Pathophysiology of Shock

Path. Res. Pract. 165,

200 -2II

(1979)

Review

The Departments of Anesthesiology I, Anatomy (Lab. of Experimental Biology) and Histology, University of Gotebo rg, Goteborg, Sweden

Pathophysiology of Shock 1 Pathophysiologie desSchocks H. HAL]AM.KE, B. AMUNDSON, U. BAGGE, E. ]ENNISCHE, and P.-I. BRANEMARK

Circulatory shock is a complex syndrome which severely disturbs the homeostasis of the entire organism. It may be caused by such different conditions as hemorrhage, trauma, dehydration, sept icemia, anaphylaxis or acute heart failure. According to current definitions, the common , pathophysiological denominator in shock is an acute failure of the circulation to meet the nutritive demands of vital tissues. As a result of this hemodynamic disturbance, functional and structural changes occur in the organs affected. It follows that despite obvious differences in pathogenetic events, depending upon type of shock , basic similarities in tissue reaction to shock should exist regardless of cause. In this survey we will examine the sequence of events occurring during hypovolemic shock caused by hemorrhage or deh ydration. The acute loss of circul at ing blood or plasma, often in combination with a certain amount of mechanical or biochemical tissue trauma, initiates an intense neurohumoral activation. The catecholamine input increases and the sympathetic nervous system is activated (Rosenberg et al., 1961; Chien, 1967). An important defense mechanism of the body is hereby put into action, the aim of which is to try to maintain sufficient blood flow to the central organs. This redistribution of flow favours mainly heart, brain, kidneys, and liver at the expense of highly reduced flow to more peripheral tissues such as skin and skeletal muscle (Bond et a1. , 1967; Ru1 This work was supported by grant s from the Swedish Medical Research Council, The Medical Faculty in Gorcborg, Trygg -Hansa So-year Fund, Tore Nilssons Fund for Medical Research, and Pharmacia All, Uppsala , Sweden.

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therford et a1., 1968; Mellander and Johansson, 1968). The cellular content and the metabolic demands of these tissues as a whole are considerable, however. Skeletal muscle alone constitutes 40 to 50 per cent of the total cellular mass of the body. Due to vasoconstriction during shock, the blood flow to resting skeletal muscle is reduced to 15-20 per cent of normal (Rutherford et a1., 1968). This remaining flow is insufficient to cope with the oxygen demands of the tissue, and anaerobic metabolism will ensue (Baue et a1., 1974; Schumer and Erve, 1975). However, metabolites such as lactic acid do not reach the central circulation until late in the course of a hypovolemic shock condition. Instead, peripheral tissues in general and skeletal muscle in particular seem to have an extracellular "buffer" capacity with respect to their own degradation products in such emergency situations as shock. Thus, while nutritive blood flow is redistributed to vital organs, the anaerobically produced, potentially toxic metabolites are prevented from reaching the central circulation through interstitial immobilization. Through these mechanisms, "hidden" local cellular changes take place (Bergentz et a1., 1969; Haljamae, 1970a). At the stage of irreversibility, however, the demands of the peripheral tissues apparently become overwhelming, and fluid is lost into the hypoxic areas. Toxic metabolites are cleared and thus affect the function of the heart and the brain. It is becoming increasingly obvious that the majority of important pathophysiological changes which take place during shock occur in peripheral cellular tissues. In the present survey, we will focus upon the interplay between microvascular, interstitial, and cellular changes in skeletal muscle during hypovolemic shock.

Cardio-Vascular Responses to Shock Acute hypovolemia leads to the activation of a number of compensatory mechanisms (Fig. I). The cardiovascular adjustments in the initial phase seem to be conveyed mainly by circulating hormones and only to a lesser extent by adrenergic nerves (Hall et a1., 1976; Anderson and Ludbrook, 1976). Vasoconstrictor fiber discharge is also considerably acceleated, however, and contributes to increased vascular resistance in peripheral tissues. Skeletal muscle is one of the main targets for these vasomotor reflexes. In resting skeletal muscle, approximately 80 per cent of total resistance resides in the precapillary vessels and 20 per cent in the postcapillary vessels (d. Mellander and Johansson, 1968). During shock there is a marked increase in this pre- to postcapillary resistance ratio, due to arteriolar constriction. This constriction leads to a drastic reduction in volume flow, decreased capillary hydrostatic pressure, and consequently

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al.

Peripheral nssues.s 9 skin and skeletal muscles

Fig. 1. Redistribution of blood flow to vital central organs at the expense of flow to peripheral tissues during shock. 1. - Increased pre- to postcapillary resistance ratio and plasma hyperosmolarity due to catecholamine-induced hyperglycemia favor: 2. - net absorption of extravascular fluid. 3. - Reduced tissue perfusion and preferential channel type of flow.

to a net absorption of extravascular fluid into the blood. (Mellander and

Lewis, 1963). Skin and skeletal muscle are the main sources from which fluid is mobilized into the circulation. In spite of these compensatory adjustments, there is usually a tachycardia and a decrease in cardiac output. The proportion of cardiac output reaching the vital organs is increased, but total organ blood flow is nonetheless usually subnormal; this decrease in flow is more pronounced in liver and kidneys than in heart and brain (Rutherford et al., 1968).

Microvascular Changes During Shock Several vital microscopic techniques have been used for direct observation of the microcirculatory events in skeletal muscle during shock (Branemark and Eriksson, 1972; Hutchins et al., 1973; Harris et al., 1975). Further improvement of preparative procedures and careful control of the tissue environment have made it possible to obtain preparations which seem highly representative for unexposed tissue (Amundson et al., 1979a). Acute hemorrhage results in drastic changes in the microvascular flow patterns in skeletal muscle as evidenced from studies on the m. tenuissimus

Pathophysiology of Shock . 2 0 3

Fig. 2 . Schemati c micro vascular networ k showing micro circulatory flo w disturbances during hemorrhagic shock. I. - Redu ced bulk flow and blo od hematocrit . 2. - Thoroughfar e channel with increased flow rat e. 3. - WBC plu gging capilla ry. 4. - Train flow. s. - Flow cessation without cellular plu gging. 6. - WBCs stic king to the walls of venules. 7. - O ccasional diapedesis of RBC. 8. - Ext ravasation of WBCs through ven ules.

preparation in cat (Eriksson and Lisander, 1972 ; Amundson et al., I97 9b). An intense initial vasoconstriction usually occurs, leading to almost complete cessation of blood flow for 5 to 15 minute s. This vasoconstriction occurs in central as well as tr ansverse arterioles, where as terminal arterioles do not constrict. When flo w reappears, the harmonious on-and-off pattern typical of resting skeletal muscle capillary circulation is replaced by an uneven distribution of flow (Fig 2). The transverse arteriol es may remain constricted for one hour or more. Distal arterioles are often unperfused. On th e capillary level, the number of perfused vessels is redu ced to 30 to 50 per cent of norm al, and usually three groups of capillaries can be distingui shed: capillaries perfu sed constantly, capillaries perfused at irregular intervals, and capillaries with no flow. The flow cha racteristics of the capillary bed thus seem to agree with the hypothesis of preferential or thoroughfare channels (see Zweifach, 1973).

204 . H. Haljamae et al.

Some of the flow irregularities might be due to white blood cells (WBCs), which seem to appear in increased numbers in the capillary bed in shock. The WBCs, which even normally have a tendency to plug individual capillaries temporarily (d. Bagge and Branemark, 1977), now frequently impede capillary flow for several minutes, and appear to be the single cause of permanent flow arrest in many capillaries. The retarded passage of WBCs through the capillaries may also lead to disturbed flow in red blood cells (RBCs), which become packed in columns trailing each WBC ("train-flow"). Red blood cells are also seen adhering to the endothelium in loose aggregates, and are occasionally found traversing the endothelium in a process of true diapedesis (Skalak et aI., 1970). Furthermore venular blood flow is partially obstructed because of the massive adherence of WBCs to the venular endothelium. Slow flow in the venules favors red cell aggregation, which has the adverse effect of elevating local blood viscosity. This mechanism forces single, distal capillaries to a standstill, due to local increases in venular resistance. Platelets, which play a decisive role in the late embolic and hemostatic complications in shock, are never seen to form aggregates in the muscle microcirculation during the acute hypovolemic phase, but appear as discrete, single corpuscles.

Interstitial Changes During Shock The interstitial compartment surrounds most cells of the body (Fig. 3). Its main constituents are fibrillar structures and an amorphous ground substance. The ground substance consists of various macromolecular mucopolysaccharides, which in their disaccharide subunits contain charged anionic groups such as carboxylate and/or sulphate groups. Consequently, there is a high density of negative colloidal charge along the molecular chains of these mucopolysaccharides. The relative mobility and distribution of water and small diffusible cations and anions in the interstitium is affected by the high negative charge density of mucopolysaccharides (Haljamae, 1978a). The osmotic effects of the mucopolysaccharides are also of importance in tissue homeostasis. It must be remembered that the osmotic behavior of these substances is extremely nonideal, i.e., the osmotic pressure is not directly proportional to concentration but rises rapidly with increasing concentration. Diffusional transport through the interstitium is thus also dependent upon the density of the interstitial ground substance. In the early phase of hypovolemia, the increase in pre- to postcapillary resistance ratio results in a net absorption of extravascular fluid principally from skin and skeletal muscle into the vascular compartment (see

Pathophysiology of Shock .

20 5

RESTING CONDITION, HYPOVOLEMIC SHOCK PO -90mV

AEROBIC METABOLISM

CELLS

-o

ANAEROBIC @ 3 METABOLISM LACTIC

o

+

(7)PO -lOmV

DEFICIENT ENERGY @

ACID W H+ W PRO~U~~J~+N

K'

Fig. 3. Schematic presentation of the suggested sequence of events during hypovolemic shock. Left panel. Resting conditions with largely aerobic metabolism and homeostatic equilibrium in exchange processes between cellular, interstitial, and vascular compartments. Right panel: r, - Decreased tissue perfusion resulting in 2. - interstitial dehydration and 3. - tissue hypoxia with a shift towards anaerobic metabolism. 4. - Metabolites are retained in the interstitial phase, i.e., "hidden" changes take place. 5. - Deficient cellular energy production results in 6. - leakage of intracellular electrolytes into the interstitium and 7. - a decrease in transmembrane potential (PD) takes place as an indication of cellular functional disturbances. 8. - Competitive effects of metabolites on vascular smooth muscle abolishes sympathogenic effects and leads to vasodilatation and 9. - loss of intravascular fluid into the hyperosmotic interstitium. Cardiovascular deterioration and irreversibility is the result of severe, untreated hypovolemic shock

Mellander, 1978). The early increased output of catecholamines activates glycogenolysis, and results in a hyperglycemia. The ensuing increase in plasma osmolarity further favors mobilization of fluid from the extravascular to the vascular compartment (Jarhult, 1973). The interstitial consequence is decreased hydration and thus increased concentration of im-

mobile ground substance molecules. This increased aggregation of ground substance of course increases the negative charge density as well as the interstitial osmotic effects. At the same time, diffusional transport through the interstitium is considerably restricted (Haljamae, 197oa; Haljamae, 1978b).

Cellular Metabolic Consequences of Shock The early metabolic changes during shock are dominated by increased adrenal catecholamine output. Therefore, glycogenolysis is stimulated and hyperglycemia occurs. In cellular tissues, increased levels of G6-P, glucose, and the high energy phosphagens ATP and CP are demonstrable (Myrwold et al., 1975; Amundson and Haljamae, 1976). During prolonged

206 . H. Haljarnae et al.

shock, however, oxygen transport to the tissues will be disturbed since it is flow limited (Crowell, 1970). At the same time, oxygen demand remains mainly unchanged. At an arterial blood pressure of about 40 mm Hg, tissue oxygen tension approaches zero and completely arrests aerobic metabolism (Brantigan et al., 1974). A variable amount of tissue hypoxia and anaerobic metabolism is present above this blood pressure level (Baue et al., 1974; Schumer and Erve, 1975). Sustained shock will thus affect the oxidative mitochondrial metabolism (Baue and Sayeed, 1970; Baue et al., 1972; Mela et al., 1971). There is increasing depletion of tissue high energy phosphagen stores, and the tissue content of lactate increases (Jennische et al., 1978a; ]ennische et al., 1978b). Cellular membrane function is disturbed, as evidenced by disturbances in the electrolyte transport characteristics of single cells (Haljamae, 1970b) and tissue slices (Baue et al., 1973; Lindberg et al., 1978). The cellular transmembrane potential decreases during shock, from a resting level of around - 90 mV to values as low as - 70 to - 5° mV (Campion et al., 1969; Cunningham et al., 1971; Shires et al., 1972; Trunkey et al., 1973). The decrease in transmembrane potential seems directly correlated to the extent of cellular metabolic disturbance, i.e., there are linear correlations between membrane potential decrease in - mV on the one hand and tissue increase in lactate or decrease in pH or high energy phosphagens on the other hand (Jennische et al., 1978a; ]ennische et al., 1978b; Amundson et al., 1979b). There are marked differences in metabolic and transmembrane potential changes between adjacent cells, due to heterogenity in microcirculatory distribution of nutritive blood flow (Haljamae et al., 1977). The majority of these cellular metabolic changes remain "hidden", i.e. they are only poorly reflected in blood variables (Bergentz et al., 1969; Haljamae, 197oa). It has repeatedly been shown that skeletal muscle pH decreases from values around 7.30-7.40 to levels of 6,5°-6.9° during hypovolemic shock, while arterial pH remains largely unchanged (Lemieux et al., 1969; Couch et al., 1971; Filler et al., 1971; Weintraub et al., 1972; Kung et al., 1976; Medegard et al., 1978). This discrepancy must depend upon disturbances in the exchange processes between cells and the vascular compartment during shock.

Interplay Between Microvascular, Interstitial and Cellular Changes During Shock In a critical situation such as acute hypovolemia, one of the defence mechanisms of the body is to redistribute blood flow to vital organs from less important peripheral tissues such as skin and skeletal muscle. At the

Pathophysiology of Shock . 207

same time, the potentially toxic metabolites produced in anoxic tissues which have been deprived of their nutritive blood flow must be prevented from reaching the circulation. The interplay between the microvascular, interstitial, and cellular compartments seems to be of major importance in this context (Haljamae, 197oa; Haljamae, 1978b). The above microcirculatory changes participate in a deviation of flow from peripheral tissues. The remaining flow, probably in part of the preferential channel type, is insufficient for clearance of metabolites. At the same time, however, there are profound changes in the functional capacity of the interstitial phase (Fig. 3). The increased density of interstitial ground substance, caused by initial mobilization of fluid into the vascular compartment, markedly affects the transport of substances between blood and cells. There is a much higher charge density per volume of interstitial tissue, which affects the distribution and transport of all charged substances. The increased charge density profoundly limits free diffusion and increases local osmotic effects. Therefore, one expects a defect in interstitial exchange processes in excess of the limitations caused by reduction in blood flow. This has also been shown experimentally. The development of techniques for direct sampling of interstitial fluid (Haljamae, 1969; 1970C) has made it possible to show that potassium lost from hypoxic muscle cells is immobilized in the interstitium during shock (Hagberg et al., 1968). The cellular effects of this "hidden" potassium leakage are reflected as changes in transmembrane potential as shown above. Disturbances in tissue-blood exchange during shock are also demonstrable by local isotope clearance techniques (Appelgren and Lewis, 1972; Appelgren, 1972; Koven et al., 1975), which clearly show a restricted diffusion of ionized tracers in tissues with low, heterogenous flow. The gradients between arterial pH and skeletal muscle pH, demonstrated in dehydration shock (Medegard and Haljarnae, 1979), is another evidence for interstitial immobilization, in this case of hydrogen ions. In summary, it may be concluded that signs of cellular damage from hypoxia in peripheral tissues become "hidden" from the central circulation due to simultaneous changes in microcirculatory flow distribution and interstitial hydration. The changes remain "hidden" until the shock state is either treated or starts to decompensate.

Aspects Concerning Irreversibility in Shock The maintenance of "hidden" cellular changes during prolonged shock requires sustained vasoconstriction in peripheral tissues. The hypoxia and local interstitial accumulation of potassium, lactate, and hydrogen ions,

208 . H. Haljamae et al.

however, eventually affect the metabolism of the vascular smooth muscle cells as well. This leads to decreased responsiveness of the vascular wall to sympathetic vasoconstrictor activity (Skinner and Powell, 1967; Skinner and Costin, 1969; Hilton, 1971; Mellander, 1971; Zweifach and Fronek, 1975). Precapillary vessels, which are the main target of sympathetic activity, are more sensitive to this local dilating influence than postcapillary vessels (Lundgren et al., 1964). In an advanced shock state, this "vessel fatigue" gradually decreases precapillary tone and consequently diminishes the pre- to postcapillary resistance ratio. This results in slowly increasing capillary perfusion to hypoxic tissues, which have acquired a highly hyperosmotic interstitium due to dehydration and accumulation of metabolites. Outward diffusion of water and interstitial dilution are hereby promoted. Increased capillary flow then starts to clear some of the previously immobilized metabolites, which may now upset critical plasma equilibria and endanger the function of the myocardium and the brain. Retransfusion of blood or blood subtitutes usually do not affect the outcome at this stage. The transfused fluid is rapidly lost to the peripheral tissues, leading to a rise in circulating levels of potassium, acidic metabolites, and in many cases proteolytic enzymes from deteriorating cells. A vicious cycle is thus established through which further impairment of cardiovascular function ensues.

References Amundson, B., Bagge, D., and Haljamae, H.: Control of tissue environment during vital microscopy of the microcirculation in m. tenuisslmus in cat. Acta Physiol. Scand. (I979a, in press) Amundson, B., and Haljamae, H.: Skeletal muscle metabolites as possible indicators of imminent death in acute hemorrhage. Europ. Surg. Res. 8, pI-pO (1976) Amundson, B., Jennische, E., and Haljarnae, H.: Correlative analysis of microcirculatory and metabolic events in skeletal muscle during hemorrhagic shock. Acta Physiol. Scand. (1979b, in press) Anderson, W. P., and Ludbrook, J.: Effects of the sympathetic nervous system and the adrenal medullary hormones on dog hind limb blood flow after haemorrhage. Aust, J. expo BioI. Med. Sci. 54, 169-180 (1976) Appelgren, L.: Perfusion and diffusion in shock. A study of disturbed tissue-blood exchange in low flow states in canine skeletal muscle by a local clearance technique. Acta Physiol. Scand. Suppl. 478 (1972) Appelgren, K. L., and Lewis, D. H.: Capillary flow and capillary transport in dog skeletal muscle in hemorrhagic shock. Europ. Surg. Res. 4, 29-45 (1972) Bagge, D., and Branemark, P-I.: White blood cell rheology. An intravital study in man. Advanc. Microcirc. 7, 1-17 (1977) Baue, A. E., Chaudry, I. H., Wurth, M. A., and Sayeed, M. M.: Cellular alterations with shock and ischemia. Angiology 25, 31-42 (1974)

Pathophysiology of Shock . 209 Baue, A. E., and Sayeed, M. M.: Alterations in the functional capacity of mitochondria in hemorrhagic shock. Surgery 68, 40-47 (1970) Baue, A. E., Wurth, M. A., Chaudry, 1. H., and Sayeed, M. M.: Impairment of cell membrane transport during shock and after treatment. Ann. Surg. 178, 412-421 (1973) Baue, A. E., Wurth, M. A., and Sayeed, M. M.: The dynamics of altered ATP-dependent and ATP-yielding cell processes in shock. Surgery 72,94-101 (1972) Bergentz, S.-E., Carlsten, A., Gelin, L.-E., and Kreps, J.: "Hidden acidosis" in experimental shock. Ann. Surg. 169,227-232 (1969) Bond, R. F., Manley jr., E. S., and Green, H. D.: Cutaneous and skeletal muscle vascular responses to hemorrhage and irreversible shock. Amer. J. Physiol. 212,488-497 (1967) Brantigan, J. W., Ziegler, E. c., Hynes, K. M., Miyazawa, T. Y., and Smith, A. M.: Tissue gases during hypovolemic shock.]. Appl, Physiolv jj', 117-122 (1974) Campton, D. S., Lynch, L. J., Rector jr., F. c., Carter, N., and Shires, T.: Effect of hemorrhagic shock on transmembrane potential. Surgery 66, 1°51-1°59 (1969) Chien, S.: Role of the sympathetic nervous system in hemorrhage. Physiol. Rev. 47, 214-288 (1967) Couch, N. P., Dmochowski, ]. R., Van de Water, ]. M., Harken, D. E., and Moore, F. D.: Muscle surface pH as an index of peripheral perfusions in man. Ann. Surg. 17], 173- 183 (1971) Crowell, ]. W.: Oxygen transport in the hypotensive state. Fed. Proc. 29, 1848-1853 (197°) Cunningham jr., ]. N., Shires, G. T., and Wagner, Y.: Cellular transport defects in hemorrhagic shock. Surgery 70, 215-222 (1971) Eriksson, E., and Lisander, B.: Changes in precapillary resistance in skeletal muscle vessels studied by intravital microscopy. Acta Physiol. Scand. 84, 295-305 (1972) Filler, R. M., Das, ]. B., Haase, G. M., and Donahoe, P. K.: Muscle surface pH as a monitor of tissue perfusion and acid-base status. ]. Pediat, Surg. 6, 535-541 (1971) Hagberg, S., Haljamae, H., and Rockert, H.: Shock reactions in skeletal muscle. III. The electrolyte content of tissue fluid and blood plasma before and after induced hemorrhagic shock. Ann. Surg. 168,243-248 (1968) Haljamae, H.: Electrolyte changes in single skeletal muscle cells induced by experimental haemorrhagic shock. Thesis at University of Goreborg, Sweden (1969) Haljamae, H.: "Hidden" cellular electrolyte response to hemorrhagic shock and their significance. Rev. Surg. 27, 315-324 (I 970a) Haljarnae, H.: Effects of hemorrhagic shock and treatment with hypothermia on the potassium content and transport of single mammalian skeletal muscle cells. Acta Physio!. Seand. 78,189-200 (1970b) Haljamae, H.: Sampling of nanoliter volumes of mammalian subcutaneous tissue fluid and ultra-micro flame photometric analyses of the K and Na concentrations. Acta Physio!. Scand. 78, 1-10 (1970C) Haljarnae, H.: Anatomy of the interstitial tissue. Lymphology. II, 128-132 (1978a) Haljamae, H.: The dynamics of the interstitium during hypovolemic shock. In preparation (I 978b) Haljamae, H., Jennische, E., and Medegard, A.: Transmembrane potential measurements as an indicator of heterogenous distribution of nutritive blood flow in skeletal muscle during shock. Acta Physio!. Scand. 101,458-467 (1977) Hall, ]. E., Schwinghamer, ]. M., and Lalone, B.: Mechanisms of blood vessel constriction during hemorrhage. Amer. J. Physiol, 2]0, 569-578 (1976)

210 . H. Haljarnae et al. Harris, P. D ., Longnecker, D. E., Greenwald, E. K., and Miller, F. N .: Small vessel constriction in the rat cremaster during the early phase of moderate hemorrhagic hypotension. Microva sc. Res. 10,29-37 (1975) Hilton, S. M.: Local chemical factors involved in vascular control. Angiologica 8, 174186 (1971) Hutchins, P. M., Gold stone, J., and Wells, R.: Effects of hemorrhagic shock on the micro vasculature of skeletal muscle. Microvasc. Res. 5, 131-140 (1973) J ennische, E., Enger, E., Mcdcgard, A., App elgren, L., and H aljamae, H .: Correlation betwe en tissue pH , cellular transmembrane potentials, and cellular energy metabolism durin g shock and during ischemia. Cir cul. Shock, 5, 251-2 60 (1978a) Jenn ische, E., Medegard, K. A. 1., and H aljamae, H .: Tr ansmembrane potential changes as an indicator of cellular metabol ic deterioration in skeletal muscle during shock. Europ. Surg. Res. 10, 125-1 33 (1978b) jarhult, J.: Osmotic flu id transfer from tissue to blood dur ing hemorrhagic hypotension. Act a Physiol. Scand. 89, 2 I 3-226 (1973) Koven , J. H., Mac Millan, N., Lo, S., and Zhuk, A.: Correction by hyaluronidase of the interstitial tissue transport defect dur ing shock: A new approach to therapy. ]. Trauma If , 992-99 7 (1975) Kun g, T. L., LeBlanc jr., O. H. , and Moss, G.: Percutaneous microsensing of muscle pH durin g shock and resuscitation . J. Surg. Res. 2 I, 285-289 (1976) Lemieux, M. D., Smith, R. N., and Couch, N. P.: Surface pH and redo x potential of skeleta l muscle in gra ded hemorrhage. Surgery 6f, 457-461 (1969) Lindberg, B., Haljamae, H ., Jons son, 0 ., and Pettersson, S.: Effect of glucagon and blood transfusion on liver metabol ism in hemorrhagic shock. Ann. Surg. 187, 103109 (1978) Lundgren, 0., Lundwall, J ., and Mellander, S.: Range of sympathetic discharge and refle x vascular adjustment in skeletal muscle during hemorrhagic hypotension. Acta Physiol. Scand . 62, 380-390 (1964) Medegl rd, K. A. 1., and H aljarnae , H .: Cellular functi onal disturbances durin g acute dehyd rat ion shock in dogs. Submitted for publication (1979) Mela, L., Bacalzo jr., L. V., and Miller , L. D. : Defective oxidative metabolism of rat liver mitochondria in hemorrhagic and endotoxin shock. Amer. J. Ph ysiol. 220, 571577 (197 1) Mellander, S.: Interaction of local and nervous factors in vascular control. Angiologica 8, 187-201 (1971) Mellande r, S.: On the control of capillary fluid transfer by precap illary and postcapill ar y vascular adjustments. A brief review with special emphasis on myogenic mechan isms. Microvasc. Res. If, 319-330 (1978) Mellander, S., and Joh ansson, B.: Control of resistance, exchange, and capacitance fun ction s in the periph eral circulation. Phar macol. Rev. 20, II 7-196 (1968) Mellander, S., and Lewis, D. H .: Effect of hemorrhagic shock on the reactivity of resistance and capacita nce vessels and on capill ar y filtration transfer in cat skeletal muscle. Circ . Res. I ] , 1°5- 118 (1963) Myr vold , H. Eo, Enger, E., and Haljamae, H. : Earl y effects of endotoxin on tissue phosphagen levels in skeletal muscle and liver of the dog. Europ. Surg, Res. 7, 181192 (1975) Rosenberg, J. c., Lillehei, R. c., Longerbeam, ]., and Zimmermann, B.: Studies on hemorrhagic and endotoxin shock in relati on to vasomotor changes and endogenous circulating epinephrine, norepinephrine and serotonin. Ann. Surg. 154, 6II-627 (1961)

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Rutherford, R. B., Kaihara, S., Schwentke r, E. P., and Wagner jr., H. N.: Regional blood flow in hemorrhagic shock by the distr ibut ion of labelled microspheres. Surg. Forum 19,14-1 5 (1968) Shumer, W., and Er ve, P. R. : Cellul ar metaboli sm in shock. Circul. Shock 2, 109-U7 (1975) Shires, G. T., Cunningham, ]. N ., Baker, C. R. F., Reeder, S. F., IIIner, H. , Wagner, ]. Y., and Maher, ].: Alterations in cellular membrane function dur ing hemorrhagic shock in primat es. Ann. Surg. 176, 288-294 (1972) Skalak , R., Branemark, P. I., and Ekholm, R.: Erythrocyte ad herence and diaped esis. Some aspects of a possible mechanism based on vita l and electron microscopic observations. Angiology 21, 224-239 (1970) Skinner jr., N . S., and Costen, ]. c.: Role of 0 2 and K + in abolition of sympathetic vasoconstr iction in dog skeleta l muscle. Amer. ]. Physiol. 217,438- 444 (1969) Skinner jr., N. S., and Powell jr., W. ]. : Action of oxygen and pota ssium on vascular resistance in dog skeletal muscle. Amer. ]. Physiol. 212, 533-540 (1967) Trunkey, D. D., IIIner, H ., Wagner, ]. Y., and Shires, G. T.: The effect of hemorrhagic shock on intracellular muscle action potentials in the pr imate. Surgery 74, 241-25° (1973) Weintr aub , W. H., Roback , S. A., Devad as, M., Rysavy, ]., and Leonard , A. S.: Muscle surfac e pH: Comparison with card iac output and arte rial pH in the critically ill subject.]. Pediar, 5u rg. 7, 505-510 (1972) Zweifach, B. W.: Microcirculatio n. Amer. Rev. Physio!. 35, II7- 150 (1973) Zweifach, B. W., and Fronek, A.: Th e interplay of central and peripheral factors in irreversible hemorrh agic shock. Pro gr. Cardiovasc. Dis. 18, 147-180 (1975)

Received Septembe r 12, 1978 . Accepted No vember

I,

1978

Key w ords: Pathophysiology - H ypovolemic Shock - Microcirculation - Cellular metabolism - Inte rstitial tissue H. H aljarnae, M.D., Ph.D., Dept . of Anesthesiology, Sahlgren s Hosp ital , 5-41345 Gotcborg, Sweden