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Cryobiology as viewed by the surgeon
CRYOBIOLOGY Vol.
1, No.
1, 1964
CRYOBIOLOGY
AS VIEWED IRVING
Department
of Neurological
Surgery,
BY THE SURGEON”t
S. COOPER
Barnabas Hospital,
St.
The use of cold for biological and surgical purposes is not new. There have been many who have sensed t’he possible usefulness of cold as a surgical tool for more than 100 years.” 45t458El During the past 20 years, there have been classic advances in cryobiology, as exemplified by the work of Luyet and Gehenio,% Rey,48 Smith,“” Parkes,41 and others which clarify the effect of cold upon biological tissue.20s30,“I 41*4*.U The investigations of these workers form a reservoir of basic information applicable to medical and surgical research. Cryogenic engineeringa has now reached the point in which the application of cryogenics to surgery will be limited only by the imagination of t,he surgeons and their interest in investigating this new approach. A combination of efforts on the part of biologists, cryogenic engineers, and surgeons offers t,he possibilit,y of productive investigation and therapy, not only in t,he central nervous system but in many other areas of human disease as well. Extreme cold may serve as a valuable physical agent in surgery. It fulfills many of the criteria for an ideal method of destroying biological tissue. These criteria are reversibility, consistent reproducibility, sharp delimitation, hemostasis, flexibility, safety, simplicity, and rapidity of application. The creation of physiological inhibition”, “, ‘I. ~2,38,ji or lesion creation?. 8,8.2;. 18.‘$, 48 bv heat transfer: within the brain is dependent upon known physical laws.‘33 3c Consequently the method is scientifically controllable or modifiable, although biological variations38Z ” must still be studied and appreciated when these techniques are applied in the laboratory or operating room. * Presented at the First Annual Meeting, Society for Cryobiology, August 24-26, 1964, Washington, D. C. ? Supported by a grant from the John A. Hartford Foundation, New York, New York; and by a contract #4396 (00) from the Office of Naval Research, Department of the Navy. 2 Also U. Hinojosa, I. S. Cooper, M. Matsumato, L. Bergmann, and I. H. Feigin, unpublished data.
New
York,
New
York
A complete system of cryogenic surgery:” employing liquid nitrogen as a coolant, and vacuum insulation for protection of all tissues except those being surgically attacked, has been developed. Its usefulness for physiological inhibition and lesion creation has been documented in animals and in humans. The refrigerant which we have found to be ideally suited for this purpose is liquid nitrogen, the temperature of which is -196°C. A series of special probes has been developed, which are insulated except at the tip, and which are capable of producing temperatures as low as the actual temperature of liquid nitrogen. Although we have experimented with various types of insulation, including a heating element in the wall of the cannula, and silk insulation of the cannula wall, the most efficient cannula is insulated by a vacuum,§ which is presently the most effective insulation used in cryogenic engineering. The smallest cannula has an over-all diameter of 2.2 mm which includes an outer layer of vacuum insulat,ion, an innermost tube for passage of liquid nitrogen to the freezing tip, and an intermediate layer for escape of gaseous nitrogen, after the state of the liquid nitrogen has been changed to gas by transfer of heat from contiguous brain at the freezing tip. (The cannula is supplied with thermocouples at the freezing tip, so that the tip temperature may be monitored throughout the procedure.) An electronically controlled system has been developed which regulates liquid nitrogen flow through the vacuum-insulated line to maintain a preselected temperature at the tip of the probe. This desired temperature is selected by adjusting the temperature selector dial on the control console of the cryogenic apparatus until the desired temperature is indicated on t,his gauge. From this point on, the desired temperature may be cont’rolled automatically, or, if the surs The vacuum insulated cannula and automatic cryogenic system is produced by the Linde Corporation Laboratory, Indianapolis, Indiana.
44
CRYOBIOLOGY
AS VIEWED
BY SURGEON
45
FIG. 1. Composite photograph demonstrating cryosurgical system described in this report. The components lettered for identification are as follows: A. Front view of console containing various components of the unit. B. Dewar for liquid nitrogen storage. C. Back view of console. D. Inkwriting temperature recorder. E. On-off control of pressurization. F. On-off control of liquid nitrogen supply. G. Vacuum-insulated feedline to carry liquid nitrogen to cannula. H. Supporting arm to maintain instrument in desired position. 1. Special brain surgical cannula. geon wishes, may be controlled by an alternate manual cont)rol system on the control console. This syst)em is capable of maintaining any desired temperature between 37” and -196°C at the distal extremity of the cryogenic probe. The body of the probe remains at the temperature of its environment since it is protect,ed by vacuum insulation. This unit (Fig. 1) is capable of producing physiological blockade or physiological inhibition around the tip of the probe at a temperature range of +19” to O”C, or may produce predictable sharply circumscribed lesions ranging from 3 mm to more than 10 cm in diameter. Larger lesions may be readily produced by two or more applications of the probe, or by employing multiple probes at the same time. Various probes of different sizes and shapes may be employed with the same basic cryogenic system to produce lesions of any desired volume or shape. Freezing produces cellular destruction by the following methods :‘. ‘, In. “5 ‘I, 34,El dehydration and concentrat,ion of electrolytes due to removal of water from solution; crystallization with rupture of cellular membrane; denat,ura-
tion of liquid-protein molecules within the cell membrane; thermal shock: and vascular stasis. The lesions which are produced by the freezing cannula employed in this study are spherical or ovoid, essentially hemostatic, and sharply delimited from adjacent normal nervous tissue. Cryogenic neurosurgical t’echniques have been applied to basal ganglia surgery14* I’. m (Fig. 2A, B), intracerebral neoplasms,l’* Ii, ” hypophysectomy, and other operations, in a consecut,ive series of more than 1500 cases. In the first 1000 consecutive cases of cryothalamectomy for parkinsonism, tremor and rigidity were successfully relieved in 93% of cases. The mortality rate was 1.1%. The mean postoperative hospitalization time was 7 days. Recurrence of symptoms occurred in 12%, most of whom were re-operated to provide abolition of the recurrent symptoms. This method has been employed successfully for the freezing and destruction of deep intracerebral tumors by the relatively simple method of placement’ of the cannula into the tumor through a trephine opening. The method is safe, well tolerated by the pat’ient, simple, and offers promise as an investigative approach to this otherwise inoperable group of brain tumors. It
46
I. S. COOPER
FIG. 2A. Anterior-posterior ventriculogram, demonstrating cryogenic cannula in place, with its noninsulated tip in the ventrolateral region of the thalamus. may also be used for the removal of more superficial mass lesions, by permitting the lesion to be frozen solid and to be removed en bloc, thereby removing technical difficulties and lessening intracerebral bleeding (Fig. 3A, B). A separate phase of our investigation of cryosurgery has demonstrated that localized malignancies may be destroyed in situ by similar application of freezing temperatures by this method.‘, I8332*59 We have investigated the effect of applying extremely low temperatures, that is between -50” and -196”C, to malignant growths in various parts of the body. Although earlier studies had indicated the potential value of the physical modality of extreme cold”“, SE in therapy of some malignancies, proper utilization of extreme cold for this purpose has not heretofore been possible because of lack of satisfactory instrumentation. Because of the insulating properties of vascularized biological tissue, and the sharp heat gradient within bio-
logical tissue, it is necessary to apply temperatures within the cryogenic range in order to obtain a satisfactory destructive effect upon malignant tissue. The development of vacuuminsulated surgical instruments, refrigerated by liquid nitrogen, now make the controlled application of temperatures as low as -196°C a relatively simple and safe procedure. As Bory” has pointed out cold is valuable as a potential cancer-destructive agent, because of its anesthetic, coagulant, and destructive properties. These properties make it possible to produce necrosis of cancer tissue in viva, and the use of the instrumentation which we have employed provides a great margin of safety in the application of this technique. We have found that virtually all living biological tissue which is subjected to a temperature of -20°C or below for one minute or longer will undergo cryogenic congelation and necrosis. The muscular walls of large arteries
CRYOBIOLOGY
AS VIEWED
BY SURGEON
47
FIG. 2B. Cross section of human brain demonstrating two cryosurgical lesions in the thalamus on either side. The small lesion on the right side, represents the frozen lesion one year after its creation in this patient. The spherical lesion on the left side demonstrates the sharply circumscribed, clearly delineated lesion in the thalamus two months after its infliction. This patient died suddenly of coronary occlusion two months after the latter operation. Necropsy afforded the opportunity to observe the effects of freezing in the cryogenic temp’erature range in the human brain two months, and one year after infliction of the lesions. seem to form a singular exception to this finding, and have proved to be remarkably resistant to the effects of freezing, even within the cryogenic temperature range. Moreover, although major arteries may be frozen solid during the application of extreme cold to biological tissue, clotting does no-t take place in these large arteries. Rather, dluring the thawing process the frozen blood within the large vessels is lyzed, and normal arterial circulation results in the large art’eries. On the other hand, capillaries and small arterioles and venules are necrosed along with the adjacent biological tissue when they are subjected to application of extreme cold. One of the immediate and most salutary effects, resulting from freezing and necrosis of
neoplasms, is the destruction of free nerve endings subserving pain within, and immediately adjacent to the tumor. Thus, one can be virtually assured of obtaining the relief of localized pain caused by a tumor mass, when this neoplasm is subjected to cryogenic temperatures. Since the relief of pain is one of the palliative measures most often sought in the treatment of advanced cancer, cryogenic congelation of t,he localized tumor mass provides a safe, rapid means of achieving this end, in those instances in which the pain is localized to the neoplasm and its immediate environs. We have employed local freezing in tumorbearing animals in the laboratory, and in a series of diverse far-advanced cases of various types of malignancy in humans, in order to
48
I. S. COOPER
FIG. 3A. Demonstration of large vascular tumor of the brain, which was frozen solid and removed en bloc. A larger special tumor probe was used in this instance. assess its effect upon cancer, and upon the patient harboring various types of neoplasm. Inasmuch as the investigation has been largely confined to patient,s who have inoperable cancer, or who have cancer already subjected to operation, radiation therapy, and various types of chemotherapy of cancer, the goal in virtually all instances has been palliation rather than total eradication of t.he neoplasm, which in many inst.ances was aIready metastatie. In order to obtain necrosis of neoplastic tissue by subjecting it to extreme cold, one must be certain that, all of the tissue has reached a temperature of at least, -20°C. For this purpose, we have devised a series of special cannulae which enable us to freeze relatively large tumors rapidly and to rewarm these tumors for rapid thawing following a suitable period at the cryogenic temperature range. Moreover, it is necessary to monitor temperatures in various portions of the tumor, and in the adjacent normal tissue, in order t,o verify the fact that the tumor has been adequately frozen. Because of
the temperature gradient within biological tissue, t,he danger of freezing adjacent normal tissues is negligible, since the depth of temperature within the freezing cannulae can be automatically controlled. There is a greater danger of insufficient freezing of the neoplastic tissue t,han of inadvertent freezing of adjacent normal tissues. The extension of this investigation of cryogenic principles into other surgical speciaIties, such as ophthalmology for cataract removalZeSao or det)ached retina,3. 34otolaryngology for tonsillectomy or treatment of laryngeal papillomata,” and gynecology for controlled destruct’ion of endomet,rium, indicat,es varied possibilities of application of the use of controlled extreme cold. Furt,her multidisciplinary efforts by cryobiologists, biophysicists, cryogenic engineers, and surgeons may be expected t,o broaden our basic knowledge of the effect of extreme cold on normal and neoplastic tissue, as well as to contribute practically to the art and science of surgical t,herapy.
CRYOBIOLOGY
AS VIEWED
FIG. 3B. Demonstration of a gliomatous tumor of the brain frozen solid, dissected free, and removed en bloc. It is lifted gently and gradually from the brain by a specially devised tumor crank holding the cryosurgical probe.
REFERENCES 1. Arnott, J. B. On treatment of cancer by the regulated application of an anaesthetic temperature. London, J. & A. Churchill, 1951. 2. Balthasar, K. IL. Direct cold injuries in the cerebral cortex of the cat. Deutsch. Z. Nervenheilk., 176: 173-199, 1957. 3. Bietti, G. B. Ricerche sulle variazione di temperature di alcune zone de1 bulbo oculaire der diatermocoagulazioni episclerali, termocauterizzaziosni e criocausticazioni. Contributo allo studio dell’ insorgenza di una cataratta nelle operazioni contra il distacco retinico. Boll. oculist, 12: 1427-1457,1933. 4. Bory, L. The action of cold on normal and cancerous tissue, Progr. Med. (Paris), 88: 7579, 1960. 5. Bory, L. Rational evaluation of cryotherapy of tumors. Presse Med. 67: 45-46, 1959. 6. Bory, L. Logique de la cryotherapie dans le traitement des tumeurs. Presse Med., 67 (2): 4&6,1959. 7. Bravo, J. G., and Cooper, I. S. Chemopallidec-
BY SURGEON
49
tomy-two recent technical additions. J. Amer. Geriat. Sot., 4: 651-655, 1957. 8. Cooper, I. S., and Lee, A. St. J. Cryothalamectomy-hypothermic congelation: a technical advance in basal ganglia surgery ; preliminary report. J. Amer. Geriat. Sot., 9: 714718, 1961. 9. Cooper, I. S., and Lee, A. St. J. A system for producing a limited controlled region of cooling or freezing of biologic tissues. J. Nerv. Ment Dis., 1SS: 3,1961. 10. Cooper, I. S., Grissman, F., and Johnston, P. A complete system for cryogenic surgery. St. Barnabas Med. Bull., 1: 11-16, 1962. 11. Cooper, I. S. Intracerebral injection of procaine into the globus pallidus in hyperkinetic disorders. Science, 119: 417-418, 1954. 12. Cooper, I. S., and Poloukhine, N. Chemopallidectomy: a neurosurgical technique useful in geriatric parkinsonians. J. Amer. Geriat. sot., 3: 839~859,1955. 13. Cooper, I. S. Parkinsonism: its medical and surgical therapy. Charles C Thomas, Springfield, Ill., 1961. 14. Cooper, I. S., Waltz, J., Stellar, S., and Riklan, M. Cryothalamectomy for parkinsonism : a follow-up study. In press. 15. Cooper, I. S. Cryogenic surgery of the basal ganglia. J. A. M. A., 1~91:600-604, 1962. 16. Cooper, I. S. Cryogenic surgery: a new method of destruction of extirpation of benign or malignant tissues. New Engl. J. Med. 268: 743-749,963. 17. Cooper, I. S. Cryogenic freezing of brain tumors for excision or destruction in situ. J. Neurosurg., 20: 921-930, 1963. 18. Cooper, I. S., Grissman, F., Gorek, E., and Williams, R. Cryogenic congelation and necrosis of cancer: preliminary report. J. Amer. Geriat. Sot., 10: 289-293, 1962. 19. Denny-Brown, D., Adams, R. D., Brenne, C., and Doherty, M. M. Pathology of injury of nerve induced by cold. J. Neuropath. Exp. Neurol., 4: 305, 1945. 20. Deutschmann, R. Die Behandlung der Netshautablosung mit Jodtinktur unf Kohlensaureschnee. Klin. Mbl. Augenheilk., 94: 349, 1935. 21. Dondey, M., Rey, L., and LeBeau, J. Presentation d’un instrument permettant le refroidissement controle de structures cerebrales superficielles. Rev. Neurol. (Paris), 105: 3: 220, 1960. 22. Douglas, W. W., and Malcolm, J. L. The effects of localized cooling on conduction in cats nerves. Nat. Inst. Med. Res., London, 1955. 23. Efron, A. Heat, pp. 200-202. John F. Rider, Inc., 1957. 24. Eltorm, H. Effect of relatively low temperatures on cancer cells: review of experimental
50
25. 26.
27.
28. 29. 30. 31. 32.
33. 34.
35.
36.
37. 38.
39.
40.
41.
42.
I. S. COOPER and clinical studies. Nord. Med., 18: 551-554, 1943. Fay, T. Refrigeration therapy. In Medical physics, vol. 1, 0. Glasser, ed., pp. 12261229. Year Book Publishers, Chicago, 1944. Gaillard. R. Effets de la refrigeration locale sur les prbcessus d’excitation des nerfs moteurs in situ chew l’homme. C. R. Sot. Biol. (Paris), 149: 209&2092,1955. Haas, G. H., and Taylor, C. B. Quantitative hypothermal method for production of local iniurv to tissue. A. M. A. Arch. Path., , L5: 563-580, 1948. Hall, F. Advantages and limitations of liquid nitrogen in the therapy of skin lesions. A. M. A. Arch. Dermat., 8%‘: 9-16,196O. Kelman, C., and Cooper, I. S. Cryogenic ophthalmic surgery. Amer. J. Ophthal., 56: 1963. Krawicz, T. Intracapsular extraction of intumescent cataract by application of low temperature. Brit. J. Ophthal., 45: 279, 1961. Kreyberg, L. Local freezing. Proc. Roy. Sot. (Biol.), 147B: 546, 1957. LeMariey, A., and Muler, H. Attempt to apply cryotherapy to the treatment of infantile laryngeal papillomata. Ann. Otolaryng. (Paris), 77 : 279-285,196O. Lewis, Robert B. Cold injury, pp. 24-26. Hildreth Press, Inc., 1952. Lincoff, H. A., and McLean, J. M. Cryosurgical treatment of retinal detachment. Paper presented at American Academy of Ophthalmology and Otolaryngology Meeting, New York Hilton Hotel, 1963. Luyet, B. J., and Gehenio, P. M. Life and death at low temperatures. Biodynamics, Normandy, MO., 1940. Lovelock, J. E. The denaturation of lipidprotein complexes as a cause of damage by freezing. Proc. Roy. Sot. (Biol.), 147B-929: 427-433,1957. McAdams, W. H. Heat transmission. McGrawHill Book Co., New York, 1954. Mark, V. H., Chato, J. C., Eastman, F. G., Aronow, S., and Ervin, F. R. Localized cooling in the brain. Science, 134: 152lX1521, 1961. Marshall, C., Nims, C. L., and Stone, W. Chemical changes in cerebral cortex following local thermo-coagulation and freezing. Yale J. Biol. Med., 13: 485-8, 1941. Meryman, H. T. Mechanics of freezing in living cells and tissues. Science, 124: 515-521, 1956. Meryman, H. T. Physical limitations of the rapid freezing method. Proc. Roy. Sot. (Biol.). lL7B: 452-459.1957. , Nims, C.‘L:, Marshall, C., and Nielsen, A. Effect of local freezing on the electrical activity of cerebral cortex. Yale J. Biol. Med., 13: 477-484, 1941.
43. Openchowski, S. Sur l’action localisee du froid applique a la surface de la region corticale du cerveau. C. R. Sot. Biol., 5: 3%43, 1883. 44. Parkes, A. S. Introductory remarks. Proc. Roy. Sot. (Biol.), 147B: 424,i957. 45. Ponne. J. K. Use of cold air blast on (orecanLeio&) skin. Surgery, 11: 460-465, 1542. 46. Rahn, J. General sequels of the local effect of cold on the cerebral cortex of rabbits. Arch. Psychiat. Nervenh., 194: 5&i-596,1956. 47. Rewarts, G. Brain lesions due to cold: preliminarv renort. Klin. Wschr. d6: 249-250. 1948. ” 48. Rey, L. R. Applications biologiques et meditales dues au froid. Evolution et perspectives de I’avenir. Techn. Hosp. (Paris). 141: 33-34, 1959. 49. Ries, L., and Tytus, J. S. Rapid freezing: a surgical technique (preliminary report). Bull. Mason Clin. (Seattle), 14: 2C26, 1960. 50. Rowbotham, G. F., Haigh; A. L., ‘and Leslie, W. G. Cooline: cannula for use in the treatment of cerebyal neoplasm. Lancet, 1: 7062: 12-15, 1959. 51. Sano, M. E., and Smith, L. W. Behavior of tumor cells in tissue culture subjected to reduced temperatures. Cancer Res., B: 32-39, 1942. 52. Scholar, F. Experimentelle erzeugung von aderhaut-netzhautentzunding durch kohlensaureschnee. Klin. Mbl. Augenheilk, 94: 349,1935. 53. Scott, R. B. Cryogenic engineering. D. Van Nostrand Co., Princeton, 1959. 54. Smith, L. W. Refrigeration: pathologic observations in 100 advanced cancer cases. New York J. Med., 40: 1355-1361,194O. 55. Smith, A. U. Problems in the resuscitation of mammals from body temperatures below 0°C. Proc. Roy. Sot. (Biol.), 147B: 533, 1957. 56. Sweet, W. H., and Mark, V. H. Unipolar anodal electrolytic lesions in the brain of man and cat. A. M. A. Arch. Neurol., 70: 224234, 1953. 57. Tanche, M., Chatonnet, J., and Cabanac, M. Description et utilization d’un neuvel appareil a refroidissement cerebral localise. J. Med. Lyon, 13-15, 1961. 58. Taylor, C. The effect of rate of cooling on survival of frozen tissues. Proc. Roy. Sot. (Biol.), 147B: 466, 1957. 59. Taylor, L. H. Cancer and cryotherapy: a review. J Amer. Osteopath. Assn., 69: 90%912, 1960. 60. Walton, G. Cold shock of spermatozoa. Proc. Roy. Sot. (Biol.), 147B: 508,1957. 61. Warner, P. T. J. C., and Gostling, J. V. T. Effect of freezing and freeze-drying on transplantation of sarcoma 37. Brit. J. Cancer, 4: 380-395,195o. 62. Weil, L., Chanteur, J., and Dondey, M. Dis-
CRYOBIOLOGY
AS VIEWED
positif pour le refroidissement controle de certaines structures cerebrales profondes. C. R. Acad. Soi. (Paris), 2947-2948,1961. 63. Whittier, J. R., and Mettler, F. A. Studies on the subthalamus of the rhesus monkey. I. Anatomy a.nd fiber connections of the sub-
BY SURGEON
51
thalamic nucleus of luys. J. Comp. Neurol., 90: 281317,1949. 64. Zimmerman, H. M., and Dusser de Barenne, J. G. Changes in the central cortex produced by thermocoagulation. A. M. A. Arch. Neurol., 55: 12331,1935.
1, No.
1, 1964
CRYOBIOLOGY
AS VIEWED IRVING
Department
of Neurological
Surgery,
BY THE SURGEON”t
S. COOPER
Barnabas Hospital,
St.
The use of cold for biological and surgical purposes is not new. There have been many who have sensed t’he possible usefulness of cold as a surgical tool for more than 100 years.” 45t458El During the past 20 years, there have been classic advances in cryobiology, as exemplified by the work of Luyet and Gehenio,% Rey,48 Smith,“” Parkes,41 and others which clarify the effect of cold upon biological tissue.20s30,“I 41*4*.U The investigations of these workers form a reservoir of basic information applicable to medical and surgical research. Cryogenic engineeringa has now reached the point in which the application of cryogenics to surgery will be limited only by the imagination of t,he surgeons and their interest in investigating this new approach. A combination of efforts on the part of biologists, cryogenic engineers, and surgeons offers t,he possibilit,y of productive investigation and therapy, not only in t,he central nervous system but in many other areas of human disease as well. Extreme cold may serve as a valuable physical agent in surgery. It fulfills many of the criteria for an ideal method of destroying biological tissue. These criteria are reversibility, consistent reproducibility, sharp delimitation, hemostasis, flexibility, safety, simplicity, and rapidity of application. The creation of physiological inhibition”, “, ‘I. ~2,38,ji or lesion creation?. 8,8.2;. 18.‘$, 48 bv heat transfer: within the brain is dependent upon known physical laws.‘33 3c Consequently the method is scientifically controllable or modifiable, although biological variations38Z ” must still be studied and appreciated when these techniques are applied in the laboratory or operating room. * Presented at the First Annual Meeting, Society for Cryobiology, August 24-26, 1964, Washington, D. C. ? Supported by a grant from the John A. Hartford Foundation, New York, New York; and by a contract #4396 (00) from the Office of Naval Research, Department of the Navy. 2 Also U. Hinojosa, I. S. Cooper, M. Matsumato, L. Bergmann, and I. H. Feigin, unpublished data.
New
York,
New
York
A complete system of cryogenic surgery:” employing liquid nitrogen as a coolant, and vacuum insulation for protection of all tissues except those being surgically attacked, has been developed. Its usefulness for physiological inhibition and lesion creation has been documented in animals and in humans. The refrigerant which we have found to be ideally suited for this purpose is liquid nitrogen, the temperature of which is -196°C. A series of special probes has been developed, which are insulated except at the tip, and which are capable of producing temperatures as low as the actual temperature of liquid nitrogen. Although we have experimented with various types of insulation, including a heating element in the wall of the cannula, and silk insulation of the cannula wall, the most efficient cannula is insulated by a vacuum,§ which is presently the most effective insulation used in cryogenic engineering. The smallest cannula has an over-all diameter of 2.2 mm which includes an outer layer of vacuum insulat,ion, an innermost tube for passage of liquid nitrogen to the freezing tip, and an intermediate layer for escape of gaseous nitrogen, after the state of the liquid nitrogen has been changed to gas by transfer of heat from contiguous brain at the freezing tip. (The cannula is supplied with thermocouples at the freezing tip, so that the tip temperature may be monitored throughout the procedure.) An electronically controlled system has been developed which regulates liquid nitrogen flow through the vacuum-insulated line to maintain a preselected temperature at the tip of the probe. This desired temperature is selected by adjusting the temperature selector dial on the control console of the cryogenic apparatus until the desired temperature is indicated on t,his gauge. From this point on, the desired temperature may be cont’rolled automatically, or, if the surs The vacuum insulated cannula and automatic cryogenic system is produced by the Linde Corporation Laboratory, Indianapolis, Indiana.
44
CRYOBIOLOGY
AS VIEWED
BY SURGEON
45
FIG. 1. Composite photograph demonstrating cryosurgical system described in this report. The components lettered for identification are as follows: A. Front view of console containing various components of the unit. B. Dewar for liquid nitrogen storage. C. Back view of console. D. Inkwriting temperature recorder. E. On-off control of pressurization. F. On-off control of liquid nitrogen supply. G. Vacuum-insulated feedline to carry liquid nitrogen to cannula. H. Supporting arm to maintain instrument in desired position. 1. Special brain surgical cannula. geon wishes, may be controlled by an alternate manual cont)rol system on the control console. This syst)em is capable of maintaining any desired temperature between 37” and -196°C at the distal extremity of the cryogenic probe. The body of the probe remains at the temperature of its environment since it is protect,ed by vacuum insulation. This unit (Fig. 1) is capable of producing physiological blockade or physiological inhibition around the tip of the probe at a temperature range of +19” to O”C, or may produce predictable sharply circumscribed lesions ranging from 3 mm to more than 10 cm in diameter. Larger lesions may be readily produced by two or more applications of the probe, or by employing multiple probes at the same time. Various probes of different sizes and shapes may be employed with the same basic cryogenic system to produce lesions of any desired volume or shape. Freezing produces cellular destruction by the following methods :‘. ‘, In. “5 ‘I, 34,El dehydration and concentrat,ion of electrolytes due to removal of water from solution; crystallization with rupture of cellular membrane; denat,ura-
tion of liquid-protein molecules within the cell membrane; thermal shock: and vascular stasis. The lesions which are produced by the freezing cannula employed in this study are spherical or ovoid, essentially hemostatic, and sharply delimited from adjacent normal nervous tissue. Cryogenic neurosurgical t’echniques have been applied to basal ganglia surgery14* I’. m (Fig. 2A, B), intracerebral neoplasms,l’* Ii, ” hypophysectomy, and other operations, in a consecut,ive series of more than 1500 cases. In the first 1000 consecutive cases of cryothalamectomy for parkinsonism, tremor and rigidity were successfully relieved in 93% of cases. The mortality rate was 1.1%. The mean postoperative hospitalization time was 7 days. Recurrence of symptoms occurred in 12%, most of whom were re-operated to provide abolition of the recurrent symptoms. This method has been employed successfully for the freezing and destruction of deep intracerebral tumors by the relatively simple method of placement’ of the cannula into the tumor through a trephine opening. The method is safe, well tolerated by the pat’ient, simple, and offers promise as an investigative approach to this otherwise inoperable group of brain tumors. It
46
I. S. COOPER
FIG. 2A. Anterior-posterior ventriculogram, demonstrating cryogenic cannula in place, with its noninsulated tip in the ventrolateral region of the thalamus. may also be used for the removal of more superficial mass lesions, by permitting the lesion to be frozen solid and to be removed en bloc, thereby removing technical difficulties and lessening intracerebral bleeding (Fig. 3A, B). A separate phase of our investigation of cryosurgery has demonstrated that localized malignancies may be destroyed in situ by similar application of freezing temperatures by this method.‘, I8332*59 We have investigated the effect of applying extremely low temperatures, that is between -50” and -196”C, to malignant growths in various parts of the body. Although earlier studies had indicated the potential value of the physical modality of extreme cold”“, SE in therapy of some malignancies, proper utilization of extreme cold for this purpose has not heretofore been possible because of lack of satisfactory instrumentation. Because of the insulating properties of vascularized biological tissue, and the sharp heat gradient within bio-
logical tissue, it is necessary to apply temperatures within the cryogenic range in order to obtain a satisfactory destructive effect upon malignant tissue. The development of vacuuminsulated surgical instruments, refrigerated by liquid nitrogen, now make the controlled application of temperatures as low as -196°C a relatively simple and safe procedure. As Bory” has pointed out cold is valuable as a potential cancer-destructive agent, because of its anesthetic, coagulant, and destructive properties. These properties make it possible to produce necrosis of cancer tissue in viva, and the use of the instrumentation which we have employed provides a great margin of safety in the application of this technique. We have found that virtually all living biological tissue which is subjected to a temperature of -20°C or below for one minute or longer will undergo cryogenic congelation and necrosis. The muscular walls of large arteries
CRYOBIOLOGY
AS VIEWED
BY SURGEON
47
FIG. 2B. Cross section of human brain demonstrating two cryosurgical lesions in the thalamus on either side. The small lesion on the right side, represents the frozen lesion one year after its creation in this patient. The spherical lesion on the left side demonstrates the sharply circumscribed, clearly delineated lesion in the thalamus two months after its infliction. This patient died suddenly of coronary occlusion two months after the latter operation. Necropsy afforded the opportunity to observe the effects of freezing in the cryogenic temp’erature range in the human brain two months, and one year after infliction of the lesions. seem to form a singular exception to this finding, and have proved to be remarkably resistant to the effects of freezing, even within the cryogenic temperature range. Moreover, although major arteries may be frozen solid during the application of extreme cold to biological tissue, clotting does no-t take place in these large arteries. Rather, dluring the thawing process the frozen blood within the large vessels is lyzed, and normal arterial circulation results in the large art’eries. On the other hand, capillaries and small arterioles and venules are necrosed along with the adjacent biological tissue when they are subjected to application of extreme cold. One of the immediate and most salutary effects, resulting from freezing and necrosis of
neoplasms, is the destruction of free nerve endings subserving pain within, and immediately adjacent to the tumor. Thus, one can be virtually assured of obtaining the relief of localized pain caused by a tumor mass, when this neoplasm is subjected to cryogenic temperatures. Since the relief of pain is one of the palliative measures most often sought in the treatment of advanced cancer, cryogenic congelation of t,he localized tumor mass provides a safe, rapid means of achieving this end, in those instances in which the pain is localized to the neoplasm and its immediate environs. We have employed local freezing in tumorbearing animals in the laboratory, and in a series of diverse far-advanced cases of various types of malignancy in humans, in order to
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I. S. COOPER
FIG. 3A. Demonstration of large vascular tumor of the brain, which was frozen solid and removed en bloc. A larger special tumor probe was used in this instance. assess its effect upon cancer, and upon the patient harboring various types of neoplasm. Inasmuch as the investigation has been largely confined to patient,s who have inoperable cancer, or who have cancer already subjected to operation, radiation therapy, and various types of chemotherapy of cancer, the goal in virtually all instances has been palliation rather than total eradication of t.he neoplasm, which in many inst.ances was aIready metastatie. In order to obtain necrosis of neoplastic tissue by subjecting it to extreme cold, one must be certain that, all of the tissue has reached a temperature of at least, -20°C. For this purpose, we have devised a series of special cannulae which enable us to freeze relatively large tumors rapidly and to rewarm these tumors for rapid thawing following a suitable period at the cryogenic temperature range. Moreover, it is necessary to monitor temperatures in various portions of the tumor, and in the adjacent normal tissue, in order t,o verify the fact that the tumor has been adequately frozen. Because of
the temperature gradient within biological tissue, t,he danger of freezing adjacent normal tissues is negligible, since the depth of temperature within the freezing cannulae can be automatically controlled. There is a greater danger of insufficient freezing of the neoplastic tissue t,han of inadvertent freezing of adjacent normal tissues. The extension of this investigation of cryogenic principles into other surgical speciaIties, such as ophthalmology for cataract removalZeSao or det)ached retina,3. 34otolaryngology for tonsillectomy or treatment of laryngeal papillomata,” and gynecology for controlled destruct’ion of endomet,rium, indicat,es varied possibilities of application of the use of controlled extreme cold. Furt,her multidisciplinary efforts by cryobiologists, biophysicists, cryogenic engineers, and surgeons may be expected t,o broaden our basic knowledge of the effect of extreme cold on normal and neoplastic tissue, as well as to contribute practically to the art and science of surgical t,herapy.
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FIG. 3B. Demonstration of a gliomatous tumor of the brain frozen solid, dissected free, and removed en bloc. It is lifted gently and gradually from the brain by a specially devised tumor crank holding the cryosurgical probe.
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tomy-two recent technical additions. J. Amer. Geriat. Sot., 4: 651-655, 1957. 8. Cooper, I. S., and Lee, A. St. J. Cryothalamectomy-hypothermic congelation: a technical advance in basal ganglia surgery ; preliminary report. J. Amer. Geriat. Sot., 9: 714718, 1961. 9. Cooper, I. S., and Lee, A. St. J. A system for producing a limited controlled region of cooling or freezing of biologic tissues. J. Nerv. Ment Dis., 1SS: 3,1961. 10. Cooper, I. S., Grissman, F., and Johnston, P. A complete system for cryogenic surgery. St. Barnabas Med. Bull., 1: 11-16, 1962. 11. Cooper, I. S. Intracerebral injection of procaine into the globus pallidus in hyperkinetic disorders. Science, 119: 417-418, 1954. 12. Cooper, I. S., and Poloukhine, N. Chemopallidectomy: a neurosurgical technique useful in geriatric parkinsonians. J. Amer. Geriat. sot., 3: 839~859,1955. 13. Cooper, I. S. Parkinsonism: its medical and surgical therapy. Charles C Thomas, Springfield, Ill., 1961. 14. Cooper, I. S., Waltz, J., Stellar, S., and Riklan, M. Cryothalamectomy for parkinsonism : a follow-up study. In press. 15. Cooper, I. S. Cryogenic surgery of the basal ganglia. J. A. M. A., 1~91:600-604, 1962. 16. Cooper, I. S. Cryogenic surgery: a new method of destruction of extirpation of benign or malignant tissues. New Engl. J. Med. 268: 743-749,963. 17. Cooper, I. S. Cryogenic freezing of brain tumors for excision or destruction in situ. J. Neurosurg., 20: 921-930, 1963. 18. Cooper, I. S., Grissman, F., Gorek, E., and Williams, R. Cryogenic congelation and necrosis of cancer: preliminary report. J. Amer. Geriat. Sot., 10: 289-293, 1962. 19. Denny-Brown, D., Adams, R. D., Brenne, C., and Doherty, M. M. Pathology of injury of nerve induced by cold. J. Neuropath. Exp. Neurol., 4: 305, 1945. 20. Deutschmann, R. Die Behandlung der Netshautablosung mit Jodtinktur unf Kohlensaureschnee. Klin. Mbl. Augenheilk., 94: 349, 1935. 21. Dondey, M., Rey, L., and LeBeau, J. Presentation d’un instrument permettant le refroidissement controle de structures cerebrales superficielles. Rev. Neurol. (Paris), 105: 3: 220, 1960. 22. Douglas, W. W., and Malcolm, J. L. The effects of localized cooling on conduction in cats nerves. Nat. Inst. Med. Res., London, 1955. 23. Efron, A. Heat, pp. 200-202. John F. Rider, Inc., 1957. 24. Eltorm, H. Effect of relatively low temperatures on cancer cells: review of experimental
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positif pour le refroidissement controle de certaines structures cerebrales profondes. C. R. Acad. Soi. (Paris), 2947-2948,1961. 63. Whittier, J. R., and Mettler, F. A. Studies on the subthalamus of the rhesus monkey. I. Anatomy a.nd fiber connections of the sub-
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thalamic nucleus of luys. J. Comp. Neurol., 90: 281317,1949. 64. Zimmerman, H. M., and Dusser de Barenne, J. G. Changes in the central cortex produced by thermocoagulation. A. M. A. Arch. Neurol., 55: 12331,1935.