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Traumatic shock
Traumatic shock From the Departments of Surgery, Harvard Medical School and the Beth· Israel Hospital, Boston, Massachusetts
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JACOB FINE, M.D., F.A.C.S. Professor of Surgery; Director of Surgery
DIAGNOSIS OF SHOCK
WE HAVE heard with increasing frequency that the term traumatic shock ought to be discarded because the clinical disorders that are luinped under this term are so varied and disparate as to make the term meaningless. Those who take this position evidently believe that it is correct to include within the syndrome of traumatic shock various states of hypotension that most clinicians would not include because they do not elicit the classical signs of traumatic shock. These signs are sufficiently distinctive to allow the diagnosis to be made at the bedside. They are as follows: The skin is pale; the mucous membranes are pale and bluish; the hands and feet are cold and moist; and the urine output has ceased or is rapidly declining. The pulse is weak, rapid and increasing in rate. The mean arterial systolic pressure in the full-blown state of shock is 80 mm. Hg or below and the pulse pressure is below normal and falling. Taken together, these signs represent the state of traumatic shock, a disorder in which the fundamental feature is an acute and persisting deficiency in the blood supply to the tissues. Because this condition evokes hyperactivity of the sympathetic nervous system, the skin is moist and cold. Sluggish flow produces peripheral cyanosis. The cardiac output is belo~' normal and falling steadily because the volume of blood returning to th~'heart is below normal and falling steadily. With the fall in cardiac output, the compensation that vasoconstriction supplies is for· time adequate to sustain the blood pressure at its original level. But when this compensation fails, the blood pressure falls. The pulse is weak b~cause of the reduced stroke volume of the heart. This induces tachycardia. The steadily declillingblood ;pressure and blood supply to the' kidneys reduces glomerular filtrate; hence the
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progressive oliguria. All the classical signs of shock are thus accounted for. TYPES OF SHOCK
Hypovolemic Shock
We have next to consider what produces an acute deficiency in the blood supply to the tissues. A severe hypovolemia is the most obvious cause. In a previously healthy person shock will be fully developed when about one-third of the normal volume has been lost. In an individual who lacks the capacity for vigorous compensation, a smaller loss will induce the fully developed disorder. Hypovolemia results from loss of whole blood. It can also result from a loss of plasma, as in peritonitis, pancreatitis, massive soft tissue trauma and burns. In rapidly dehydrating disorders such as severe vomiting, diarrhea, or obstruction of the small intestine, shock may occur because plasma as well as extracellular fluid is lost. Hemorrhagic shock is perhaps the commonest variety of hypovolemic shock. The hematocrit will not drop until after extravascular fluid has returned to the circulation. On the other hand, in burns and other conditions in which there is a preferential loss of plasma, the hematocrit rises. This increases the blood viscosity and the peripheral resistance, so that the blood pressure does not fall in proportion to the fall in blood volume. It remains higher than it would be if the deficiency were whole blood. The inexperienced, who tend to rely too heavily on the blood pressure to make the diagnosis, may allow hypovolemia to reach a critically low level before the shock is recognized, and, therefore, may be late in treating the hypovolemia. N ormovolemic Shock
There are several varieties of shock in which there is no hypovolemia. One of these is secondary to acute myocardial failure. When damage to the myocardium, as by acute coronary thrombosis, produces defective ventricular contractility, cardiac output falls and an acute deficiency in blood supply to the tissues necessarily follows. This is a type of normovolemic shock in which giving blood or plasma can readily induce fatal pulmonary edema. The primary therapy must be aimed at improving function of the heart rather than of the peripheral circulation. A number of investigators regard myocardial weakness as the primary cause of death in shock, regardless of how the shock is produced. It is true that the myocardium shows declining contractile power in the preterminal state of traumatic shock, and this justifies efforts aimed at sustaining the heart, such as by norepinephrine, Aramine or Angiotensin II to improve coronary flow. Most investigators, however, believe that
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in shock that is not caused by myocardial failure the primary therapeutic objective should be to improve venous return to the heart. Another type of normovolemic shock is that caused by a toxin. Of the various possible toxins those of bacterial origin are the commonest; and of these the commonest by a considerable margin are the endotoxins, which are derived chiefly from gram-negative bacteria. Shock caused by bacterial activity is not always normovolemic, because, in addition to the vascular injury caused by the toxin, there may be an inflammatory reaction with a large loss of plasma, as for example in various forms of acute enterocolitis, in streptococcal empyema or in acute pancreatitis. But even when there is a substantial hypovolemia in shock caused by bacteria, treatment of the hypovolemia may not relieve the shock. The plasma or blood given may be lost immediately into the area of increased capillary permeability. Even if it is retained in the circulation, it will rarely cure the shock, for the hypovolemia is seldom more than of secondary importance. Little is known of the mechanism by which bacterial toxins interfere with flow in the peripheral vessels. In the case of the exotoxins almost nothing is known. Endotoxins potentiate the action of the catechol amines. 10 • 21 These can be harmful if their action is excessive and prolonged. Whether endotoxins produce shock as a result of damage inflicted in this manner, or in some other way, is a subject of current intensive study. Reversal of shock caused by endotoxins can often be achieved by antibiotics or by surgery whenever these serve to prevent further invasion of the circulation by bacteria or their toxins. Current studies suggest that when endotoxic shock is refractory to such measures, agents directed at blocking the catechol amines or the sympathetic nerves that elaborate them may eventually prove to be useful. Thus, we have recently demonstrated in dogs and rabbits that denervation of the liver, spleen and intestine prevents death from otherwise fatal endotoxic or hemorrhagic shock. 9 Irreversible Shock When no form of therapy restores flow to normal through the peripheral vessels, we call the shock irreversible. There are many who dislike the term "irreversible shock," i.e., shock that we do not know how to reverse, or, for all we know, cannot be reversed. One cannot and should not make this diagnosis in man until all appropriate therapy has been given in vain, and death has occurred. Needless to say, there are patients whose shock is thought to be irreversible, but later proves to be reversible on application of therapy for remediable deficiencies that had been overlooked. This does not mean that one can always prevent death from shock regardless of its cause. There are patients who will die of infectious or. toxic shock so long as we lack specific therapy for t.he infecting or toxic agent.
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TREATMENT OF SHOCK Assessment of Blood Volume Loss and Effectiveness of Blood Volume Therapy
Once the diagnosis of traumatic shock has been made, it is manifestly basic to proper therapy to dermine whether it is hypovolemic or normovolemic. Full-blown hypovolemic shock develops when 30 per cent or more of the normal blood volume is lost. The normal volume is about 7 per cent of the lean body weight. One can, therefore, restore the blood volume to near normal in the average adult in hypovolemic shock with little or no danger of producing pulmonary edema, by giving 1200 to 1500 ml. of whole blood or plasma, depending on which has been lost. When neither is immediately available, it is appropriate to begin replacement by administering up to 1 liter of 5 per cent dextran, * preferably with a uniform molecular weight of about 100,000. t Only blood or plasma should be given thereafter. If the blood volume deficit is not much greater than 30 per cent, the signs of shock will vanish in response to this therapy. The skin will get warm and dry and of good color, the urine output will rise, the pulse will slow down, and the blood pressure and pulse pressure revert to normal. Blood loss is commonly underestimated. The most unreliable guesses are those which assess concealed loss in traumatized tissues, as in fracture of the femur or pelvis. 22 Even the surgeon who can see the hemorrhage he produces is often very wide of the mark, not rarely by as much as 1500 m1. 24 Counting and weighing blood-soaked sponges ignores losses of the blood or plasma into tissues. Usually replacement therapy is interrupted as soon as the signs of shock have disappeared. If the deficit is not fully restored, the patient must sustain himself by the use of compensating mechanisms until the deficit is fully restored. If these mechanisms fail to do so for lack of sufficient extravascular fluid, or because of a slow continuing loss of blood or plasma, the patient remains in a marginal state of balance until he exhausts his compensating mechanisms, and then relapses into shock. With each successive relapse the compensating mechanisms may become weaker as tissue injury mounts because of lack of sufficient time for adequate repair between successive periods of shock. In such a situation a recurrence of shock may leave no time for further restorative therapy, and death may follow quickly. When shock persists in spite of the certainty that the blood volume is normal or nearly so, something else than hypovolemia is responsible. But to be certain one should measure the blood volume directly. One cannot rely on the hematocrit as an index of the blood volume, for it,
* Five per cent human albumin is about equal to dextran in oncotic value.
t More than a liter of dextran containing molecules much larger than 100,000 may produce bleeding.
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used alone, is often misleading. Experience with a precision method (see below) for blood volume determinations has demonstrated that changes in hematocrit often fail to indicate whether it is the plasma volume or the red cell volume which has shifted. 23 . 24 The hematocrit can, however, be used for calculating whole blood volume if the plasma or red cell volume has been measured according to the formula: Plasma volume _ Red cell volume _ B V I-Ret - B.V. or Ret -. .
Such measllrements require RISA or Evans Blue Dye for measuring plasma volume, or Cr51-labeled red cells for measuring red cell volume. In most hospitals the problems involved in obtaining the personnel and materials required for obtaining these data, and the time that elapses between the request and receipt of the data, discourage the effort to obtain these measurements. Even when they are obtainable, more than one determination is so large an undertaking that it is only rarely carried out. When more than two determinations are made, the increasing amount of radioactivity or the dye concentration in the blood becomes unduly large, and the cumulative errors become prohibitive. l l Thus, it has not heretofore been possible to monitor the blood volume continuously, even in the best circumstances. This state of affairs has recently been improved by the availability of an apparatus for quick, accurate and repeated blood volume determinations (Fig. 1). Such readings can be obtained every 30 minutes by any technician who can draw blood and inject solutions with precision into the veins, since all measurements and calculations are done on drawn blood samples by the apparatus, which is brought to the bedside, the emergency ward or the operating theater.22 The apparatus operates on the basis of the dilution principle, and requires a prepared packaged dose of RISA containing less than 5 micro curies of p31, so that the person using the apparatus does not need to take precautions against radiation hazard. One can, of course, use Cr51-labeled red cells, but this is a more cumbersome method which is used only when accurate red cell volumes are desired. With RISA one can measure the blood volume frequently, up to ten times a day if needed, because the total amount of radiation in 20 determinations does not exceed the dose delivered in taking a single chest film. The method reads the whole blood volume if whole blood is the sample used, or plasma volume if plasma is used. Determinations in man and animals in or out of shock made in this way are very close to the more precise determinations obtained by the double (P31 and Cr51 ) isotope technique. 6 Hence the latter method is not needed except in special circumstances. A single reading after a mixing time of ten minutes gives a value that is not significantly different from one obtained after 15 or 20 minutes, so that serial readings for a single
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Fig. 1. An apparatus for repeated blood volume determinations (the Volemetron, manufactured by the Atomium Corporation, Billerica, Mass.).
determination are unnecessary; and even in the preterminal state of shock a mixing time of 15 minutes will be reliable. The hypovolemia of shock caused by loss of plasma is usually not as great as that which results from severe hemorrhage. But it can be very large in extensive burns, and in other types of massive trauma, as for example following abdominoperineal resection for carcinoma of the rectum, or exenteration of the pelvis for cervical cancer. The injured capillaries may leak so fast that the infused plasma leaves them almost as soon as it enters the veins. The classical experimental example of this phenomenon is shock following release of a tourniquet applied for eight to ten hours to the extremity of a dog.' This shock persists in spite of
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massive and repeated plasma transfusions. Compression therapy, when it is feasible, as in burns or tourniquet shock of the extremities, helps to prevent or to stop this kind of shock. The fatal diarrhea of cholera is a process. perhaps not unlike that of tourniquet injury. If hypovolemia is not a significant factor, and the shock is normovolemic or nearly so, blood volume therapy is useless. Moreover, in the patient who cannot get rid of an excess of plasma, such therapy can be lethal, especially in shock caused by myocardial injury. It is imperative to distinguish cardiogenic shock from other types of normovolemic shock. The diagnosis must not depend upon changes in values of circulating enzymes, because enzyme leakage from injured tissues occurs in all types of shock. A fall in cardiac output is also a finding common to all types of shock. A falling central venous pressure is more likely to be present in traumatic shock than in cardiogenic shock. But catheterization of the great veins to obtain such data is only rarely indicated. Antibiotics
As a rule, normovolemic shock is caused by toxins, and, in the vast majority of cases, by bacterial toxins. Of these, the endotoxins from gram-negative bacteria are the commonest offenders. Examples of shock with this etiology are the shock caused by generalized peritonitis, whether from a ruptured appendix, gangrenous bowel, ruptured peptic ulcer, acute pancreatitis, diverticulitis with perforation, etc. In such circumstances the most effective therapy for the shock is the prompt application of the most effective antibiotic in the most effective manner. In peritonitis the intraperitoneal instillation of solutiot:J.s of antibiotics, e.g., kanamycin or neomycin, at the site of most intense bacterial activity, supplemented where indicated by surgical control of the cause of the infection, will be the most rewarding therapy. Vasopressor Agents
Such measures require time to take effect. Meanwhile the hypotension is dealt with directly. In order to improve coronary flow, and hopefully a better cardiac output in consequence, a pressor agent is commonly used. Norepinephrine is widely employed; and since some patients respond to its use with an improved mental awareness, resumption of urine flow and better cardiac output, it is considered a useful therapy. At the same time there are good reasons for doubting that this drug in the long run is an advantage, because its benefits as a pressor agent may be more than counterbalanced by the reduced flow it produces in other critical areas, such as spleen, liver and intestine. 4 If a pressor drug is to be used, Aramine, which is said to be as effective as norepinephrine, may be preferred because it does not cause a slough in case of leakage. But Angiotensin II appears to be superior to both, because (a) its action is, restricted to the arterioles, i.e., it does not affect the venules; and
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(b) it appears to be free of the tachyphylaxis that characterizes the response to norepinephrine. There is mounting evidence that drugs which can reduce vasoconstriction are to be preferred to pressor drugs. Thus chlorpromazine, whose site of action is in the central nervous system, and dibenzyline, which is anti-adrenergic, protect against death from experimental shock when given prophylactically, because they facilitate better perfusion of viscera, even though they lower the systemic arterial pressure. But when they are given during experimental shock, striking benefits are not achieved. Even so, their clinical value is presently being appraised, and considerable benefit is said to have occurred in a number of instances. 8 The measure of their value will have to be made in terms of their effects on cardiac output, circulation time, renal function, central venous pressure, venous oxygen concentration, blood pH and other parameters.
Miscellaneous Agents
Electrolyte imbalance is common, and should be treated as indicated. Because of renal shut-down, an initial potassium deficiency is not likely to persist, and K + ion should be given only if there is a severe depletion, and even then with extreme caution because excess K + is toxic to the myocardium. In this connection one should remember that bank blood contains a considerable amount of released K+. Other therapeutic agents that are in wide usage are of uncertain benefit. There is good reason to treat the acidosis of shock. The continuous production of acid metabolites is inevitable in shock, and the lowered pH is a measure of the rate of their production. A pH below 7.25 and getting lower is a progressively increasing burden on the respiratory tract, as well as a sign of the worsening state of affairs in the peripheral circulation. Therefore, it is appropriate to give sodium lactate or bicarbonate to raise the blood pH. The critical importance of this therapy, however, has not been proved, however vigorous the claims for its value. Such therapy cannot get to the central problem of shock, which is the inadequate peripheral flow. The peripheral venous blood in shock usually is deficient in oxygen, not because the arterial blood is incompletely saturated but because of prolonged stay in the capillaries and venules. Unless the arterial oxygen concentration is below normal because of respiratory difficulties, the inhalation of 95 per cent or 100 per cent oxygen is an unnecessary maneuver, because it can only raise the oxygen content of the arterial blood by a few volumes per cent in physical solution. In principle, hypothermia is of value because it reduces metabolic requirements and slows up the depletion of reserves. For the same reason, reducing the fever of a patient in shock by cooling devices is also desirable. Both measures may be regarded as ancillary therapeutic agents, but further experience is needed to establish their value.
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The adrenal gland has been thought to be involved somehow, even though there is clear evidence that the level of corticosteroid production is adequate. 15 There are claims for the benefit of corticosteroid therapy which most investigators have not been able to confirm. The use of massive doses of corticosteroids, presumably on the basis that pharmocologic doses are required to suppress vicious cellular responses, even if they cannot be identified, continues to commend itself to a number of investigators. 2o Recently claims have been made for the prophylactic value of aldosterone in experimental endotoxic shock. 1 Others have found it useful only when given during experimental endotoxic shock. Clinical experience with this drug is lacking. The Management of Refractory Shock
What can be done for shock when the foregoing measures are not effective? This depends on what we take to be the cause of the progressive deterioration that accounts for death. There are those who believe that when shock caused by massive soft tissue injury persists in spite of proper therapy, something more than hypovolemia and bacterial activity is responsible. Proper therapy of wound shock implies correction of hypovolemia, adequate debridement of the damaged tissue and control of bacterial activity. It is usually possible to determine whether or not the devitalized tissue has been removed, and with the newest equipment (vide supra) one can, be certain that normovolemia has been achieved. But what is the basis for a conclusion that bacterial activity has been controlled, eliminated or is not a significant factor? THE ROLE OF A BACTERIAL FACTOR. The operation of a bacterial factor is frequently overlooked or dismissed on the ground that the signs of infection are absent. Since these signs are predominantly those of the reaction of defense, which is absent or very weak in shock, the assertion that death following wound shock was not due to bacterial action because none was seen is not acceptable. The literature on shock in relation to bacteria in wounds is sparse, and the bacteriologic study of such wounds in patients has not been sufficiently searching. The presence of bacterial activity in open wounds is more likely than not. Etiologically significant bacterial activity is often dismissed because cultures of surface swabs were sterile, grew few bacteria, or grew bacteria that were classified as nonpathogenic. In view of the very high susceptibility of the shocked animal to bacterial toxins, one cannot dismiss bacteria from consideration in wound shock on the basis of data obtained by prevailing clinical cultural techniques, and in the absence of data on the pathogenicity of the infecting organisms in the particular victim. Furthermore, continuous absorption of bacterial toxin from the gastrointestinal tract is a phenomenon that is not yet generallyappreciated.13 THE ROLE OF ENDOTOXINS. There is growing acceptance of the view
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that the catechol amines, and norepinephrine in particular, are the major offenders in the development of the refractory state of shock. This is the result of two facts: (a) anti-adrenergic compounds prevent this development in hemorrhagic shock; and (b) even in endotoxic shock the endotoxins make the circulation refractory by inducing excessive adrenergic activity rather than by direct injury to the peripheral vessels. 9 It is, therefore, necessary to focus attention on the role of the catechol amines. The liver, spleen and intestine suffer a more severe rednction in blood flow during shock than do the brain, heart and adrenals. There is a large body of evidence in the experimental literature to show that if the ischemia of the liver and spleen persists for hours, the reticuloendothelial system, most of which is concentrated in the liver and spleen, loses its ability to destroy bacteria and bacterial products. This has been shown by the greatly increased susceptibility of the experimental animal in shock to challenge with a very small dose of bacterial endotoxin15 or to an intravenous dose of bacteriaP It has also been shown by comparing the ability of water-soluble extracts of normal and shocked liver and of spleen to split and detoxify bacterial endotoxins. 14 The normal spleen in vivo, perfused with endotoxin, destroys the endotoxin immediately, whereas the spleen in the shocked animal is impotent. Endotoxemia has been shown to develop during prolonged hemorrhagic shock,12. 16 and the source of this endotoxin is the intestine,3 from which it is being continuously absorbed. Experimental proof that this endotoxin causes or contributes to the development of the irreversible state is the observation that hemorrhagic shock does not become irreversible to transfusion in animals pretreated with repeated doses of endotoxin for a week or ten days,19 and that the oral administration of nonabsorbable antibiotics reduces or prevents the endotoxemia as well as the irreversible state of hemorrhagic shock. 6 Therefore, there is good reason for the use of antibiotics in shock in the absence of infection, as well as in shock caused by infection. To suppress the intestinal flora, nonabsorbable antibiotics by the oral route are to be preferred. But patients in shock are often unable to swallow or retain fluids. Antibiotics may then be given parenterally for the same objective; and although they are not as effective by this route, they may help to the degree that they are excreted into the gut. THE ROLE OF THE NERVOUS SYSTEM. Since the anti-adrenergic measures now available have not yet proved themselves when applied during shock, we have undertaken a study of the effect of suppressing nervous activity that leads to the production of catechol amines. The experimental data demonstrate that tissue injury and death from hemorrhagic and endotoxic shock can be prevented by de nervation of the intestine, liver and spleen. They confirm the hypothesis that the key lesion responsible for death lies in these organs, and that the locally produced rather than the circulating catechol amines inflict the damage. 9 An
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anti-adrenergic agent applied during shock that would stop the production or block the action of these compounds in these organs would seem to be a promising therapeutic objective. In the absence of such an agent, chemical denervation of the coeliac plexus by a long-acting anesthetic should be worth exploiting. This therapy is now being evaluated. THE ROLE OF CARDIAC FUNCTION. There is evidence from the foregoing experimental data that there is no promise in therapy aimed at controlling such substances as histamine, or a large variety of circulating metabolites thought to be damaging to capillaries (e.g., kallikrein, toxic proteases, etc.).7.18 On the other hand, attention to cardiac function may prove to be of value, for even though the intestine, liver and spleen are the site of the lesion leading to death, the progressive decline in cardiac output is a critical consequence of the disturbance in these organs. Improving venous return, so long as it is inadequate, usually improves cardiac output. This is why most students of the problem do not regard the heart as the primary site of the irreversible process. In time, however, the heart does not respond even to increased venous return. Myocardial damage might then determine the subsequent downward trend, and improved coronary perfusion might become the only remaining recourse. On that account the use of agents for improving coronary perfusion is thought to be justified, and considered more appropriate not after, but prior to the development of the myocardial injury. The limitations of pressor drugs for such an objective have been discussed. Current efforts are aimed at observing the value of relieving the injured heart by a pump which removes blood from the aorta at the height of the systolic thrust, and drives it toward the periphery during diastole. Such measures belong to the field of experimental research. Now that the methods and the equipment for the study of shock in man have developed so that reliable evaluation of therapy is possible, such measures as can be applied without adding injury should be tested in patients who do not respond to the conventional measures. REFERENCES 1. Bein, H. J.: Aldosterone and alterations in circulatory reactivity following endotoxins. In Shock: Prevention and Therapy, Ciba Symposium (K. D.
Bock, Ed.). Stockholm, Springer-Verlag, 1962, pp. 162-168. 2. Fine, J., Frank, H. A. and Seligman, A. M.: Traumatic shock. VIII. Studies in the therapy and hemodynamics of tourniquet shock. J. elin. Invest. 23: 5, 1944. 3. - - , Rutenburg, S. H. and Schweinburg, F. B.: Role of the reticulo-endothelial syst.em in hemorrhagic shock. J. Exper. Med. 110: 547-569,1959. 4. Frank, E. D., Frank, H. A., Jacob, S., Weizel, H., Korman, H. and Fine, J.: Effect of norepinephrine on circulation of the dog in hemorrhagic shock. Am. J. Physiol. 186: 74, 1956. 5. Hechter, 0 .• Macchi, I. A., Korman, H., Frank, E. D. and Frank, H. A.: Quanti-
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tative variations in the adrenocortical secretion of dogs. Am. J. Physiol. 182: 1, 1955. 6. Jacob, S .. Weizel, H., Gordon, E., Korman, H., Schweinburg, F., Frank, H. A. and Fine, J.: Bacterial action in development of irreversibility to transfusion in hemorrhagic shock in the dog. Am. J. Physiol. 179: 523, 1954. 7. Miles, A. A.: Local and systemic factors in shock. Fed. Proc. Supp. No.9, July, 1961, pp. 141-149. 8. Nickerson, M.: Drug therapy of shock. In Shock: Pathogenesis and Therapy. Ciba Symposium (K. D. Bock, Ed.). Stockholm, Springer-Verlag, 1962, pp. 356-370. 9. Palmerio, C., Israel, J., Shammash, J., Zetterstrom, B., Frank, H. A. and Fine, J.: Effect of denervation of the abdominal viscera on the course of hemorrhagic and endotoxic shock. In preparation. 10. - - - , Ming, S. C., Frank, E. D. and Fine, J.: Cardiac tissue response to endotoxin. Proc. Soc. Exper. BioI. & Med. 109: 773-776, 1962. 11. Peden, J. C., Maxwell, M., Ohin, A. and Moyer, C. A.: Consideration of indications for preoperative transfusions based on analysis of normal and malnourished patients with and without cancer. Ann. Surg. 151: 303,1960. 12. Ravin, H. A., Schweinburg, F. B. and Fine, J.: Host resistance in hemorrhagic shock. XV. Isolation of toxic factor from hemorrhagic shock plasma. Proc. Soc. Exper. BioI. & Med. 99: 426, 1958. 13. - - - , Rowley, D., Jenkins, C. and Fine, J.: On the absorption of bacterial endotoxin from the gastro-intestinal tract of the normal and shocked animal. J. Exper. Med. 112: 783-792, 1960. 14. Rutenburg, S. H., Smith, E. E., Rutenburg, A. M. and Fine, J.: Degradation of endotoxin by splenic extracts. Antimicrobial Agents & Chemotherapy 1: 142147 (May) 1961. 15. Schweinburg, F. B. and Fine, J.: Resistance to bacteria in hemorrhagic shock. II. Effect of transient vascular collapse on sensitivity to endotoxin. Proc. Soc. Exper. BioI. & Med. 88: 589, 1955. 16. Idem: Evidence for a lethal endotoxemia as the fundamental feature of irreversibility in three types of traumatic shock. J. Exper. Med. 112: 793-800, 1960. 17. Schweinburg, F. B., Frank, H. A. and Fine, J.: Bacterial factor in experimental hemorrhagic shock. Evidence for development of a bacterial factor which accounts for irreversibility to transfusion and for the loss of the normal capacity to destroy bacteria. Am. J. PhysioI. 179: 523, 1954. 18. Sherry, S.: Hemostatic mechanisms and proteolysis in shock. Fed. Proc. Supp. No.9, July, 1961, pp. 209-218. 19. Smiddy, F. G. and Fine, J.: Host resistance to hemorrhagic shock. X. Induction of resistance by shock plasma and by endotoxins. Proc. Soc. Exper. BioI. & Med. 96: 558-562, 1957. 20. Spink, W. W.: Pathogenesis and management of shock due to infection. A.M.A. Arch. Int. Med. 106: 433-442, 1960. 21. Thomas, L.: Role of epinephrine in reactions produced by endotoxins of gramnegative bacteria. I. Hemorrhagic necrosis produced by epinephrine in skin of endotoxin-treated rabbits. J. Exper. Med. 104: 865-880, 1956. 22. Williams, J. A. and Fine, J.: Measurement of blood volume with a new apparatus. New England J. Med. 264: 842, 1961. 23. - - - and Grable, E.: Simultaneous measurements of red cell mass and plasma volume with Cr 61 tagged red cells and 1125 labelled albumin. In preparation. 24. - - - , Grable, E., Frank, H. A. and Fine, J.: Blood losses and plasma volume shifts during and following major surgical operations. Ann. Surg. 156: 648653,1962. 330 Brookline Avenue Boston 15, Massachusetts
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JACOB FINE, M.D., F.A.C.S. Professor of Surgery; Director of Surgery
DIAGNOSIS OF SHOCK
WE HAVE heard with increasing frequency that the term traumatic shock ought to be discarded because the clinical disorders that are luinped under this term are so varied and disparate as to make the term meaningless. Those who take this position evidently believe that it is correct to include within the syndrome of traumatic shock various states of hypotension that most clinicians would not include because they do not elicit the classical signs of traumatic shock. These signs are sufficiently distinctive to allow the diagnosis to be made at the bedside. They are as follows: The skin is pale; the mucous membranes are pale and bluish; the hands and feet are cold and moist; and the urine output has ceased or is rapidly declining. The pulse is weak, rapid and increasing in rate. The mean arterial systolic pressure in the full-blown state of shock is 80 mm. Hg or below and the pulse pressure is below normal and falling. Taken together, these signs represent the state of traumatic shock, a disorder in which the fundamental feature is an acute and persisting deficiency in the blood supply to the tissues. Because this condition evokes hyperactivity of the sympathetic nervous system, the skin is moist and cold. Sluggish flow produces peripheral cyanosis. The cardiac output is belo~' normal and falling steadily because the volume of blood returning to th~'heart is below normal and falling steadily. With the fall in cardiac output, the compensation that vasoconstriction supplies is for· time adequate to sustain the blood pressure at its original level. But when this compensation fails, the blood pressure falls. The pulse is weak b~cause of the reduced stroke volume of the heart. This induces tachycardia. The steadily declillingblood ;pressure and blood supply to the' kidneys reduces glomerular filtrate; hence the
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progressive oliguria. All the classical signs of shock are thus accounted for. TYPES OF SHOCK
Hypovolemic Shock
We have next to consider what produces an acute deficiency in the blood supply to the tissues. A severe hypovolemia is the most obvious cause. In a previously healthy person shock will be fully developed when about one-third of the normal volume has been lost. In an individual who lacks the capacity for vigorous compensation, a smaller loss will induce the fully developed disorder. Hypovolemia results from loss of whole blood. It can also result from a loss of plasma, as in peritonitis, pancreatitis, massive soft tissue trauma and burns. In rapidly dehydrating disorders such as severe vomiting, diarrhea, or obstruction of the small intestine, shock may occur because plasma as well as extracellular fluid is lost. Hemorrhagic shock is perhaps the commonest variety of hypovolemic shock. The hematocrit will not drop until after extravascular fluid has returned to the circulation. On the other hand, in burns and other conditions in which there is a preferential loss of plasma, the hematocrit rises. This increases the blood viscosity and the peripheral resistance, so that the blood pressure does not fall in proportion to the fall in blood volume. It remains higher than it would be if the deficiency were whole blood. The inexperienced, who tend to rely too heavily on the blood pressure to make the diagnosis, may allow hypovolemia to reach a critically low level before the shock is recognized, and, therefore, may be late in treating the hypovolemia. N ormovolemic Shock
There are several varieties of shock in which there is no hypovolemia. One of these is secondary to acute myocardial failure. When damage to the myocardium, as by acute coronary thrombosis, produces defective ventricular contractility, cardiac output falls and an acute deficiency in blood supply to the tissues necessarily follows. This is a type of normovolemic shock in which giving blood or plasma can readily induce fatal pulmonary edema. The primary therapy must be aimed at improving function of the heart rather than of the peripheral circulation. A number of investigators regard myocardial weakness as the primary cause of death in shock, regardless of how the shock is produced. It is true that the myocardium shows declining contractile power in the preterminal state of traumatic shock, and this justifies efforts aimed at sustaining the heart, such as by norepinephrine, Aramine or Angiotensin II to improve coronary flow. Most investigators, however, believe that
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in shock that is not caused by myocardial failure the primary therapeutic objective should be to improve venous return to the heart. Another type of normovolemic shock is that caused by a toxin. Of the various possible toxins those of bacterial origin are the commonest; and of these the commonest by a considerable margin are the endotoxins, which are derived chiefly from gram-negative bacteria. Shock caused by bacterial activity is not always normovolemic, because, in addition to the vascular injury caused by the toxin, there may be an inflammatory reaction with a large loss of plasma, as for example in various forms of acute enterocolitis, in streptococcal empyema or in acute pancreatitis. But even when there is a substantial hypovolemia in shock caused by bacteria, treatment of the hypovolemia may not relieve the shock. The plasma or blood given may be lost immediately into the area of increased capillary permeability. Even if it is retained in the circulation, it will rarely cure the shock, for the hypovolemia is seldom more than of secondary importance. Little is known of the mechanism by which bacterial toxins interfere with flow in the peripheral vessels. In the case of the exotoxins almost nothing is known. Endotoxins potentiate the action of the catechol amines. 10 • 21 These can be harmful if their action is excessive and prolonged. Whether endotoxins produce shock as a result of damage inflicted in this manner, or in some other way, is a subject of current intensive study. Reversal of shock caused by endotoxins can often be achieved by antibiotics or by surgery whenever these serve to prevent further invasion of the circulation by bacteria or their toxins. Current studies suggest that when endotoxic shock is refractory to such measures, agents directed at blocking the catechol amines or the sympathetic nerves that elaborate them may eventually prove to be useful. Thus, we have recently demonstrated in dogs and rabbits that denervation of the liver, spleen and intestine prevents death from otherwise fatal endotoxic or hemorrhagic shock. 9 Irreversible Shock When no form of therapy restores flow to normal through the peripheral vessels, we call the shock irreversible. There are many who dislike the term "irreversible shock," i.e., shock that we do not know how to reverse, or, for all we know, cannot be reversed. One cannot and should not make this diagnosis in man until all appropriate therapy has been given in vain, and death has occurred. Needless to say, there are patients whose shock is thought to be irreversible, but later proves to be reversible on application of therapy for remediable deficiencies that had been overlooked. This does not mean that one can always prevent death from shock regardless of its cause. There are patients who will die of infectious or. toxic shock so long as we lack specific therapy for t.he infecting or toxic agent.
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TREATMENT OF SHOCK Assessment of Blood Volume Loss and Effectiveness of Blood Volume Therapy
Once the diagnosis of traumatic shock has been made, it is manifestly basic to proper therapy to dermine whether it is hypovolemic or normovolemic. Full-blown hypovolemic shock develops when 30 per cent or more of the normal blood volume is lost. The normal volume is about 7 per cent of the lean body weight. One can, therefore, restore the blood volume to near normal in the average adult in hypovolemic shock with little or no danger of producing pulmonary edema, by giving 1200 to 1500 ml. of whole blood or plasma, depending on which has been lost. When neither is immediately available, it is appropriate to begin replacement by administering up to 1 liter of 5 per cent dextran, * preferably with a uniform molecular weight of about 100,000. t Only blood or plasma should be given thereafter. If the blood volume deficit is not much greater than 30 per cent, the signs of shock will vanish in response to this therapy. The skin will get warm and dry and of good color, the urine output will rise, the pulse will slow down, and the blood pressure and pulse pressure revert to normal. Blood loss is commonly underestimated. The most unreliable guesses are those which assess concealed loss in traumatized tissues, as in fracture of the femur or pelvis. 22 Even the surgeon who can see the hemorrhage he produces is often very wide of the mark, not rarely by as much as 1500 m1. 24 Counting and weighing blood-soaked sponges ignores losses of the blood or plasma into tissues. Usually replacement therapy is interrupted as soon as the signs of shock have disappeared. If the deficit is not fully restored, the patient must sustain himself by the use of compensating mechanisms until the deficit is fully restored. If these mechanisms fail to do so for lack of sufficient extravascular fluid, or because of a slow continuing loss of blood or plasma, the patient remains in a marginal state of balance until he exhausts his compensating mechanisms, and then relapses into shock. With each successive relapse the compensating mechanisms may become weaker as tissue injury mounts because of lack of sufficient time for adequate repair between successive periods of shock. In such a situation a recurrence of shock may leave no time for further restorative therapy, and death may follow quickly. When shock persists in spite of the certainty that the blood volume is normal or nearly so, something else than hypovolemia is responsible. But to be certain one should measure the blood volume directly. One cannot rely on the hematocrit as an index of the blood volume, for it,
* Five per cent human albumin is about equal to dextran in oncotic value.
t More than a liter of dextran containing molecules much larger than 100,000 may produce bleeding.
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used alone, is often misleading. Experience with a precision method (see below) for blood volume determinations has demonstrated that changes in hematocrit often fail to indicate whether it is the plasma volume or the red cell volume which has shifted. 23 . 24 The hematocrit can, however, be used for calculating whole blood volume if the plasma or red cell volume has been measured according to the formula: Plasma volume _ Red cell volume _ B V I-Ret - B.V. or Ret -. .
Such measllrements require RISA or Evans Blue Dye for measuring plasma volume, or Cr51-labeled red cells for measuring red cell volume. In most hospitals the problems involved in obtaining the personnel and materials required for obtaining these data, and the time that elapses between the request and receipt of the data, discourage the effort to obtain these measurements. Even when they are obtainable, more than one determination is so large an undertaking that it is only rarely carried out. When more than two determinations are made, the increasing amount of radioactivity or the dye concentration in the blood becomes unduly large, and the cumulative errors become prohibitive. l l Thus, it has not heretofore been possible to monitor the blood volume continuously, even in the best circumstances. This state of affairs has recently been improved by the availability of an apparatus for quick, accurate and repeated blood volume determinations (Fig. 1). Such readings can be obtained every 30 minutes by any technician who can draw blood and inject solutions with precision into the veins, since all measurements and calculations are done on drawn blood samples by the apparatus, which is brought to the bedside, the emergency ward or the operating theater.22 The apparatus operates on the basis of the dilution principle, and requires a prepared packaged dose of RISA containing less than 5 micro curies of p31, so that the person using the apparatus does not need to take precautions against radiation hazard. One can, of course, use Cr51-labeled red cells, but this is a more cumbersome method which is used only when accurate red cell volumes are desired. With RISA one can measure the blood volume frequently, up to ten times a day if needed, because the total amount of radiation in 20 determinations does not exceed the dose delivered in taking a single chest film. The method reads the whole blood volume if whole blood is the sample used, or plasma volume if plasma is used. Determinations in man and animals in or out of shock made in this way are very close to the more precise determinations obtained by the double (P31 and Cr51 ) isotope technique. 6 Hence the latter method is not needed except in special circumstances. A single reading after a mixing time of ten minutes gives a value that is not significantly different from one obtained after 15 or 20 minutes, so that serial readings for a single
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Fig. 1. An apparatus for repeated blood volume determinations (the Volemetron, manufactured by the Atomium Corporation, Billerica, Mass.).
determination are unnecessary; and even in the preterminal state of shock a mixing time of 15 minutes will be reliable. The hypovolemia of shock caused by loss of plasma is usually not as great as that which results from severe hemorrhage. But it can be very large in extensive burns, and in other types of massive trauma, as for example following abdominoperineal resection for carcinoma of the rectum, or exenteration of the pelvis for cervical cancer. The injured capillaries may leak so fast that the infused plasma leaves them almost as soon as it enters the veins. The classical experimental example of this phenomenon is shock following release of a tourniquet applied for eight to ten hours to the extremity of a dog.' This shock persists in spite of
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massive and repeated plasma transfusions. Compression therapy, when it is feasible, as in burns or tourniquet shock of the extremities, helps to prevent or to stop this kind of shock. The fatal diarrhea of cholera is a process. perhaps not unlike that of tourniquet injury. If hypovolemia is not a significant factor, and the shock is normovolemic or nearly so, blood volume therapy is useless. Moreover, in the patient who cannot get rid of an excess of plasma, such therapy can be lethal, especially in shock caused by myocardial injury. It is imperative to distinguish cardiogenic shock from other types of normovolemic shock. The diagnosis must not depend upon changes in values of circulating enzymes, because enzyme leakage from injured tissues occurs in all types of shock. A fall in cardiac output is also a finding common to all types of shock. A falling central venous pressure is more likely to be present in traumatic shock than in cardiogenic shock. But catheterization of the great veins to obtain such data is only rarely indicated. Antibiotics
As a rule, normovolemic shock is caused by toxins, and, in the vast majority of cases, by bacterial toxins. Of these, the endotoxins from gram-negative bacteria are the commonest offenders. Examples of shock with this etiology are the shock caused by generalized peritonitis, whether from a ruptured appendix, gangrenous bowel, ruptured peptic ulcer, acute pancreatitis, diverticulitis with perforation, etc. In such circumstances the most effective therapy for the shock is the prompt application of the most effective antibiotic in the most effective manner. In peritonitis the intraperitoneal instillation of solutiot:J.s of antibiotics, e.g., kanamycin or neomycin, at the site of most intense bacterial activity, supplemented where indicated by surgical control of the cause of the infection, will be the most rewarding therapy. Vasopressor Agents
Such measures require time to take effect. Meanwhile the hypotension is dealt with directly. In order to improve coronary flow, and hopefully a better cardiac output in consequence, a pressor agent is commonly used. Norepinephrine is widely employed; and since some patients respond to its use with an improved mental awareness, resumption of urine flow and better cardiac output, it is considered a useful therapy. At the same time there are good reasons for doubting that this drug in the long run is an advantage, because its benefits as a pressor agent may be more than counterbalanced by the reduced flow it produces in other critical areas, such as spleen, liver and intestine. 4 If a pressor drug is to be used, Aramine, which is said to be as effective as norepinephrine, may be preferred because it does not cause a slough in case of leakage. But Angiotensin II appears to be superior to both, because (a) its action is, restricted to the arterioles, i.e., it does not affect the venules; and
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(b) it appears to be free of the tachyphylaxis that characterizes the response to norepinephrine. There is mounting evidence that drugs which can reduce vasoconstriction are to be preferred to pressor drugs. Thus chlorpromazine, whose site of action is in the central nervous system, and dibenzyline, which is anti-adrenergic, protect against death from experimental shock when given prophylactically, because they facilitate better perfusion of viscera, even though they lower the systemic arterial pressure. But when they are given during experimental shock, striking benefits are not achieved. Even so, their clinical value is presently being appraised, and considerable benefit is said to have occurred in a number of instances. 8 The measure of their value will have to be made in terms of their effects on cardiac output, circulation time, renal function, central venous pressure, venous oxygen concentration, blood pH and other parameters.
Miscellaneous Agents
Electrolyte imbalance is common, and should be treated as indicated. Because of renal shut-down, an initial potassium deficiency is not likely to persist, and K + ion should be given only if there is a severe depletion, and even then with extreme caution because excess K + is toxic to the myocardium. In this connection one should remember that bank blood contains a considerable amount of released K+. Other therapeutic agents that are in wide usage are of uncertain benefit. There is good reason to treat the acidosis of shock. The continuous production of acid metabolites is inevitable in shock, and the lowered pH is a measure of the rate of their production. A pH below 7.25 and getting lower is a progressively increasing burden on the respiratory tract, as well as a sign of the worsening state of affairs in the peripheral circulation. Therefore, it is appropriate to give sodium lactate or bicarbonate to raise the blood pH. The critical importance of this therapy, however, has not been proved, however vigorous the claims for its value. Such therapy cannot get to the central problem of shock, which is the inadequate peripheral flow. The peripheral venous blood in shock usually is deficient in oxygen, not because the arterial blood is incompletely saturated but because of prolonged stay in the capillaries and venules. Unless the arterial oxygen concentration is below normal because of respiratory difficulties, the inhalation of 95 per cent or 100 per cent oxygen is an unnecessary maneuver, because it can only raise the oxygen content of the arterial blood by a few volumes per cent in physical solution. In principle, hypothermia is of value because it reduces metabolic requirements and slows up the depletion of reserves. For the same reason, reducing the fever of a patient in shock by cooling devices is also desirable. Both measures may be regarded as ancillary therapeutic agents, but further experience is needed to establish their value.
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The adrenal gland has been thought to be involved somehow, even though there is clear evidence that the level of corticosteroid production is adequate. 15 There are claims for the benefit of corticosteroid therapy which most investigators have not been able to confirm. The use of massive doses of corticosteroids, presumably on the basis that pharmocologic doses are required to suppress vicious cellular responses, even if they cannot be identified, continues to commend itself to a number of investigators. 2o Recently claims have been made for the prophylactic value of aldosterone in experimental endotoxic shock. 1 Others have found it useful only when given during experimental endotoxic shock. Clinical experience with this drug is lacking. The Management of Refractory Shock
What can be done for shock when the foregoing measures are not effective? This depends on what we take to be the cause of the progressive deterioration that accounts for death. There are those who believe that when shock caused by massive soft tissue injury persists in spite of proper therapy, something more than hypovolemia and bacterial activity is responsible. Proper therapy of wound shock implies correction of hypovolemia, adequate debridement of the damaged tissue and control of bacterial activity. It is usually possible to determine whether or not the devitalized tissue has been removed, and with the newest equipment (vide supra) one can, be certain that normovolemia has been achieved. But what is the basis for a conclusion that bacterial activity has been controlled, eliminated or is not a significant factor? THE ROLE OF A BACTERIAL FACTOR. The operation of a bacterial factor is frequently overlooked or dismissed on the ground that the signs of infection are absent. Since these signs are predominantly those of the reaction of defense, which is absent or very weak in shock, the assertion that death following wound shock was not due to bacterial action because none was seen is not acceptable. The literature on shock in relation to bacteria in wounds is sparse, and the bacteriologic study of such wounds in patients has not been sufficiently searching. The presence of bacterial activity in open wounds is more likely than not. Etiologically significant bacterial activity is often dismissed because cultures of surface swabs were sterile, grew few bacteria, or grew bacteria that were classified as nonpathogenic. In view of the very high susceptibility of the shocked animal to bacterial toxins, one cannot dismiss bacteria from consideration in wound shock on the basis of data obtained by prevailing clinical cultural techniques, and in the absence of data on the pathogenicity of the infecting organisms in the particular victim. Furthermore, continuous absorption of bacterial toxin from the gastrointestinal tract is a phenomenon that is not yet generallyappreciated.13 THE ROLE OF ENDOTOXINS. There is growing acceptance of the view
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that the catechol amines, and norepinephrine in particular, are the major offenders in the development of the refractory state of shock. This is the result of two facts: (a) anti-adrenergic compounds prevent this development in hemorrhagic shock; and (b) even in endotoxic shock the endotoxins make the circulation refractory by inducing excessive adrenergic activity rather than by direct injury to the peripheral vessels. 9 It is, therefore, necessary to focus attention on the role of the catechol amines. The liver, spleen and intestine suffer a more severe rednction in blood flow during shock than do the brain, heart and adrenals. There is a large body of evidence in the experimental literature to show that if the ischemia of the liver and spleen persists for hours, the reticuloendothelial system, most of which is concentrated in the liver and spleen, loses its ability to destroy bacteria and bacterial products. This has been shown by the greatly increased susceptibility of the experimental animal in shock to challenge with a very small dose of bacterial endotoxin15 or to an intravenous dose of bacteriaP It has also been shown by comparing the ability of water-soluble extracts of normal and shocked liver and of spleen to split and detoxify bacterial endotoxins. 14 The normal spleen in vivo, perfused with endotoxin, destroys the endotoxin immediately, whereas the spleen in the shocked animal is impotent. Endotoxemia has been shown to develop during prolonged hemorrhagic shock,12. 16 and the source of this endotoxin is the intestine,3 from which it is being continuously absorbed. Experimental proof that this endotoxin causes or contributes to the development of the irreversible state is the observation that hemorrhagic shock does not become irreversible to transfusion in animals pretreated with repeated doses of endotoxin for a week or ten days,19 and that the oral administration of nonabsorbable antibiotics reduces or prevents the endotoxemia as well as the irreversible state of hemorrhagic shock. 6 Therefore, there is good reason for the use of antibiotics in shock in the absence of infection, as well as in shock caused by infection. To suppress the intestinal flora, nonabsorbable antibiotics by the oral route are to be preferred. But patients in shock are often unable to swallow or retain fluids. Antibiotics may then be given parenterally for the same objective; and although they are not as effective by this route, they may help to the degree that they are excreted into the gut. THE ROLE OF THE NERVOUS SYSTEM. Since the anti-adrenergic measures now available have not yet proved themselves when applied during shock, we have undertaken a study of the effect of suppressing nervous activity that leads to the production of catechol amines. The experimental data demonstrate that tissue injury and death from hemorrhagic and endotoxic shock can be prevented by de nervation of the intestine, liver and spleen. They confirm the hypothesis that the key lesion responsible for death lies in these organs, and that the locally produced rather than the circulating catechol amines inflict the damage. 9 An
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anti-adrenergic agent applied during shock that would stop the production or block the action of these compounds in these organs would seem to be a promising therapeutic objective. In the absence of such an agent, chemical denervation of the coeliac plexus by a long-acting anesthetic should be worth exploiting. This therapy is now being evaluated. THE ROLE OF CARDIAC FUNCTION. There is evidence from the foregoing experimental data that there is no promise in therapy aimed at controlling such substances as histamine, or a large variety of circulating metabolites thought to be damaging to capillaries (e.g., kallikrein, toxic proteases, etc.).7.18 On the other hand, attention to cardiac function may prove to be of value, for even though the intestine, liver and spleen are the site of the lesion leading to death, the progressive decline in cardiac output is a critical consequence of the disturbance in these organs. Improving venous return, so long as it is inadequate, usually improves cardiac output. This is why most students of the problem do not regard the heart as the primary site of the irreversible process. In time, however, the heart does not respond even to increased venous return. Myocardial damage might then determine the subsequent downward trend, and improved coronary perfusion might become the only remaining recourse. On that account the use of agents for improving coronary perfusion is thought to be justified, and considered more appropriate not after, but prior to the development of the myocardial injury. The limitations of pressor drugs for such an objective have been discussed. Current efforts are aimed at observing the value of relieving the injured heart by a pump which removes blood from the aorta at the height of the systolic thrust, and drives it toward the periphery during diastole. Such measures belong to the field of experimental research. Now that the methods and the equipment for the study of shock in man have developed so that reliable evaluation of therapy is possible, such measures as can be applied without adding injury should be tested in patients who do not respond to the conventional measures. REFERENCES 1. Bein, H. J.: Aldosterone and alterations in circulatory reactivity following endotoxins. In Shock: Prevention and Therapy, Ciba Symposium (K. D.
Bock, Ed.). Stockholm, Springer-Verlag, 1962, pp. 162-168. 2. Fine, J., Frank, H. A. and Seligman, A. M.: Traumatic shock. VIII. Studies in the therapy and hemodynamics of tourniquet shock. J. elin. Invest. 23: 5, 1944. 3. - - , Rutenburg, S. H. and Schweinburg, F. B.: Role of the reticulo-endothelial syst.em in hemorrhagic shock. J. Exper. Med. 110: 547-569,1959. 4. Frank, E. D., Frank, H. A., Jacob, S., Weizel, H., Korman, H. and Fine, J.: Effect of norepinephrine on circulation of the dog in hemorrhagic shock. Am. J. Physiol. 186: 74, 1956. 5. Hechter, 0 .• Macchi, I. A., Korman, H., Frank, E. D. and Frank, H. A.: Quanti-
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tative variations in the adrenocortical secretion of dogs. Am. J. Physiol. 182: 1, 1955. 6. Jacob, S .. Weizel, H., Gordon, E., Korman, H., Schweinburg, F., Frank, H. A. and Fine, J.: Bacterial action in development of irreversibility to transfusion in hemorrhagic shock in the dog. Am. J. Physiol. 179: 523, 1954. 7. Miles, A. A.: Local and systemic factors in shock. Fed. Proc. Supp. No.9, July, 1961, pp. 141-149. 8. Nickerson, M.: Drug therapy of shock. In Shock: Pathogenesis and Therapy. Ciba Symposium (K. D. Bock, Ed.). Stockholm, Springer-Verlag, 1962, pp. 356-370. 9. Palmerio, C., Israel, J., Shammash, J., Zetterstrom, B., Frank, H. A. and Fine, J.: Effect of denervation of the abdominal viscera on the course of hemorrhagic and endotoxic shock. In preparation. 10. - - - , Ming, S. C., Frank, E. D. and Fine, J.: Cardiac tissue response to endotoxin. Proc. Soc. Exper. BioI. & Med. 109: 773-776, 1962. 11. Peden, J. C., Maxwell, M., Ohin, A. and Moyer, C. A.: Consideration of indications for preoperative transfusions based on analysis of normal and malnourished patients with and without cancer. Ann. Surg. 151: 303,1960. 12. Ravin, H. A., Schweinburg, F. B. and Fine, J.: Host resistance in hemorrhagic shock. XV. Isolation of toxic factor from hemorrhagic shock plasma. Proc. Soc. Exper. BioI. & Med. 99: 426, 1958. 13. - - - , Rowley, D., Jenkins, C. and Fine, J.: On the absorption of bacterial endotoxin from the gastro-intestinal tract of the normal and shocked animal. J. Exper. Med. 112: 783-792, 1960. 14. Rutenburg, S. H., Smith, E. E., Rutenburg, A. M. and Fine, J.: Degradation of endotoxin by splenic extracts. Antimicrobial Agents & Chemotherapy 1: 142147 (May) 1961. 15. Schweinburg, F. B. and Fine, J.: Resistance to bacteria in hemorrhagic shock. II. Effect of transient vascular collapse on sensitivity to endotoxin. Proc. Soc. Exper. BioI. & Med. 88: 589, 1955. 16. Idem: Evidence for a lethal endotoxemia as the fundamental feature of irreversibility in three types of traumatic shock. J. Exper. Med. 112: 793-800, 1960. 17. Schweinburg, F. B., Frank, H. A. and Fine, J.: Bacterial factor in experimental hemorrhagic shock. Evidence for development of a bacterial factor which accounts for irreversibility to transfusion and for the loss of the normal capacity to destroy bacteria. Am. J. PhysioI. 179: 523, 1954. 18. Sherry, S.: Hemostatic mechanisms and proteolysis in shock. Fed. Proc. Supp. No.9, July, 1961, pp. 209-218. 19. Smiddy, F. G. and Fine, J.: Host resistance to hemorrhagic shock. X. Induction of resistance by shock plasma and by endotoxins. Proc. Soc. Exper. BioI. & Med. 96: 558-562, 1957. 20. Spink, W. W.: Pathogenesis and management of shock due to infection. A.M.A. Arch. Int. Med. 106: 433-442, 1960. 21. Thomas, L.: Role of epinephrine in reactions produced by endotoxins of gramnegative bacteria. I. Hemorrhagic necrosis produced by epinephrine in skin of endotoxin-treated rabbits. J. Exper. Med. 104: 865-880, 1956. 22. Williams, J. A. and Fine, J.: Measurement of blood volume with a new apparatus. New England J. Med. 264: 842, 1961. 23. - - - and Grable, E.: Simultaneous measurements of red cell mass and plasma volume with Cr 61 tagged red cells and 1125 labelled albumin. In preparation. 24. - - - , Grable, E., Frank, H. A. and Fine, J.: Blood losses and plasma volume shifts during and following major surgical operations. Ann. Surg. 156: 648653,1962. 330 Brookline Avenue Boston 15, Massachusetts