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Newer Attitudes in Management of Hemorrhagic Shock: The Use of Chlorpromazine as an Adjunct
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Newer Attitudes in Management of Hemorrhagic Shock The Use of Chlorpromazine as an Adjunct
VINCENT J. COLLINS, M.D.* RONALD J. JAFFE, M.D.** IVAN ZAHONY, M.D. ***
Irreversible shock is still a major threat to the life of surgical patients in spite of almost unlimited availability of whole blood, plasma, antibiotics, a much better understanding of fluid and electrolyte balance and refined surgical techniques. It is believed that the classic treatment of shock has been found wanting. The traditional goals of raising blood pressure to a predetermined level by massive transfusion or by the use of vasopressors has not been effective in preventing irreversible shock. In contrast, it is believed that the removal of persistent vasoconstrictor impulses, which in the last analysis may represent a misdirected attempt by nature to maintain central economy at the expense of organs and tissues, will provide better tissue perfusion. The essential purpose of the lung-heart system is to sustain tissue oxygenation. This can be best accomplished by good capillary perfusion. We propose, first, to review briefly the laboratory background relating to shock and, secondly, to present clinical experience utilizing an adrenergic blocking agent to foster tissue perfusion in a large series of patients in profound shock. From the Department of Anesthesiology, Cook County Hospital, Chicago, Illinois
* Director of Anesthesiology ** Former Resident *** Associate in Anesthesiology
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VINCENT J. COLLINS, RONALD J. JAFFE, IVAN ZAHONY
PATHOPHYSIOLOGY OF SHOCK
Shock may be defined as the general response of the body to an acute reduction in cardiac output, primary or secondary in nature. It is a syndrome with a decrease in effective circulating blood volume accompanied by depression of many systems and in which impairment steadily progresses until it is climaxed in a state of irreversible failure. The physiological adjustments to acute hypovolemia have been elucidated by many workers14 . 16, 30, 32, 39, 41, 43, 45, 49 and reviewed by Hershey.20 An immediate response to hemorrhage is vasoconstriction of the small blood vessels. With hemorrhage as a stimulus, cortical and subcortical impulses elicit a hypothalamic response. Adrenergic influences result in functional closure of the precapillary sphincters and opening of arteriovenous shunts, and subsequent short-circuiting of oxygenated blood into the central circulation assuring vital centers of an adequate blood supply but excluding peripheral tissues. 47 In experimental animals an overcompensated vasoconstrictor response to hemorrhage sometimes occurs, causing mild hypertension. 34 A similar response in the early stages of clinical shock has been recognized but soon the usual picture of hypotension, tachycardia, pallor, sweating and increased respiration develops. These physiological responses may persist and become self-perpetuaing. Ensuing biochemical derangements may sustain the peripheral circulatory failure and thus act as an independent noxious stimulus. As the stressing phenomenon continues, the extreme vasoconstriction persists, causing hypoxia of the peripheral tissues. Certain regions are particularly vulnerable and their functional derangement further enhances the general circulatory decompensation in the kidneys, liver, splanchnic bed and extremities. As ischemia persists, these tissues release vasoactive materials and breakdown products which further damage the already anoxic capillary beds, increasing permeability and fluid loss across the altered membrane and further decreasing the effective circulating volume. Hence, a vicious cycle may be initiated. In experimental animals a decrease of 75 per cent of femoral artery blood flow was demonstrated after the induction of nonhemorrhagic shock. IS This change occurred before any noticeable change in clinical blood pressure. Savlov37 has shown by direct measurement in the renal vein that renal blood flow decreased from the control of 110 rnl./min. to 35 rnl./min. in hemorrhagic shock of the experimental animal. Friedman19 has measured the distribution of radioiodinated plasma and radioiron-labeled red blood cells between the liver, intestine and spleen during tourniquet shock in mice. He found that plasma and red blood cells are distributed differentially in the splanchnic beds in a manner causing the plasma volume of liver, intestine and spleen to remain depressed for the entire shock interval, as does splenic red cell volume. After an early decline, the red cell volume of liver and intestine becomes elevated to a level above control. This differ-
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ential distribution of plasma and red cells in liver and intestine is attributed to alterations in peripherovascular tone and suggests that a venous component becomes prominent late in shock and may act to pool blood out of active circulation, which is already depleted, and the peripheral circulatory failure is event.ually followed by central failure and death.
EXPERIMENTAL STUDIES
Numerous observers have noted that shock failed to produce death in a number of cases in which blockade of the central nervous system existed. Total sympathectomy in dogs produced increased resistance to hemorrhagic shockY Similar results were produced with spinal anesthesia. 13 , 32 High transection of the spinal cord produced resistance to traumatizing procedures. 33 The conclusion drawn from these observations was that noxious body reactions in acute hypovolemic states can be initiated through nervous pathways.40 In 1947, Wiggers and co-workers42 , 44 medicated dogs with dibenzyl betachlorethyl amine hydrochloride (dibenamine) and found that irreversible hemorrhagic shock was prevented or delayed when they were exposed to graded hemorrhage. Since that time medication with ganglionic blocking agents like dibenamine,3, 22, 23, 29, 35, 46, 48 trimethaphan camphorsulfonate (Arfonad)8, 9, 10 and chlorpromazine has been observed to afford protection against the onset of irreversible shock. Chlorpromazine is an outstanding example among the agents found to have an influence on the responses to a wide variety of noxious stimuli. In 1953, Courvoisierl l described a number of actions of the drug including ganglioplegic, adrenolytic, antipyretic, anticonvulsant, anti-emetic, antifibrillatory, and anti-edema properties. The drug exhibits a marked adrenolytic effect on the periphery along with marked central effect on the hypothalamus and reticular activating system. It appears to act by suppression of the pituitary-adrenal axis at the level of the hypothalamus. This axis is probably responsible for many of the body's reactions to stress.
Traumatic Shock The administration of 1 to 5 mg. of chlorpromazine 20 minutes prior to induced drum shock increased the survival in rats from 35 per cent in the control group to 90 per cent in the treated group.48 Chlorpromazine not only served to protect from the lethal effects of a standard dose of drum trauma, but it was possible to increase the severity of trauma considerably without the development of lethal shock. Chlorpromazine-treated rats withstood as many as 1000 revolutions in the standard Noble-Collip drum with only 20 per cent mortality in contrast to 100 per cent mortality in the control group.
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Hemorrhagic Shock Courvoisierll reported that chlorpromazine protected animals while 83 per cent of controls died following hemorrhagic shock. Hershey and co-workers21 noted that the drug is capable of eliminating or attenuating many of the decompensatory vascular phenomena associated with the irreversible phase of hemorrhagic shock. The animals showed significant difference in the manner in which they responded to blood administration, and there was an absence of gross visceral lesions associated with irreversible shock, the most striking of which is necrosis of the bowel.
Endotoxin Shock Fine1• presented extensive evidence implicating enteric endotoxins as the most important factor in his concept of the breakdown of bacterial defense mechanisms as the fundamental defect in shock. Animals treated with chlorpromazine were protected against the lethal effects of hemorrhagic shock despite the presence of bacterial contaminants in the blood, liver and spleen. This probably supports the contention that bacterial factors are secondary in shock and not necessarily of decisive importance.
General Several recent papers have focused attention on more specific areas than general survival in shock. Lillehei28 in 1957 noted that the marked mucosal necrosis as well as the severe congestion present in the bowel of dogs are factors that have not been fully appreciated when these animals were subjected to irreversible shock. He states that this necrosis is apparently the result of ischemia during the shock period. Perfusion of the superior mesenteric artery during hemorrhagic shock forestalled these changes and prevented irreversibility from occurring in 90 per cent of the animals so protected. 27 Lillehei also points out that death in a shocklike state has been"produced in dogs without hemorrhage by Erlanger and Gasser12 by the repeated injection of epinephrine. The only significant lesion present at the autopsy was mucosal congestion and bowel necrosis identical to the lesions found in dogs dying of hemorrhagic shock. It is probable that bowel ischemia resulting from the chronic epinephrine injections was the cause of death in these animals. He notes that there have been many reports on the beneficial effects of pretreating experimental animals prior to hemorrhagic shock with adrenolytics, vasodilators and hypothermia. The salutary effects obtained by these procedures probably resulted from maintaining blood flow to the bowel or from decreasing the oxygen need of the bowel during shock, thus preventing the development of lethal bowel ischemia. In 1959, Inglis and co-workers24 reported the use of chlorpromazine in the treatment of shock after the shock state has been established (method of Fine). The mesenteric vein blood flow in ml./kg./min. was determined
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in dogs prior to and after the induction of hemorrhagic shock to a systolic blood pressure of 30 mm. Hg. The administration of divided doses of 2 mg. of chlorpromazine (0.1 to 0.15 mg./kg.) every 15 minutes was followed by a doubling of mesenteric vein blood flow even though the systolic blood pressure remained the same. The survival time of dogs treated with chlorpromazine following the induction of shock was more than double that of control animals. Savlov and Regelson38 demonstrated diuresis during extremely low levels of blood pressure after hemorrhage in dogs treated with small doses of chlorpromazine (0.2 mg./kg.). They noted that, while animals treated with this dosage of chlorpromazine usually survived their technique of hemorrhage (technique of Wiggers), larger doses usually caused almost immediate drop in blood pressure and death. Because the nature of the diuresis following chlorpromazine in hemorrhagic shock was not understood, studies of renal hemodynamics and tubular reabsorption were done and reported by Savlov. 37 He found that renal blood flow (RBF) in hemorrhagic hypotension of a dog (50 mm. Hg systolic blood pressure) by direct measurement in the renal vein rose significantly after chlorpormazine 0.2 mg./kg. was given (control RBF: 110 ml./min., after bleeding, RBF: 35 ml./min., after chlorpromazine, RBF: 70 ml./min., and after partial reinfusion of blood, RBF: 100 ml./min.). An increased vasaculrization of the kidney of the rat in shock following chlorpromazine was also shown using the fluorescent dye Vasoflavine. While glomerular perfusion was increased to some degree, the circulation in the medullary portion of the kidney was improved more significantly. He also measured renal blood flow after the combined use of norepinephrine and chlorpromazine and found that the administration of norepinephrine in dosage sufficient to elevate the blood pressure during hemorrhagic hypotension in the face of preliminary administration of chlorpromazine maintained the peripheral vasoconstriction. Renal blood flow did not increase. He remarked that the use of chlorpromazine in the treatment of shock has not been accepted widely, primarily because experimental studies of postshock treatment have not demonstrated improvement in survival. It may be inferred from his study, however, that doses of a smaller order than those usually employed experimentally will increase perfusion of the kidney without significant lowering of the blood pressure. The arteriosclerotic or otherwise borderline kidney is particularly susceptible to ischemia and might be protected from irreversible damage by a small increment in perfusion such as adrenergic blockade might afford.
RECENT CLINICAL STUDIES
In 1953, Laborit and Huguenard 25 reported on the use of the "lytic cocktail" to produce artificial hibernation in patients with severe shock.
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Lear and co-workers26 used chlorpromazine as an adjunct to premedication in over 1100 cases of major surgery. The dosage schedule ranged from 25 to 50 mg. intramuscularly. The most alarming side effect of chlorpromazine that he encountered was a severe hypotension. In 1959, Savlov37 pointed out the importance of using small doses of chlorpromazine (0.2 mg./kg.) after hemorrhage in dogs in order to avoid hypotension. In our own experience, we have observed chlorpromazine hypotension (20 per cent fall or more in systolic pressure) only in those patients who were acutely or chronically hypovolemic prior to the administration of the drug. Therefore, it is quite possible that in Lear's series those patients who developed severe hypotension (as low as 50/30 mm. Hg) were hypovolemic and that 25 to 50 mg. doses of chlorpromazine were a relative overdose. The dosage of the drug, the degree of hypotension, and the amount of blood or plasma required to restore homeostasis in our patients have been clinical guides to the severity of their pre-existing hypovolemia. Chlorpromazine hypotension has not been met in patients who were well prepared for elective surgery. The occurrence of hypotension in patients following a small dose of chlorpromazine (5 to 15 mg. I.V. [0.1 to 0.2 mg./ kg.]) leads us to suspect hypovolemia in these persons, and invariably they respond to therapy that expands their intravascular compartment (Collins-Zahony test, in press). In October, 1958, we embarked on a program to determine the efficacy of using chlorpromazine as an adjunct in the management of patients with hemorrhagic shock or impending shock.
Method Conventional premedication was ordered for all patients as indicated by their preoperative condition. Chlorpromazine was also administered to all patients, except the control groups, either preoperatively and/or during the operation. The dose of chlorpromazine varied from 5 mg. to 100 mg. in divided doses. An adequate dose was judged as having been given when the patient's color was pink, capillary refill was good and, in general, perfusion of all tissues appeared to be adequate. Whenever possible, blood replacement was restricted until the hemorrhage was surgically controlled. No attempt was Inade to raise blood pressure with the use of vasopressors. Until bleeding was controlled, blood replacement was limited to that necessary to maintain vital signs at a perfusion level. After bleeding was controlled, blood replacement was undertaken rapidly until the normovolemic state was judged to have been nearly reached. Where the differential diagnostic problem of possibly overloading the circulation arose, blood replacement was guided by the changes in central venous pressure. In almost all cases cyclopropane-oxygen endotracheal anesthesia was used. Surgery and anesthesia were performed by the resident house staff at Bellevue Hospital and Cook County Hospital. Patients were considered to have survived if they were alive 14 days after surgery.
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Selection of Patients
Three categories of patients were investigated. Group I (Table 1). Only patients requiring emergency surgery because of massive upper gastrointestinal hemorrhage with shock or impending shock were included in this group. All patients were classified into physical status VI and VII.36 Fifty-one patients received chlorpromazine and 79 received none and acted as controls. The control group consisted of patients operated on before October, 1958, and whose charts were obtained from the operating room emergency record book. Group II (Table 2). Patients in hemorrhagic shock due to other than gastrointestinal hemorrhage represent this group. Eighty-six such patients were investigated. One hundred and twelve patients comprised the control group and had been operated on before October, 1958. Group III (Table 3). Patients requiring massive transfusion greater than 5 pints of blood during surgery and developing shock in the intraoperative period were placed in this group. Thirty-six patients received chlorpromazine and 32 who did not receive the drug acted as controls.
Table 1. Group I: Shock in Emergency Surgery for Gastrointestinal Bleeding CHLORPROMAZINE
TREATED
Number of patients ............................ Average age ................................... Overall mortality .............................. Mortality from emergency gastrectomy for benign peptic ulcer with massive hemorrhage. . . . . . . . .. Mortality from all other types of gastrointestinal hemorrhage necessitating emergency surgery .... Vasopressor therapy ............................ Postoperative anuria or severe oliguria ............ Average urine output, first 24 hours postoperative ..
CLASSICAL THERAPY
51 60.9 years 27.5%
79 62.7 years 43% (34)
20.0% (7/35)
3Q.4% (17/56)
43.7% (7/16) 0 0 1,578 ml. (13 cases) Complications, cerebrovascular or myocardial. . . .. 0
73.9% (17/23) 20.2% 8.8% Depressedunder 300 mI. 3.75%
Table 2. Group II: Hemorrhagic Shock Other Than That Due to Gastrointestinal Bleeding USE OF CHLORPROMAZINE
Number of patients. . . . . . . . . . . . . . . . . . . . . . . .. Average age... .. . . . . . . . . .. .... .. ... . .. .. . .. Mortality.. . ... .. . . . .. ... .. . . .. . .. . . . ... ... Vasopressor therapy. . . . . . . . . . . . . . . . . . . . . . . .. Oliguria or anuria, postoperative. . . . . . . . . . . . .. Average urinary output, 24 hra., postoperative
86 46.3 years 11.6% (10/86) 0 0 1,272 mI. (15 cases) Complications, cerebrovascular or myocardial. .. 0
NO CHLORPROMAZINE
112 44.2 years 28.5% (32/112) 24% 9% Under 200 mI. 2.4%
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Table 3.
Group III: Shock Developing During Anesthesia and SurgeryTransfusion Requirement Massive CHLORPROMAZINE TREATED
Number of patients ........................ Average age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Mortality ................................. Vasopressor therapy (Norepinephrine) ........ Oliguria or anuria, postoperative ............. Average urine output, 24 hrs. postoperative ...
36 48.8 years 22.2% (8) 0 0 2,260 ml. (5 cases)
Complications, cerebrovascular or myocardial .. 0
NO CHLORPROMAZINE
32 47.2 years 53.1%(17) 21.8% (7) 6.3% (2) Depressed under 400 ml. 6.3% (2)
Results. In groups I, II and III the mortality rates of the chlorpromazine-treated patients were markedly less than those of the patients treated classically-27.5 per cent, 11.6 per cent and 22.2 per cent respectively compared to 43 per cent, 28.5 per cent and 53.1 per cent. Although the total patient population here is only 396, the trend is definitely toward greater survival in the chlorpromazine groups. A noteworthy and striking observation is the complete absence of postoperative renal depression in all 173 cases treated with chlorpromazine (no postoperative anuria in the chlorpromazine groups compared with 8.8 per cent, 9 per cent and 6.3 per cent of the control groups). This has traditionally been a problem following surgery and shock. Also noteworthy is the absence of cardiovascular complications in these same patients postoperatively. DISCUSSION OF THE USE OF CHLORPROMAZINE IN HEMORRHAGIC SHOCK
A number of the clinical features of shock such as low or absent blood pressure, subungual cyanosis and pallor can be explained on the basis of extreme vasoconstriction. Obviously, a patient with no blood pressure or pulse is clinically dead; however, patients in shock may have such an extreme degree of vasoconstriction that no blood pressure and/or pulse may be audible or palpable on the extremity, but the patient is still alive. Although the extremities are cold, this is not a reflection of hypothermia but rather a decreased blood flow as the consequence of vasoconstriction. The same phenomenon occurs in the kidneys and also in the splanchnic bed, which appears pale, dusky and congested in the vasoconstricted phase of shock. It can readily be seen following a dose of chlorpromazine that the extreme vasoconstrictor response to hypovolemia is reversed in the extremities, which become warm and pink and now begin to display filling of the venous channels which were previously collapsed. Similarly, clinical
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observations revealed that chlorpromazine will change the appearance of the kidney from a congested cyanotic organ to a pink, viable, noncongested one. Chlorpromazine has frequently been used to overcome severe vasospasm that has occurred during induction of hypothermia, and its use is recognized as an adjunct to the cooling of the patient by increasing the circulation, where the cooling is attempted, at the surface. Before chlorpromazine is administered to patients subjected to hypothermia, sphygmomanometric blood pressure may be unobtainable although intra-arterial pressure readings are at normal values. This is referred to as "clinical disappearance" of blood pressure. 5 , 6 After administration of chlorpromazine, pressure readings are obtainable with the sphygmomanometer, and these values are similar to those obtained intra-arterially.7 It may be concluded that the severe vasospasm and rigidity of the walls of larger arteries during hypothermia prevented adequate sphygmomanometric readings and that chlorpromazine counteracted the spasm to allow subsequent readings. A number of investigators consider that vasoconstriction, which is one of the basic protective mechanisms in hypovolemia, may itself become an independent noxious stimulus. Beyond the vasoconstricted area, anoxia occurs with consequent impairment of tissue function. A point is reached at which perfusion of tissues is sacrificed in order to maintain the internal blood pressure of the body. Irreversibility in shock may be related to this extreme vasoconstriction. Besides the adrenolytic action of chlorpromazine, other effects of the drug must be considered as having a possible role in protection against irreversibility in shock. Its antiserotonic effect4 may block the vasotropic material shown by Baez and co-workersl in SMA shock (temporary ligation of the superior mesenteric artery). This substance exhibits the vasotoxic properties of ferritin and the myogenic properties of serotonin. It may also have an effect similar to Dibenzyline (phenoxybenzamine hydrochloride), which inhibits normal anaerobic formation of vasoactive ferritin and also preserves the aerobic ferritin-inactivating system from the deterioration ordinarily resulting from prolonged hepatic hypoxia. 2
SUMMARY
1. Tissue perfusion and oxygenation may be the most important factors which contribute to the outcome of a patient in severe shock. 2. Blood pressure is no criterion of blood flow, perfusion or oxygenation. 3. The use of vasopressors to maintain blood pressure may cause further vasoconstriction and tissue anoxia, thereby worsening rather than improving circulation. 4. Chlorpromazine seems to overcome effectively the severe vasocon-
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striction occurring in shock, permits adequate tissue perlusion even at low blood pressure, and most probably prevents biochemical derangements. Experimentally and clinically, survival rate is higher in shock with this drug. 5. A re-evaluation of the classic treatment of hemorrhagic shock (maintenance of blood pressure with vasopressors and massive transfusion) may be in order.
REFERENCES 1. Baez, S., Hershey, S. G. and Rovenstine, E. A.: Vasotropic substances in blood in intestinal ischemia shock. Am. J. Physiol. 200: 1245, 1961. 2. Baez, S., Srikantia, S. G. and Shorr, E.: Influence on hepatic ferritin systems of tertiary amine, G-D 131, with beneficial effects in shock. Proc. Soc. Exper. BioI. & Med. 92: 61, 1956. 3. Baez, S., Zweifach, B. W. and Shorr, E.: Protective action of dibenamine against the fatal outcome of hemorrhagic and traumatic shock in rats. Fed. Proc. 11: 7, 1952. 4. Benditt, E. P. and Rowley, D. A.: Antagonisms of 5-hydroxy-tryptamine by chlorpromazine. Science 123: 24, 1956. 5. Blair, E., Austin, R., Reed, B., Gilbert, S. and Swan, H.: Study of cardiovascular changes during cooling and rewarming in human subjects undergoing total circulatory occlusion. J. Thoracic Surg. 33: 707, 1957. 6. Collins, V. J. and Granatelli, A.: Controlled hypothermia during anesthesia in human adults. Angiology 6: 118, 1955. 7. Collins, V. J., Granatelli, A. and Zahony, I.: Unpublished data. 8. Converse, J. G. and Boba, A.: Use of ganglionic blocking agents in the treatment of hemorrhagic shock. Anesth. & Analg. Current Researches 35: 644, 1956. 9. Converse, J. G. and Boba, A.: An experimental study of Arfonad in hemorrhagic shock in dogs. Am. Surgeon. 23: 420, 1957. 10. Converse, J. G., McKechnie, F. B. and Boba, A.: Arfonad in hemorrhage. New York J. Med. 57: 731, 1957. 11. Courvoisier, S., Fournel, J., Ducrot, R., Kolsky, M. and Koetschet, P.: Proprietes pharmacodynamiques du chlorhydrate de chlora-3 (dimethyl-amino-3' propyl)10 phenothiazine (4560 RP). Arch. internat. pharmacodyn. et therap. 92: 3, 1953. 12. Erlanger, J. and Gasser, H. S.: Studies in secondary traumatic shock; circulatory failure due to adrenaline. Am. J. Physiol. 49: 345, 1919. 13. Eversole, W. J., Kleinberg, W., Overman, R. R., Remington, J. W. and Swingle, W. W.: Muscle trauma in normal dogs. Am. J. Physiol. 140: 490, 1944. 14. Fine, J.: Symposium on Shock, Chapter 5. Army Medical Service Graduate School, Washington, D.C., 1951. 15. Fine, J.: The bacterial factor in traumatic shock. Springfield, Ill., Charles C Thomas, 1954. 16. Freeman, N. E.: Burns, Shock, Wound Healing and Vascular Injuries. Philadelphia, W. B. Saunders Co., 1943. 17. Freeman, N. E., Schaffer, S. A., Shechter, A. E. and Holling, H. E.: Occurrence of shock from hemorrhage. J. Clin. Invest. 17: 359, 1938. 18. Friedberg, C. K.: Diseases of the Heart. Philadelphia, W. B. Saunders Co., 1950. 19. Friedman, J. J.: Splanchnic blood volume in traumatic shock. Am. J. Physiol. 200: 614, 1961. 20. Hershey, S. G.: Current theories of shock. Anesthesiology 21: 303, 1960. 21. Hershey, S. G., Guccione, 1. and Zweifach, B. W.: Beneficial action of pretreatment with chlorpromazine and survival following graded hemorrhage in the rat. Surg. Gynec. & Obst. 101: 431, 1955. 22. Hershey, S. G., Lanza, S. and Rovenstine, E. A.: Protection against shock induced by mesenteric artery occlusion. Fed. Proc. 17: 377, 1958.
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23. Hershey, S. G., Zweifach, B. W. and Antopol, W.: Factors associated with protection against experimental shock. Anesthesiology 17: 265, 1956. 24. Inglis, F. G., Hampson, L. G. and Gurd, F. N.: Effect of chlorpromazine on survival time and mesenteric blood flow in experimental shock. Ann. Surg. 149: 43, 1959. 25. Laborit, H. and Huguenard, P.: L'Hibernation artificielle chez Ie grand choque. Presse mM. 61: 1029, 1953. 26. Lear, E., Chiron, A. E. and Pallin, 1. N.: Chlorpromazine-an adjunct to premedication. New York J. Med. 55: 1853, 1955. 27. Lillehei, R. C.: Prevention of irreversible hemorrhagic shock in dogs by controlled cross perfusion of the superior mesenteric artery. S. Forum 7: 6, 1956. 28. Lillehei, R. C.: Intestinal factor in irreversible hemorrhagic shock. Surgery 42: 1043,1957. 29. Lillehei, R. C.: Intestinal factor in irreversible endotoxin shock. Ann. Surg. 148: 513, 1958. 30. Lin, M. K.: Factors concerned with irreversible phase of hemorrhagic shock. Nikon Univ. M. J. 18: 242, 1959. 31. Nickerson, M.: Factors of vasoconstriction and vasodilation in shock. J. Michigan M. Soc. 54: 45, 1955. 32. Phemister, D. B.: Mechanism and management of surgical shock. J.A.M.A. 127: 1109,1945. 3a. Phemister, D. B., Eichelberger, R. L. and Laestar, C. H.: Early effects on dogs of section of eighth cervical segment of spinal cord and their bearing on shock. Arch. Surg. 51: 32, 1945. 34. Remington, J. W., Hamilton, W. F., Caddell, H. M., Boyd, G. H., Jr. and Wheeler, W. C.: Vasoconstriction as precipitating factor in traumatic shock in dog. Am. J. Physiol. 161: 135, 1950. 35. Remington, J. W., Wheeler, N. C., Boyd, G. H., Jr. and Caddell, H. M.: After hemorrhage and after muscle trauma. Proc. Soc. Exper. BioI. & Med. 6.9: 150, 1948. 36. Saklad, Meyer: Grading of patients for surgical procedures. Anesthesiology 2: 281, 1941. 37. Savlov, E. D.: Effect of chlorpromazine on renal function and hemodynamics particularly during hemorrhagic hypotension. Surgery 45: 229, 1959. 38. Savlov, E. D. and Regelson, W.: Diuresis in hemorrhagic hypotension. S. Forum 7: 40,1956. 39. Shorr, E., Zweifach, B. W. and Furchgott, R. F.: On occurrence, sites and modes of origin and destruction of principles affecting compensatory vascular mechanisms in experimental shock. Science 102: 489, 1945. 40. Swingle, W. W., Kleinberg, W., Remington, J. W., Eversole, W. J. and Overman, R. R.: Factor in shock induced by muscle trauma in normal dogs. Am. J. Physiol. 141: 54, 1944. 41. Wiggers, C. J.: Physiology of Shock. Cambridge, Mass., Harvard University Press, 1950. 42. Wiggers, H. C., Goldberg, H., Roemhild, R. and Ingraham, R. C.: Impending hemorrhagic shock and course of events following administration of dibenamine. Circulation 2: 79, 1950. 43. Wiggers, H. C. and Ingraham, R. C.: Hemorrhagic shock, definition and criteria for its diagnosis. J. Clin. Invest. 25: 30, 1946. 44. Wiggers, H. C., Roemhild, F., Goldberg, H. and Ingraham, R. C.: The influence of prolonged vasoconstriction on the transition from impending to irreversible shock. Fed. Proc. 6: 226, 1947. 45. Zweifach, B. W.: Microcirculatory derangements as basis for lethal manifestations of experimental shock. Brit. J. Anaesth. 30: 466, 1958. 46. Zweifach, B. W., Baez, S. and Shorr, E.: Effect of dibenamine on humeral and vascular changes in dogs subjected to hemorrhagic shock. Fed. Proc. 11: 177, 1952. 47. Zweifach, B. W., Chambers, R. and Hyman, C.: Reactions of peripheral blood vessels in experimental hemorrhage. Ann. New York Acad. Sc. 4.9: 553, 1948. 48. Zweifach, B. W. and Hershey, S. G.: Protective mechanisms in shock. Ann. New York Acad. Sc. 66: 1010, 1957. 49. Zweifach, B. W., Lowenstein, B. E. and Chambers, R.: Responses of blood capillaries to acute hemorrhage in rats. Am. J. Physiol. 142: 80, 1944. 966 Private Road Winnetka, Illinois (Dr. Collins)
Newer Attitudes in Management of Hemorrhagic Shock The Use of Chlorpromazine as an Adjunct
VINCENT J. COLLINS, M.D.* RONALD J. JAFFE, M.D.** IVAN ZAHONY, M.D. ***
Irreversible shock is still a major threat to the life of surgical patients in spite of almost unlimited availability of whole blood, plasma, antibiotics, a much better understanding of fluid and electrolyte balance and refined surgical techniques. It is believed that the classic treatment of shock has been found wanting. The traditional goals of raising blood pressure to a predetermined level by massive transfusion or by the use of vasopressors has not been effective in preventing irreversible shock. In contrast, it is believed that the removal of persistent vasoconstrictor impulses, which in the last analysis may represent a misdirected attempt by nature to maintain central economy at the expense of organs and tissues, will provide better tissue perfusion. The essential purpose of the lung-heart system is to sustain tissue oxygenation. This can be best accomplished by good capillary perfusion. We propose, first, to review briefly the laboratory background relating to shock and, secondly, to present clinical experience utilizing an adrenergic blocking agent to foster tissue perfusion in a large series of patients in profound shock. From the Department of Anesthesiology, Cook County Hospital, Chicago, Illinois
* Director of Anesthesiology ** Former Resident *** Associate in Anesthesiology
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VINCENT J. COLLINS, RONALD J. JAFFE, IVAN ZAHONY
PATHOPHYSIOLOGY OF SHOCK
Shock may be defined as the general response of the body to an acute reduction in cardiac output, primary or secondary in nature. It is a syndrome with a decrease in effective circulating blood volume accompanied by depression of many systems and in which impairment steadily progresses until it is climaxed in a state of irreversible failure. The physiological adjustments to acute hypovolemia have been elucidated by many workers14 . 16, 30, 32, 39, 41, 43, 45, 49 and reviewed by Hershey.20 An immediate response to hemorrhage is vasoconstriction of the small blood vessels. With hemorrhage as a stimulus, cortical and subcortical impulses elicit a hypothalamic response. Adrenergic influences result in functional closure of the precapillary sphincters and opening of arteriovenous shunts, and subsequent short-circuiting of oxygenated blood into the central circulation assuring vital centers of an adequate blood supply but excluding peripheral tissues. 47 In experimental animals an overcompensated vasoconstrictor response to hemorrhage sometimes occurs, causing mild hypertension. 34 A similar response in the early stages of clinical shock has been recognized but soon the usual picture of hypotension, tachycardia, pallor, sweating and increased respiration develops. These physiological responses may persist and become self-perpetuaing. Ensuing biochemical derangements may sustain the peripheral circulatory failure and thus act as an independent noxious stimulus. As the stressing phenomenon continues, the extreme vasoconstriction persists, causing hypoxia of the peripheral tissues. Certain regions are particularly vulnerable and their functional derangement further enhances the general circulatory decompensation in the kidneys, liver, splanchnic bed and extremities. As ischemia persists, these tissues release vasoactive materials and breakdown products which further damage the already anoxic capillary beds, increasing permeability and fluid loss across the altered membrane and further decreasing the effective circulating volume. Hence, a vicious cycle may be initiated. In experimental animals a decrease of 75 per cent of femoral artery blood flow was demonstrated after the induction of nonhemorrhagic shock. IS This change occurred before any noticeable change in clinical blood pressure. Savlov37 has shown by direct measurement in the renal vein that renal blood flow decreased from the control of 110 rnl./min. to 35 rnl./min. in hemorrhagic shock of the experimental animal. Friedman19 has measured the distribution of radioiodinated plasma and radioiron-labeled red blood cells between the liver, intestine and spleen during tourniquet shock in mice. He found that plasma and red blood cells are distributed differentially in the splanchnic beds in a manner causing the plasma volume of liver, intestine and spleen to remain depressed for the entire shock interval, as does splenic red cell volume. After an early decline, the red cell volume of liver and intestine becomes elevated to a level above control. This differ-
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ential distribution of plasma and red cells in liver and intestine is attributed to alterations in peripherovascular tone and suggests that a venous component becomes prominent late in shock and may act to pool blood out of active circulation, which is already depleted, and the peripheral circulatory failure is event.ually followed by central failure and death.
EXPERIMENTAL STUDIES
Numerous observers have noted that shock failed to produce death in a number of cases in which blockade of the central nervous system existed. Total sympathectomy in dogs produced increased resistance to hemorrhagic shockY Similar results were produced with spinal anesthesia. 13 , 32 High transection of the spinal cord produced resistance to traumatizing procedures. 33 The conclusion drawn from these observations was that noxious body reactions in acute hypovolemic states can be initiated through nervous pathways.40 In 1947, Wiggers and co-workers42 , 44 medicated dogs with dibenzyl betachlorethyl amine hydrochloride (dibenamine) and found that irreversible hemorrhagic shock was prevented or delayed when they were exposed to graded hemorrhage. Since that time medication with ganglionic blocking agents like dibenamine,3, 22, 23, 29, 35, 46, 48 trimethaphan camphorsulfonate (Arfonad)8, 9, 10 and chlorpromazine has been observed to afford protection against the onset of irreversible shock. Chlorpromazine is an outstanding example among the agents found to have an influence on the responses to a wide variety of noxious stimuli. In 1953, Courvoisierl l described a number of actions of the drug including ganglioplegic, adrenolytic, antipyretic, anticonvulsant, anti-emetic, antifibrillatory, and anti-edema properties. The drug exhibits a marked adrenolytic effect on the periphery along with marked central effect on the hypothalamus and reticular activating system. It appears to act by suppression of the pituitary-adrenal axis at the level of the hypothalamus. This axis is probably responsible for many of the body's reactions to stress.
Traumatic Shock The administration of 1 to 5 mg. of chlorpromazine 20 minutes prior to induced drum shock increased the survival in rats from 35 per cent in the control group to 90 per cent in the treated group.48 Chlorpromazine not only served to protect from the lethal effects of a standard dose of drum trauma, but it was possible to increase the severity of trauma considerably without the development of lethal shock. Chlorpromazine-treated rats withstood as many as 1000 revolutions in the standard Noble-Collip drum with only 20 per cent mortality in contrast to 100 per cent mortality in the control group.
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Hemorrhagic Shock Courvoisierll reported that chlorpromazine protected animals while 83 per cent of controls died following hemorrhagic shock. Hershey and co-workers21 noted that the drug is capable of eliminating or attenuating many of the decompensatory vascular phenomena associated with the irreversible phase of hemorrhagic shock. The animals showed significant difference in the manner in which they responded to blood administration, and there was an absence of gross visceral lesions associated with irreversible shock, the most striking of which is necrosis of the bowel.
Endotoxin Shock Fine1• presented extensive evidence implicating enteric endotoxins as the most important factor in his concept of the breakdown of bacterial defense mechanisms as the fundamental defect in shock. Animals treated with chlorpromazine were protected against the lethal effects of hemorrhagic shock despite the presence of bacterial contaminants in the blood, liver and spleen. This probably supports the contention that bacterial factors are secondary in shock and not necessarily of decisive importance.
General Several recent papers have focused attention on more specific areas than general survival in shock. Lillehei28 in 1957 noted that the marked mucosal necrosis as well as the severe congestion present in the bowel of dogs are factors that have not been fully appreciated when these animals were subjected to irreversible shock. He states that this necrosis is apparently the result of ischemia during the shock period. Perfusion of the superior mesenteric artery during hemorrhagic shock forestalled these changes and prevented irreversibility from occurring in 90 per cent of the animals so protected. 27 Lillehei also points out that death in a shocklike state has been"produced in dogs without hemorrhage by Erlanger and Gasser12 by the repeated injection of epinephrine. The only significant lesion present at the autopsy was mucosal congestion and bowel necrosis identical to the lesions found in dogs dying of hemorrhagic shock. It is probable that bowel ischemia resulting from the chronic epinephrine injections was the cause of death in these animals. He notes that there have been many reports on the beneficial effects of pretreating experimental animals prior to hemorrhagic shock with adrenolytics, vasodilators and hypothermia. The salutary effects obtained by these procedures probably resulted from maintaining blood flow to the bowel or from decreasing the oxygen need of the bowel during shock, thus preventing the development of lethal bowel ischemia. In 1959, Inglis and co-workers24 reported the use of chlorpromazine in the treatment of shock after the shock state has been established (method of Fine). The mesenteric vein blood flow in ml./kg./min. was determined
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in dogs prior to and after the induction of hemorrhagic shock to a systolic blood pressure of 30 mm. Hg. The administration of divided doses of 2 mg. of chlorpromazine (0.1 to 0.15 mg./kg.) every 15 minutes was followed by a doubling of mesenteric vein blood flow even though the systolic blood pressure remained the same. The survival time of dogs treated with chlorpromazine following the induction of shock was more than double that of control animals. Savlov and Regelson38 demonstrated diuresis during extremely low levels of blood pressure after hemorrhage in dogs treated with small doses of chlorpromazine (0.2 mg./kg.). They noted that, while animals treated with this dosage of chlorpromazine usually survived their technique of hemorrhage (technique of Wiggers), larger doses usually caused almost immediate drop in blood pressure and death. Because the nature of the diuresis following chlorpromazine in hemorrhagic shock was not understood, studies of renal hemodynamics and tubular reabsorption were done and reported by Savlov. 37 He found that renal blood flow (RBF) in hemorrhagic hypotension of a dog (50 mm. Hg systolic blood pressure) by direct measurement in the renal vein rose significantly after chlorpormazine 0.2 mg./kg. was given (control RBF: 110 ml./min., after bleeding, RBF: 35 ml./min., after chlorpromazine, RBF: 70 ml./min., and after partial reinfusion of blood, RBF: 100 ml./min.). An increased vasaculrization of the kidney of the rat in shock following chlorpromazine was also shown using the fluorescent dye Vasoflavine. While glomerular perfusion was increased to some degree, the circulation in the medullary portion of the kidney was improved more significantly. He also measured renal blood flow after the combined use of norepinephrine and chlorpromazine and found that the administration of norepinephrine in dosage sufficient to elevate the blood pressure during hemorrhagic hypotension in the face of preliminary administration of chlorpromazine maintained the peripheral vasoconstriction. Renal blood flow did not increase. He remarked that the use of chlorpromazine in the treatment of shock has not been accepted widely, primarily because experimental studies of postshock treatment have not demonstrated improvement in survival. It may be inferred from his study, however, that doses of a smaller order than those usually employed experimentally will increase perfusion of the kidney without significant lowering of the blood pressure. The arteriosclerotic or otherwise borderline kidney is particularly susceptible to ischemia and might be protected from irreversible damage by a small increment in perfusion such as adrenergic blockade might afford.
RECENT CLINICAL STUDIES
In 1953, Laborit and Huguenard 25 reported on the use of the "lytic cocktail" to produce artificial hibernation in patients with severe shock.
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Lear and co-workers26 used chlorpromazine as an adjunct to premedication in over 1100 cases of major surgery. The dosage schedule ranged from 25 to 50 mg. intramuscularly. The most alarming side effect of chlorpromazine that he encountered was a severe hypotension. In 1959, Savlov37 pointed out the importance of using small doses of chlorpromazine (0.2 mg./kg.) after hemorrhage in dogs in order to avoid hypotension. In our own experience, we have observed chlorpromazine hypotension (20 per cent fall or more in systolic pressure) only in those patients who were acutely or chronically hypovolemic prior to the administration of the drug. Therefore, it is quite possible that in Lear's series those patients who developed severe hypotension (as low as 50/30 mm. Hg) were hypovolemic and that 25 to 50 mg. doses of chlorpromazine were a relative overdose. The dosage of the drug, the degree of hypotension, and the amount of blood or plasma required to restore homeostasis in our patients have been clinical guides to the severity of their pre-existing hypovolemia. Chlorpromazine hypotension has not been met in patients who were well prepared for elective surgery. The occurrence of hypotension in patients following a small dose of chlorpromazine (5 to 15 mg. I.V. [0.1 to 0.2 mg./ kg.]) leads us to suspect hypovolemia in these persons, and invariably they respond to therapy that expands their intravascular compartment (Collins-Zahony test, in press). In October, 1958, we embarked on a program to determine the efficacy of using chlorpromazine as an adjunct in the management of patients with hemorrhagic shock or impending shock.
Method Conventional premedication was ordered for all patients as indicated by their preoperative condition. Chlorpromazine was also administered to all patients, except the control groups, either preoperatively and/or during the operation. The dose of chlorpromazine varied from 5 mg. to 100 mg. in divided doses. An adequate dose was judged as having been given when the patient's color was pink, capillary refill was good and, in general, perfusion of all tissues appeared to be adequate. Whenever possible, blood replacement was restricted until the hemorrhage was surgically controlled. No attempt was Inade to raise blood pressure with the use of vasopressors. Until bleeding was controlled, blood replacement was limited to that necessary to maintain vital signs at a perfusion level. After bleeding was controlled, blood replacement was undertaken rapidly until the normovolemic state was judged to have been nearly reached. Where the differential diagnostic problem of possibly overloading the circulation arose, blood replacement was guided by the changes in central venous pressure. In almost all cases cyclopropane-oxygen endotracheal anesthesia was used. Surgery and anesthesia were performed by the resident house staff at Bellevue Hospital and Cook County Hospital. Patients were considered to have survived if they were alive 14 days after surgery.
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Selection of Patients
Three categories of patients were investigated. Group I (Table 1). Only patients requiring emergency surgery because of massive upper gastrointestinal hemorrhage with shock or impending shock were included in this group. All patients were classified into physical status VI and VII.36 Fifty-one patients received chlorpromazine and 79 received none and acted as controls. The control group consisted of patients operated on before October, 1958, and whose charts were obtained from the operating room emergency record book. Group II (Table 2). Patients in hemorrhagic shock due to other than gastrointestinal hemorrhage represent this group. Eighty-six such patients were investigated. One hundred and twelve patients comprised the control group and had been operated on before October, 1958. Group III (Table 3). Patients requiring massive transfusion greater than 5 pints of blood during surgery and developing shock in the intraoperative period were placed in this group. Thirty-six patients received chlorpromazine and 32 who did not receive the drug acted as controls.
Table 1. Group I: Shock in Emergency Surgery for Gastrointestinal Bleeding CHLORPROMAZINE
TREATED
Number of patients ............................ Average age ................................... Overall mortality .............................. Mortality from emergency gastrectomy for benign peptic ulcer with massive hemorrhage. . . . . . . . .. Mortality from all other types of gastrointestinal hemorrhage necessitating emergency surgery .... Vasopressor therapy ............................ Postoperative anuria or severe oliguria ............ Average urine output, first 24 hours postoperative ..
CLASSICAL THERAPY
51 60.9 years 27.5%
79 62.7 years 43% (34)
20.0% (7/35)
3Q.4% (17/56)
43.7% (7/16) 0 0 1,578 ml. (13 cases) Complications, cerebrovascular or myocardial. . . .. 0
73.9% (17/23) 20.2% 8.8% Depressedunder 300 mI. 3.75%
Table 2. Group II: Hemorrhagic Shock Other Than That Due to Gastrointestinal Bleeding USE OF CHLORPROMAZINE
Number of patients. . . . . . . . . . . . . . . . . . . . . . . .. Average age... .. . . . . . . . . .. .... .. ... . .. .. . .. Mortality.. . ... .. . . . .. ... .. . . .. . .. . . . ... ... Vasopressor therapy. . . . . . . . . . . . . . . . . . . . . . . .. Oliguria or anuria, postoperative. . . . . . . . . . . . .. Average urinary output, 24 hra., postoperative
86 46.3 years 11.6% (10/86) 0 0 1,272 mI. (15 cases) Complications, cerebrovascular or myocardial. .. 0
NO CHLORPROMAZINE
112 44.2 years 28.5% (32/112) 24% 9% Under 200 mI. 2.4%
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Table 3.
Group III: Shock Developing During Anesthesia and SurgeryTransfusion Requirement Massive CHLORPROMAZINE TREATED
Number of patients ........................ Average age. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Mortality ................................. Vasopressor therapy (Norepinephrine) ........ Oliguria or anuria, postoperative ............. Average urine output, 24 hrs. postoperative ...
36 48.8 years 22.2% (8) 0 0 2,260 ml. (5 cases)
Complications, cerebrovascular or myocardial .. 0
NO CHLORPROMAZINE
32 47.2 years 53.1%(17) 21.8% (7) 6.3% (2) Depressed under 400 ml. 6.3% (2)
Results. In groups I, II and III the mortality rates of the chlorpromazine-treated patients were markedly less than those of the patients treated classically-27.5 per cent, 11.6 per cent and 22.2 per cent respectively compared to 43 per cent, 28.5 per cent and 53.1 per cent. Although the total patient population here is only 396, the trend is definitely toward greater survival in the chlorpromazine groups. A noteworthy and striking observation is the complete absence of postoperative renal depression in all 173 cases treated with chlorpromazine (no postoperative anuria in the chlorpromazine groups compared with 8.8 per cent, 9 per cent and 6.3 per cent of the control groups). This has traditionally been a problem following surgery and shock. Also noteworthy is the absence of cardiovascular complications in these same patients postoperatively. DISCUSSION OF THE USE OF CHLORPROMAZINE IN HEMORRHAGIC SHOCK
A number of the clinical features of shock such as low or absent blood pressure, subungual cyanosis and pallor can be explained on the basis of extreme vasoconstriction. Obviously, a patient with no blood pressure or pulse is clinically dead; however, patients in shock may have such an extreme degree of vasoconstriction that no blood pressure and/or pulse may be audible or palpable on the extremity, but the patient is still alive. Although the extremities are cold, this is not a reflection of hypothermia but rather a decreased blood flow as the consequence of vasoconstriction. The same phenomenon occurs in the kidneys and also in the splanchnic bed, which appears pale, dusky and congested in the vasoconstricted phase of shock. It can readily be seen following a dose of chlorpromazine that the extreme vasoconstrictor response to hypovolemia is reversed in the extremities, which become warm and pink and now begin to display filling of the venous channels which were previously collapsed. Similarly, clinical
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observations revealed that chlorpromazine will change the appearance of the kidney from a congested cyanotic organ to a pink, viable, noncongested one. Chlorpromazine has frequently been used to overcome severe vasospasm that has occurred during induction of hypothermia, and its use is recognized as an adjunct to the cooling of the patient by increasing the circulation, where the cooling is attempted, at the surface. Before chlorpromazine is administered to patients subjected to hypothermia, sphygmomanometric blood pressure may be unobtainable although intra-arterial pressure readings are at normal values. This is referred to as "clinical disappearance" of blood pressure. 5 , 6 After administration of chlorpromazine, pressure readings are obtainable with the sphygmomanometer, and these values are similar to those obtained intra-arterially.7 It may be concluded that the severe vasospasm and rigidity of the walls of larger arteries during hypothermia prevented adequate sphygmomanometric readings and that chlorpromazine counteracted the spasm to allow subsequent readings. A number of investigators consider that vasoconstriction, which is one of the basic protective mechanisms in hypovolemia, may itself become an independent noxious stimulus. Beyond the vasoconstricted area, anoxia occurs with consequent impairment of tissue function. A point is reached at which perfusion of tissues is sacrificed in order to maintain the internal blood pressure of the body. Irreversibility in shock may be related to this extreme vasoconstriction. Besides the adrenolytic action of chlorpromazine, other effects of the drug must be considered as having a possible role in protection against irreversibility in shock. Its antiserotonic effect4 may block the vasotropic material shown by Baez and co-workersl in SMA shock (temporary ligation of the superior mesenteric artery). This substance exhibits the vasotoxic properties of ferritin and the myogenic properties of serotonin. It may also have an effect similar to Dibenzyline (phenoxybenzamine hydrochloride), which inhibits normal anaerobic formation of vasoactive ferritin and also preserves the aerobic ferritin-inactivating system from the deterioration ordinarily resulting from prolonged hepatic hypoxia. 2
SUMMARY
1. Tissue perfusion and oxygenation may be the most important factors which contribute to the outcome of a patient in severe shock. 2. Blood pressure is no criterion of blood flow, perfusion or oxygenation. 3. The use of vasopressors to maintain blood pressure may cause further vasoconstriction and tissue anoxia, thereby worsening rather than improving circulation. 4. Chlorpromazine seems to overcome effectively the severe vasocon-
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striction occurring in shock, permits adequate tissue perlusion even at low blood pressure, and most probably prevents biochemical derangements. Experimentally and clinically, survival rate is higher in shock with this drug. 5. A re-evaluation of the classic treatment of hemorrhagic shock (maintenance of blood pressure with vasopressors and massive transfusion) may be in order.
REFERENCES 1. Baez, S., Hershey, S. G. and Rovenstine, E. A.: Vasotropic substances in blood in intestinal ischemia shock. Am. J. Physiol. 200: 1245, 1961. 2. Baez, S., Srikantia, S. G. and Shorr, E.: Influence on hepatic ferritin systems of tertiary amine, G-D 131, with beneficial effects in shock. Proc. Soc. Exper. BioI. & Med. 92: 61, 1956. 3. Baez, S., Zweifach, B. W. and Shorr, E.: Protective action of dibenamine against the fatal outcome of hemorrhagic and traumatic shock in rats. Fed. Proc. 11: 7, 1952. 4. Benditt, E. P. and Rowley, D. A.: Antagonisms of 5-hydroxy-tryptamine by chlorpromazine. Science 123: 24, 1956. 5. Blair, E., Austin, R., Reed, B., Gilbert, S. and Swan, H.: Study of cardiovascular changes during cooling and rewarming in human subjects undergoing total circulatory occlusion. J. Thoracic Surg. 33: 707, 1957. 6. Collins, V. J. and Granatelli, A.: Controlled hypothermia during anesthesia in human adults. Angiology 6: 118, 1955. 7. Collins, V. J., Granatelli, A. and Zahony, I.: Unpublished data. 8. Converse, J. G. and Boba, A.: Use of ganglionic blocking agents in the treatment of hemorrhagic shock. Anesth. & Analg. Current Researches 35: 644, 1956. 9. Converse, J. G. and Boba, A.: An experimental study of Arfonad in hemorrhagic shock in dogs. Am. Surgeon. 23: 420, 1957. 10. Converse, J. G., McKechnie, F. B. and Boba, A.: Arfonad in hemorrhage. New York J. Med. 57: 731, 1957. 11. Courvoisier, S., Fournel, J., Ducrot, R., Kolsky, M. and Koetschet, P.: Proprietes pharmacodynamiques du chlorhydrate de chlora-3 (dimethyl-amino-3' propyl)10 phenothiazine (4560 RP). Arch. internat. pharmacodyn. et therap. 92: 3, 1953. 12. Erlanger, J. and Gasser, H. S.: Studies in secondary traumatic shock; circulatory failure due to adrenaline. Am. J. Physiol. 49: 345, 1919. 13. Eversole, W. J., Kleinberg, W., Overman, R. R., Remington, J. W. and Swingle, W. W.: Muscle trauma in normal dogs. Am. J. Physiol. 140: 490, 1944. 14. Fine, J.: Symposium on Shock, Chapter 5. Army Medical Service Graduate School, Washington, D.C., 1951. 15. Fine, J.: The bacterial factor in traumatic shock. Springfield, Ill., Charles C Thomas, 1954. 16. Freeman, N. E.: Burns, Shock, Wound Healing and Vascular Injuries. Philadelphia, W. B. Saunders Co., 1943. 17. Freeman, N. E., Schaffer, S. A., Shechter, A. E. and Holling, H. E.: Occurrence of shock from hemorrhage. J. Clin. Invest. 17: 359, 1938. 18. Friedberg, C. K.: Diseases of the Heart. Philadelphia, W. B. Saunders Co., 1950. 19. Friedman, J. J.: Splanchnic blood volume in traumatic shock. Am. J. Physiol. 200: 614, 1961. 20. Hershey, S. G.: Current theories of shock. Anesthesiology 21: 303, 1960. 21. Hershey, S. G., Guccione, 1. and Zweifach, B. W.: Beneficial action of pretreatment with chlorpromazine and survival following graded hemorrhage in the rat. Surg. Gynec. & Obst. 101: 431, 1955. 22. Hershey, S. G., Lanza, S. and Rovenstine, E. A.: Protection against shock induced by mesenteric artery occlusion. Fed. Proc. 17: 377, 1958.
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23. Hershey, S. G., Zweifach, B. W. and Antopol, W.: Factors associated with protection against experimental shock. Anesthesiology 17: 265, 1956. 24. Inglis, F. G., Hampson, L. G. and Gurd, F. N.: Effect of chlorpromazine on survival time and mesenteric blood flow in experimental shock. Ann. Surg. 149: 43, 1959. 25. Laborit, H. and Huguenard, P.: L'Hibernation artificielle chez Ie grand choque. Presse mM. 61: 1029, 1953. 26. Lear, E., Chiron, A. E. and Pallin, 1. N.: Chlorpromazine-an adjunct to premedication. New York J. Med. 55: 1853, 1955. 27. Lillehei, R. C.: Prevention of irreversible hemorrhagic shock in dogs by controlled cross perfusion of the superior mesenteric artery. S. Forum 7: 6, 1956. 28. Lillehei, R. C.: Intestinal factor in irreversible hemorrhagic shock. Surgery 42: 1043,1957. 29. Lillehei, R. C.: Intestinal factor in irreversible endotoxin shock. Ann. Surg. 148: 513, 1958. 30. Lin, M. K.: Factors concerned with irreversible phase of hemorrhagic shock. Nikon Univ. M. J. 18: 242, 1959. 31. Nickerson, M.: Factors of vasoconstriction and vasodilation in shock. J. Michigan M. Soc. 54: 45, 1955. 32. Phemister, D. B.: Mechanism and management of surgical shock. J.A.M.A. 127: 1109,1945. 3a. Phemister, D. B., Eichelberger, R. L. and Laestar, C. H.: Early effects on dogs of section of eighth cervical segment of spinal cord and their bearing on shock. Arch. Surg. 51: 32, 1945. 34. Remington, J. W., Hamilton, W. F., Caddell, H. M., Boyd, G. H., Jr. and Wheeler, W. C.: Vasoconstriction as precipitating factor in traumatic shock in dog. Am. J. Physiol. 161: 135, 1950. 35. Remington, J. W., Wheeler, N. C., Boyd, G. H., Jr. and Caddell, H. M.: After hemorrhage and after muscle trauma. Proc. Soc. Exper. BioI. & Med. 6.9: 150, 1948. 36. Saklad, Meyer: Grading of patients for surgical procedures. Anesthesiology 2: 281, 1941. 37. Savlov, E. D.: Effect of chlorpromazine on renal function and hemodynamics particularly during hemorrhagic hypotension. Surgery 45: 229, 1959. 38. Savlov, E. D. and Regelson, W.: Diuresis in hemorrhagic hypotension. S. Forum 7: 40,1956. 39. Shorr, E., Zweifach, B. W. and Furchgott, R. F.: On occurrence, sites and modes of origin and destruction of principles affecting compensatory vascular mechanisms in experimental shock. Science 102: 489, 1945. 40. Swingle, W. W., Kleinberg, W., Remington, J. W., Eversole, W. J. and Overman, R. R.: Factor in shock induced by muscle trauma in normal dogs. Am. J. Physiol. 141: 54, 1944. 41. Wiggers, C. J.: Physiology of Shock. Cambridge, Mass., Harvard University Press, 1950. 42. Wiggers, H. C., Goldberg, H., Roemhild, R. and Ingraham, R. C.: Impending hemorrhagic shock and course of events following administration of dibenamine. Circulation 2: 79, 1950. 43. Wiggers, H. C. and Ingraham, R. C.: Hemorrhagic shock, definition and criteria for its diagnosis. J. Clin. Invest. 25: 30, 1946. 44. Wiggers, H. C., Roemhild, F., Goldberg, H. and Ingraham, R. C.: The influence of prolonged vasoconstriction on the transition from impending to irreversible shock. Fed. Proc. 6: 226, 1947. 45. Zweifach, B. W.: Microcirculatory derangements as basis for lethal manifestations of experimental shock. Brit. J. Anaesth. 30: 466, 1958. 46. Zweifach, B. W., Baez, S. and Shorr, E.: Effect of dibenamine on humeral and vascular changes in dogs subjected to hemorrhagic shock. Fed. Proc. 11: 177, 1952. 47. Zweifach, B. W., Chambers, R. and Hyman, C.: Reactions of peripheral blood vessels in experimental hemorrhage. Ann. New York Acad. Sc. 4.9: 553, 1948. 48. Zweifach, B. W. and Hershey, S. G.: Protective mechanisms in shock. Ann. New York Acad. Sc. 66: 1010, 1957. 49. Zweifach, B. W., Lowenstein, B. E. and Chambers, R.: Responses of blood capillaries to acute hemorrhage in rats. Am. J. Physiol. 142: 80, 1944. 966 Private Road Winnetka, Illinois (Dr. Collins)