IT, Pontieri V, Rocha-e-Silva M Jr, et al. Hyperosmotic NaCl and severe hemorrhagic shock. Am J Physiol 1980;239:H664-H673. 78. Duling BR, Staples E. Microvascular effects of hypertonic solutions in the hamster. Microvasc Res 1976;11:51-56. 79. Chaudry IH, Baue AE. The use of substrates and energy in the treatment of shock. Adv Shock Res 1980;3:27-46. 80. Chaudry IH, Clemens MG, Baue AE. Alterations in cell function with ischemia and shock and their correction. Arch Surg 1981;116:1309-1317. 81. Fauci AS. Glucocorticoid therapy: Mechanisms of action and clinical considerations. Ann Surg 1976;84:304-315. 82. Motsay GJ, Alho A, Jaegert T, et al. Effects of corticosteroids on the circulation in shock: Experimental and clinical results. Fed Proc 1970;29:1861-1873. 83. Altura BM, Altura BT. Peripheral vascular actions of glucocorticoids and their relationship to protection in circulatory shock. J Pharmacol Exp Ther 1974:190:300-315. 84. Bryan-Brown CW, Back S, Makabali G, et al. Consumable oxygen: Availability of oxygen in relation to oxyhemoglobin dissociation. Crit Care Med 1973;1:17-21. 85. Daniel AM, Shizgal HM, MacLean LD. The anatomic and metabolic source of lactate in shock. Surg Gynecol Obstet 1978;147:697-700. 86. Shoemaker WC, Launder WJ, Castagna J, et al. Method for estimation of perfusion defect in shock. J Surg Res 1976;20:77-84. 87. Niinikoski J, Halkola L. Skeletal muscle Pas: Indicator of peripheral tissue perfusion in hemorrhagrc shock. Adv Exp Med Biol 1978;94:585-592. 88. Schonleben K, Hauss JP, Spiegel U, et al. Monitoring of tissue Pop in patients during intensive care. Adv Exp Med Biol 1978;94:593-598. 89. Couch NP, Dmochowski JR, Van de Water JM, et al. Muscle surface pH as an index of peripheral perfusion in man. Ann Surg 1971;173:173-183. 90. Filler RM, Das JB, Espinosa HM. Clinical Experience with continuous muscle pH monitoring as an index of tissue perfusion and oxygenation and acid-base status. Surgery 1972;72:23-33. 91. Laks H, Dmochowski JR, Couch NP. The relationship between muscle surface pH and oxygen transport. Ann Surg 1976;183;193-198. 92. Harrison DK, Walker WF. Tissue pH electrodes for clinical applications. J Med Eng Technol 1980;4:3-7. 93. Treasure T. The application of potassium selective electrodes in the intensive care unit. Intensive Care Med 1978;4:83-89. 94. Linton RAF, Lim M, Band DM. Continuous intravascular monitoring of plasma potassium using potassium-selective electrode catheters. Crit Care Med 1982;10:337-340. 95. McKinley BA, Houtchens BA, Janata J. Continuous monitoring of interstitial fluid potassium during hemorrhagic shock in dogs. Crit Care Med 1981;9:845-851.