Symposium on Recent Developments in Anesthesia
Anesthesia and the Immune System
John H. Lecky, M.D.*
The function of man's immune system is to recognize and respond to potentially harmful foreign substances including bacteria, viruses, tumor cells, and foreign tissue. In the perioperative period, this system should play a key role in the prevention of infection and of tumor seeding during cancer surgery. Anesthesia and operation, however, may impair the immune system so that bacterial growth and tumor spread may occur more readily, and host response to transplanted tissue and allergenic substances may be altered. It is the purpose of this article to outline briefly some basic immunologic concepts. The effects of anesthesia and operation on immune function will be outlined and suggestions will be presented regarding the anesthetic management of patients at risk from infection or tumor spread.
The Immune Process Cells of lymphoid origin mediate the immune response by recognizing and reacting to foreign molecules. Initially, polymorphonuclear neutrophils (PMN's) and monocytes migrate toward a foreign substance in response to locally increased blood flow and to chemotactic factors. These are generated by antibody-antigen-complement interaction or other less specific serum factors including elements of the properdin system and products of Hagemann factor activation. The next step is phagocytosis, an energy dependent process of antigen engulfment which may be aided by the coating of the antigen with serum proteins (opsonization- preparation for eating). These opsonins may be either specific immune antibodies, natural antibodies, or components of the complement or properdin systems which act less specifically to coat foreign substances. Following phagocytosis, intracellular processes involving lysozymes and the production of hydrogen peroxide ultimately lead to antigen destruction. Finally, through the interaction of both thymic and bone marrow derived lymphocytic cells, the antigen is prepared for programming into immunologic memory, so that future exposure to the antigen will result in proliferation of lymphocytes and rapid antibody production from sensitized plasma cells. It is important to note that the above processes are to a great extent interrelated, are energy dependent, *Assistant Professor of Anesthesia, University of Pennsylvania School of Medicine, Philadelphia
Surgical Clinics of North America- Vol. 55, No.4, August 1975
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both aerobic and anaerobic, and can be influenced by a number of factors including corticosteroids, cylic AMP levels, catecholamines, a variety of drugs,3 • 13 • 14 • 25 • 26 and the presence of disease (infection, cancer, trauma, or congenital lack of specific components). 18 • 19 • 23 Periodic variation in immune function has been described in normal man.2 The net function of the immune system, then, is the localization, recognition, and destruction of potentially harmful antigens with subsequent appropriate programming of these molecules into immunologic memory. For more complete discussion of the immune system several excellent references are available. 1 • 6 • 7. 15 • 2o. 2 4 Immunologic Effects of Anesthesia and Operation Studies both in vivo and in vitro have shown that anesthesia can interfere with many phases of the immune response.5 As early as 1911, Graham17 demonstrated that ether anesthesia inhibited leukocyte phagocytic activity. Bruce has shown that phagoycte mobilization was decreased by halothane in mice. 4 That lymphocyte function can be compromised by a variety of anesthetic agents in vivo is shown by decreased antibody production, impairment of complement fixation, and inhibition of lymphocyte transformation.2 • 6 • 22 Lymphocyte transformation is a sequence of RNA, DNA, and protein synthesis with subsequent cell division occuring when resting lymphocytes are stimulated by specific antigen or nonspecific mitogen such as phytohemagglutinin (PHA). Lymphocyte transformation may be depressed following in vitro exposure to halothane as wellP The activity of already formed antibodies does not appear to be compromised by anesthesia. PMN intracellular killing mechanisms as assayed by NBT reduction have also been shown to be depressed following anesthetic exposure in vivo but not in vitro. 8 • 11 • 22 This is a test in which PMN's are incubated with nitroblue tetrazolium (NBT) dye and the amount of dye reduced to formazan is determined spectrophometrically or cytologically. While clinical concentrations of anesthetics have been shown to interfere reversibly with both aerobic and anaerobic metabolism; this does not appear to be the mechanism for postoperative immunologic depression. If it were, one would expect that immune suppression would be seen only in the presence of the anesthetic; in fact, postoperative immunologic compromise may persist for several days (Lecky, J. H.: Unpublished data). The "stress" response to surgery involves initial catecholamine release with subsequent elevation of corticosteroid levels. In a study of the effects of nitrous oxide-d-tubocurarine (N 2 0,0 2 ,dTc) anesthesia on white cell function in human volunteers undergoing cerebral blood flow studies (essentially anesthesia without surgery), depression in NBT reduction and lymphocyte reactivity was associated with cortisol elevation, increases in neutrophil count, and slight reductions in lymphocyte count. 22 These changes in white cell function were all compatible with steroid effect. N 2 0 and dTc have no in vitro effect on these tests. Cullen recently studied the relationship of immune depression (as assayed by lymphocyte reactivity) with surgical trauma. 9 Operations were graded
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on a trauma scale which ranged from anesthesia without surgery to massive surgical trauma with minimal anesthesia. Steroid levels were not obtained but the degree of immune depression closely paralleled the extent of surgical trauma. In a study of patients undergoing staging laparotomy (splenectomy, liver biopsy, and multiple abdmninal node biopsy) for Hodgkin's disease, it was observed that a "deep anesthetic technique" (halothane-relaxant) resulted in less immune depression than did a "light technique" (N 2 0,0 2 ,dTc) (see reference in preceding paragraph). As measured by lymphocyte transformation and NBT reduction, white cell function was depressed to 50 per cent of control on the first postoperative day following a halothane anesthetic and to 30 per cent following N 2 0,02 ,dTc anesthesia with return to control values on days 4 and 7, respectively. The fact that deeper anesthetic techniques and minimal degrees of surgical trauma result in less immune comproInise than lighter anesthetic techniques and/or major surgical trauma is attributable to the degree of catecholamine and corticosteroid release, i.e., the stress response associated with major surgical trauma. The clinical significance of in vitro test results is often difficult to interpret; however, many disease states associated with high incidences of infectio:ri9 manifest depressed in vitro immunologic test results. For the average patient undergoing operation, a 20 per cent reduction in immune function probably poses no great problem. However, it is in the patient with comproinised immune function or in the critically ill patient where prolonged operation may be necessary and where a light anesthetic technique is likely to be used that the consequences of immune compromise are least desirable and yet are the most apt to be seen.
Management of the High Risk Patient Given the fact that anesthesia and operation impair immune functions, what steps Inight one take to minimize the immune comproinise? Preoperatively, care should be taken to insure optimal nutritional status and to treat any active infection. The fact that the immune system is depressed postoperatively also adds to our conviction that patients with a cold or active infections should not be operated upon unless surgery cannot be delayed. Prophylactic antibiotics might be considered. Intraoperatively, surgical technique should be impeccable, rapid, and atraumatic.16 Care should be taken to insure adequate circulatory blood volume so that perfusion of white cells to potential areas of infection can be maintained. Theoretically, it would appear that in order to miniinize the "stress" response, a depth of anesthesia as great as possible compatible with cardiovascular tolerance theoretically be employed, and agents which release catecholamines (N 2 0, fluroxene, cyclopropane) should be avoided. Unfortunately, because of shock, hypovoleinia, or a failing myocardium, one is often unable to administer more than neuromuscular blockade and Inild analgesia to the critically ill patient. Regional or local anesthetic techniques are not necessarily a good choice on immunologic grounds. While less immune depression is seen
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during abdominal surgery under spinal anesthesia, the ultimate postoperative immunologic depression is comparable to that seen with general anesthesia (see Lecky, above). Local anesthetics in clinical concentrations have been shown to directly inhibit white cell function in vitro. 10 While local anesthetics do not appear to have systemic immune effects, they are capable of inhibiting white cell function in the area into which they have been injected. At present, then, we are limited in our ability to optimize immune function in the surgical patient. Surgical trauma results in immunosuppression. Much work remains in determining the anesthetic agent or technique which will provide the least immunologic compromise. The possibility for a pharmacologic approach to enhancement of white cell function is an intriguing one and may, in fact, be a most fruitful area for future investigation.
REFERENCES 1. Alexander, J. W.: Host defense mechanisms against infections. SURG. CLIN. N. AM., 52:1367-1378, 1972. 2. Alexander, J. W., Dionigi, R., and Meakins, J. L.: Periodic variations in the antibacterial function of human neutrophils and its relationship to sepsis. Ann. Surg., 173:206-213, 1971. 3. Bourne, H. R., Lehrer, R.I., Cline, M. J., et al.: Cyclic 3'5'-adenosine monophosphate in the human leukocyte: synthesis, degradation, and effects on neutrophil .candidacidal activity. J. Clin. Invest., 50:920-929, 1971. 4. Bruce, D. L.: Effect of halothane anesthesia on experimental salmonella peritonitis in Inice. J. Surg. Res., 7:180-185, 1967. 5. Bruce, D. L., and Wingard, D. W.: Anesthesia and the immune response. Anesthesiology, 34:271-282, 1971. 6. Cooper, M. D., and Lauton, A. R.: The development of the immune system. Scientific Amer., 231:59-72, 1974. 7. Craddock, C. G., Lorigmire, R., and McMillan, R.: Lymphocytes and the .immune response. New Engl. J. Med., 285:324-331, 378-384, 1971. 8. Cullen, B. F.: The effects of halothane and nitrous oxide on phagocytosis and human leukocyte metabolism. Anesth. Analg. Curr. Res., 53:531-536, 1974. 9. Cullen, B. F.: Relationship of anesthesia and surgical stress to postoperative changes in white blood cell count and depression of lymphocyte transformation. Abstracts of Scientific Papers, 1974 Annual Meeting of the American .Society of Anesthesiologists, p. 205. 10. Cullen, B. F., Chretien, P. B., and Leventhal, B. G.: The effect of lignocaine on pHstimulated human lymphocyte transformation. Br. J. Anaes., 44:1247-1251, 1974. 11. Cullen, B. F., Hume, R. B., and Chretien, P. B.: The effect of anesthesia on phagocytosis and the reduction of nitroblue tetrazolium by human leukocytes. Abstracts of Scientific Papers, 1972 Annual Meeting of the American Society of Anesthesiologists, p. 405. 12. Cullen, B. F., Sample, F. W., and Chretien, P. B.: The effect· of halothane on phytohemagglutinin-induced transformation of human lymphocytes in vitro. Anesthesiology, 36:206-212, 1972. 13. Dale, D. C., Fauci, A. S., and Wolff, S. M.: Alternate day prednisone: Leukocyte kinetics and susceptibility to infections. N. Eng. J. Med., 291:1154-1158, 1974. 14. Dale, D. C., and Petersdorf, R. G.: Corticosteroids and infections. MED. CLIN. N. AM., 57:1277-1287, 1973. 15. Elsbach, P.: On the interaction between phagocytes and Inicro-organisms. N. Eng. J. Med.,'289:846-852, 1973. · 16. ·Feller, I., Richards, K. E., and Pierson, C. L.: Prevention of postoperative infections. $l]RG. Ci.IN. N. AM., 52:1361-1366, 1972. . 17. Graham, E. A.: The influence of ether and ether anesthesia on bacteriolysis, agglutination, and phagocytosis. J. Infect. Dis., 8:147-175, 1911.
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18. Grogan, J. B., Miller, R. C., and Hardy, J. D.: Impaired function of polymorphonuclear leukocytes in patients with bums and other trauma. Presented before the Fourth Annual Meeting of the American Bum Association, April 17, 1972. 19. Holmes, B., Quie, P. G., Windhorst, D. B., and Good, R. A.: Fatal granulomatous disease of childhood: An inbom abnormality of phagocytic function. Lancet, 1:1225-1231, 1966. 20. Hollowbrow, E. J.: An ABC of Modem immunology. Boston, Little, Brown and Co., 1968. 21. Humphrey, L. J., Wingard, D. W., and Lang, R.: Effect of halothane on spleen cells: In vitro studies on reversibility of immunosuppression. Surgery, 65:939-942, 1969. 22. Lecky, J. H., Twomey, P. L., Hume, R., and Chretien, P. B.: The effects of N,O-morphine anesthesia on white cell function in human volunteers. Abstracts of Scientific Papers, 1974 Annual Meeting of the American Scoiety of Anesthesiologists, p. 203. 23. Rosner, F., Valmont, I., Kozinn, P. R., and Caroline, L.: Leucocyte function in patients with leukemia. Cancer, 25:835-842, 1970. 24. Stossel, T.: Phagocytosis. N. Eng. J. Med., 290:717-726, 774-780, 833-839, 1974. 25. Wurster, N., Elsbach, P., Simon, E. J., et al.: The effects of the morphine analogue levorphanol on leukocytes: Metabolic effects at rest and during phagocytosis. J. Clin. Invest., 50:1091-1099, 1971. 26. Zurier, R. B., Weissman, G., Hoffstein, S., et al.: Mechanisms of lysosomal enzyme release from human leukocytes, II. Effects of cAMP and cGMP, autonomic agonists, and agents which affect microtubule function. J. Clin. Invest., 53:297-309, 1974. Department of Anesthesia Hospital of the University of Pennsylvania 3400 Spruce Street Philadelphia, Pennsylvania 19105
Anesthesia and the Immune System
John H. Lecky, M.D.*
The function of man's immune system is to recognize and respond to potentially harmful foreign substances including bacteria, viruses, tumor cells, and foreign tissue. In the perioperative period, this system should play a key role in the prevention of infection and of tumor seeding during cancer surgery. Anesthesia and operation, however, may impair the immune system so that bacterial growth and tumor spread may occur more readily, and host response to transplanted tissue and allergenic substances may be altered. It is the purpose of this article to outline briefly some basic immunologic concepts. The effects of anesthesia and operation on immune function will be outlined and suggestions will be presented regarding the anesthetic management of patients at risk from infection or tumor spread.
The Immune Process Cells of lymphoid origin mediate the immune response by recognizing and reacting to foreign molecules. Initially, polymorphonuclear neutrophils (PMN's) and monocytes migrate toward a foreign substance in response to locally increased blood flow and to chemotactic factors. These are generated by antibody-antigen-complement interaction or other less specific serum factors including elements of the properdin system and products of Hagemann factor activation. The next step is phagocytosis, an energy dependent process of antigen engulfment which may be aided by the coating of the antigen with serum proteins (opsonization- preparation for eating). These opsonins may be either specific immune antibodies, natural antibodies, or components of the complement or properdin systems which act less specifically to coat foreign substances. Following phagocytosis, intracellular processes involving lysozymes and the production of hydrogen peroxide ultimately lead to antigen destruction. Finally, through the interaction of both thymic and bone marrow derived lymphocytic cells, the antigen is prepared for programming into immunologic memory, so that future exposure to the antigen will result in proliferation of lymphocytes and rapid antibody production from sensitized plasma cells. It is important to note that the above processes are to a great extent interrelated, are energy dependent, *Assistant Professor of Anesthesia, University of Pennsylvania School of Medicine, Philadelphia
Surgical Clinics of North America- Vol. 55, No.4, August 1975
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...
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JoHN
H.
LECKY
both aerobic and anaerobic, and can be influenced by a number of factors including corticosteroids, cylic AMP levels, catecholamines, a variety of drugs,3 • 13 • 14 • 25 • 26 and the presence of disease (infection, cancer, trauma, or congenital lack of specific components). 18 • 19 • 23 Periodic variation in immune function has been described in normal man.2 The net function of the immune system, then, is the localization, recognition, and destruction of potentially harmful antigens with subsequent appropriate programming of these molecules into immunologic memory. For more complete discussion of the immune system several excellent references are available. 1 • 6 • 7. 15 • 2o. 2 4 Immunologic Effects of Anesthesia and Operation Studies both in vivo and in vitro have shown that anesthesia can interfere with many phases of the immune response.5 As early as 1911, Graham17 demonstrated that ether anesthesia inhibited leukocyte phagocytic activity. Bruce has shown that phagoycte mobilization was decreased by halothane in mice. 4 That lymphocyte function can be compromised by a variety of anesthetic agents in vivo is shown by decreased antibody production, impairment of complement fixation, and inhibition of lymphocyte transformation.2 • 6 • 22 Lymphocyte transformation is a sequence of RNA, DNA, and protein synthesis with subsequent cell division occuring when resting lymphocytes are stimulated by specific antigen or nonspecific mitogen such as phytohemagglutinin (PHA). Lymphocyte transformation may be depressed following in vitro exposure to halothane as wellP The activity of already formed antibodies does not appear to be compromised by anesthesia. PMN intracellular killing mechanisms as assayed by NBT reduction have also been shown to be depressed following anesthetic exposure in vivo but not in vitro. 8 • 11 • 22 This is a test in which PMN's are incubated with nitroblue tetrazolium (NBT) dye and the amount of dye reduced to formazan is determined spectrophometrically or cytologically. While clinical concentrations of anesthetics have been shown to interfere reversibly with both aerobic and anaerobic metabolism; this does not appear to be the mechanism for postoperative immunologic depression. If it were, one would expect that immune suppression would be seen only in the presence of the anesthetic; in fact, postoperative immunologic compromise may persist for several days (Lecky, J. H.: Unpublished data). The "stress" response to surgery involves initial catecholamine release with subsequent elevation of corticosteroid levels. In a study of the effects of nitrous oxide-d-tubocurarine (N 2 0,0 2 ,dTc) anesthesia on white cell function in human volunteers undergoing cerebral blood flow studies (essentially anesthesia without surgery), depression in NBT reduction and lymphocyte reactivity was associated with cortisol elevation, increases in neutrophil count, and slight reductions in lymphocyte count. 22 These changes in white cell function were all compatible with steroid effect. N 2 0 and dTc have no in vitro effect on these tests. Cullen recently studied the relationship of immune depression (as assayed by lymphocyte reactivity) with surgical trauma. 9 Operations were graded
ANESTHESIA AND THE IMMUNE SYSTEM
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on a trauma scale which ranged from anesthesia without surgery to massive surgical trauma with minimal anesthesia. Steroid levels were not obtained but the degree of immune depression closely paralleled the extent of surgical trauma. In a study of patients undergoing staging laparotomy (splenectomy, liver biopsy, and multiple abdmninal node biopsy) for Hodgkin's disease, it was observed that a "deep anesthetic technique" (halothane-relaxant) resulted in less immune depression than did a "light technique" (N 2 0,0 2 ,dTc) (see reference in preceding paragraph). As measured by lymphocyte transformation and NBT reduction, white cell function was depressed to 50 per cent of control on the first postoperative day following a halothane anesthetic and to 30 per cent following N 2 0,02 ,dTc anesthesia with return to control values on days 4 and 7, respectively. The fact that deeper anesthetic techniques and minimal degrees of surgical trauma result in less immune comproInise than lighter anesthetic techniques and/or major surgical trauma is attributable to the degree of catecholamine and corticosteroid release, i.e., the stress response associated with major surgical trauma. The clinical significance of in vitro test results is often difficult to interpret; however, many disease states associated with high incidences of infectio:ri9 manifest depressed in vitro immunologic test results. For the average patient undergoing operation, a 20 per cent reduction in immune function probably poses no great problem. However, it is in the patient with comproinised immune function or in the critically ill patient where prolonged operation may be necessary and where a light anesthetic technique is likely to be used that the consequences of immune compromise are least desirable and yet are the most apt to be seen.
Management of the High Risk Patient Given the fact that anesthesia and operation impair immune functions, what steps Inight one take to minimize the immune comproinise? Preoperatively, care should be taken to insure optimal nutritional status and to treat any active infection. The fact that the immune system is depressed postoperatively also adds to our conviction that patients with a cold or active infections should not be operated upon unless surgery cannot be delayed. Prophylactic antibiotics might be considered. Intraoperatively, surgical technique should be impeccable, rapid, and atraumatic.16 Care should be taken to insure adequate circulatory blood volume so that perfusion of white cells to potential areas of infection can be maintained. Theoretically, it would appear that in order to miniinize the "stress" response, a depth of anesthesia as great as possible compatible with cardiovascular tolerance theoretically be employed, and agents which release catecholamines (N 2 0, fluroxene, cyclopropane) should be avoided. Unfortunately, because of shock, hypovoleinia, or a failing myocardium, one is often unable to administer more than neuromuscular blockade and Inild analgesia to the critically ill patient. Regional or local anesthetic techniques are not necessarily a good choice on immunologic grounds. While less immune depression is seen
798
JoHN
H.
LECKY
during abdominal surgery under spinal anesthesia, the ultimate postoperative immunologic depression is comparable to that seen with general anesthesia (see Lecky, above). Local anesthetics in clinical concentrations have been shown to directly inhibit white cell function in vitro. 10 While local anesthetics do not appear to have systemic immune effects, they are capable of inhibiting white cell function in the area into which they have been injected. At present, then, we are limited in our ability to optimize immune function in the surgical patient. Surgical trauma results in immunosuppression. Much work remains in determining the anesthetic agent or technique which will provide the least immunologic compromise. The possibility for a pharmacologic approach to enhancement of white cell function is an intriguing one and may, in fact, be a most fruitful area for future investigation.
REFERENCES 1. Alexander, J. W.: Host defense mechanisms against infections. SURG. CLIN. N. AM., 52:1367-1378, 1972. 2. Alexander, J. W., Dionigi, R., and Meakins, J. L.: Periodic variations in the antibacterial function of human neutrophils and its relationship to sepsis. Ann. Surg., 173:206-213, 1971. 3. Bourne, H. R., Lehrer, R.I., Cline, M. J., et al.: Cyclic 3'5'-adenosine monophosphate in the human leukocyte: synthesis, degradation, and effects on neutrophil .candidacidal activity. J. Clin. Invest., 50:920-929, 1971. 4. Bruce, D. L.: Effect of halothane anesthesia on experimental salmonella peritonitis in Inice. J. Surg. Res., 7:180-185, 1967. 5. Bruce, D. L., and Wingard, D. W.: Anesthesia and the immune response. Anesthesiology, 34:271-282, 1971. 6. Cooper, M. D., and Lauton, A. R.: The development of the immune system. Scientific Amer., 231:59-72, 1974. 7. Craddock, C. G., Lorigmire, R., and McMillan, R.: Lymphocytes and the .immune response. New Engl. J. Med., 285:324-331, 378-384, 1971. 8. Cullen, B. F.: The effects of halothane and nitrous oxide on phagocytosis and human leukocyte metabolism. Anesth. Analg. Curr. Res., 53:531-536, 1974. 9. Cullen, B. F.: Relationship of anesthesia and surgical stress to postoperative changes in white blood cell count and depression of lymphocyte transformation. Abstracts of Scientific Papers, 1974 Annual Meeting of the American .Society of Anesthesiologists, p. 205. 10. Cullen, B. F., Chretien, P. B., and Leventhal, B. G.: The effect of lignocaine on pHstimulated human lymphocyte transformation. Br. J. Anaes., 44:1247-1251, 1974. 11. Cullen, B. F., Hume, R. B., and Chretien, P. B.: The effect of anesthesia on phagocytosis and the reduction of nitroblue tetrazolium by human leukocytes. Abstracts of Scientific Papers, 1972 Annual Meeting of the American Society of Anesthesiologists, p. 405. 12. Cullen, B. F., Sample, F. W., and Chretien, P. B.: The effect· of halothane on phytohemagglutinin-induced transformation of human lymphocytes in vitro. Anesthesiology, 36:206-212, 1972. 13. Dale, D. C., Fauci, A. S., and Wolff, S. M.: Alternate day prednisone: Leukocyte kinetics and susceptibility to infections. N. Eng. J. Med., 291:1154-1158, 1974. 14. Dale, D. C., and Petersdorf, R. G.: Corticosteroids and infections. MED. CLIN. N. AM., 57:1277-1287, 1973. 15. Elsbach, P.: On the interaction between phagocytes and Inicro-organisms. N. Eng. J. Med.,'289:846-852, 1973. · 16. ·Feller, I., Richards, K. E., and Pierson, C. L.: Prevention of postoperative infections. $l]RG. Ci.IN. N. AM., 52:1361-1366, 1972. . 17. Graham, E. A.: The influence of ether and ether anesthesia on bacteriolysis, agglutination, and phagocytosis. J. Infect. Dis., 8:147-175, 1911.
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18. Grogan, J. B., Miller, R. C., and Hardy, J. D.: Impaired function of polymorphonuclear leukocytes in patients with bums and other trauma. Presented before the Fourth Annual Meeting of the American Bum Association, April 17, 1972. 19. Holmes, B., Quie, P. G., Windhorst, D. B., and Good, R. A.: Fatal granulomatous disease of childhood: An inbom abnormality of phagocytic function. Lancet, 1:1225-1231, 1966. 20. Hollowbrow, E. J.: An ABC of Modem immunology. Boston, Little, Brown and Co., 1968. 21. Humphrey, L. J., Wingard, D. W., and Lang, R.: Effect of halothane on spleen cells: In vitro studies on reversibility of immunosuppression. Surgery, 65:939-942, 1969. 22. Lecky, J. H., Twomey, P. L., Hume, R., and Chretien, P. B.: The effects of N,O-morphine anesthesia on white cell function in human volunteers. Abstracts of Scientific Papers, 1974 Annual Meeting of the American Scoiety of Anesthesiologists, p. 203. 23. Rosner, F., Valmont, I., Kozinn, P. R., and Caroline, L.: Leucocyte function in patients with leukemia. Cancer, 25:835-842, 1970. 24. Stossel, T.: Phagocytosis. N. Eng. J. Med., 290:717-726, 774-780, 833-839, 1974. 25. Wurster, N., Elsbach, P., Simon, E. J., et al.: The effects of the morphine analogue levorphanol on leukocytes: Metabolic effects at rest and during phagocytosis. J. Clin. Invest., 50:1091-1099, 1971. 26. Zurier, R. B., Weissman, G., Hoffstein, S., et al.: Mechanisms of lysosomal enzyme release from human leukocytes, II. Effects of cAMP and cGMP, autonomic agonists, and agents which affect microtubule function. J. Clin. Invest., 53:297-309, 1974. Department of Anesthesia Hospital of the University of Pennsylvania 3400 Spruce Street Philadelphia, Pennsylvania 19105
