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Structural alterations in calves implanted with the Akutsu total artificial heart
Structural alterations in calves implanted with the Akutsu total artificial heart Edmond C. Henson, Ph.D., Hiroyuki Takagi, M.D., Hisateru Takano, M.D., Tetsuzo Akutsu, M.D., and Joel G. Brunson, M.D., Jackson, Miss.
The first report concerning implantation of a total artificial heart was by Akutsu and Kolff" in 1958. At that time such a device was implanted into a dog which survived for 2 hours. In 1963, Atsumi and associates" attained a maximum of 51;2 hours' survival in dogs in which a two-chambered waterdriven plastic heart was implanted. The latter animals at necropsy showed marked pulmonary edema and hemorrhage, with marked pooling of blood in the abdominal organs. In 1969, Cooley and associates" reported results of implanting separate left and right ventricular units into a human subject. That patient was maintained on these devices for 64 hours and then given a cardiac allograft, but he died 32 hours later. Autopsy revealed necrotizing confluent bronchopneumonia throughout both lungs. Moreover, both kidneys showed marked edema, tubular necrosis, and multiple fibrin thrombi in the glomeruli. It has taken a long while to achieve longterm survival in experimental animals in which a total artificial heart has been imFrom the Departments of Pathology (Drs. Henson and Brunson) and Surgery (Drs. Takagi, Takano, and Akutsu ) , The University of Mississippi Medical Center, Jackson, Miss. 39216. Supported by Contract NIH-69-2185 and Grant HE-06943 and Grant HL-14733-01Al from the U.S. Public Health Service. Received for publication Dec. 5, 1972.
planted. Takano and associates: in 1971 reported a maximum survival time of 60 hours in sheep with such a device, but the mean survival time was approximately one half the maximum. A separate report described in detail the pathological alterations produced in sheep, none of which survived for more than 60 hours after implantation." In the latter studies, sheep given minimal therapy showed a rapid onset of a profound "shocklike" state with a short survival time after implantation. At necropsy, these animals showed extensive changes in almost all major organ systems. Other sheep were given specific antishock therapy after implantation and showed a longer survival time than the untreated group. The pathological changes in the group given antishock therapy were generally less severe than in the nontreated group, but the lungs of both groups showed marked generalized alterations. Death in both groups was due to irreversible hypotension and respiratory failure. Recently, two separate groups of workers reported survival times of longer than 100 hours in calves in which a total artificial heart had been implanted." 7 The present report represents the first detailed study of pathological alterations in animals most of which survived for longer than 100 hours after implantation of a total artificial heart. 99
The Journal of
1 00
Henson et al.
Thoracic and Cardiovascular Surgery
Materials and methods
Five calves, some male and some female, which weighed from 70 to 90 kilograms, were implanted with the Akutsu four-chambered total artificial heart according to methods previously described.' Postoperative care was performed by methods given in the latter report." At the time of death, as determined by the absence of pupillary reflexes, the animals were studied by gross examination, and tissue sections were taken for studies by conventional light microscopy. These tissues were processed and stained with hematoxylin and eosin in the usual fashion. The organs and tissues studied were lungs, kidneys, adrenal glands, gastrointestinal tract, liver, pancreas, spleen, and lymph nodes. Results Clinical course. The five calves studied showed survival times of 80, 120, 190, 220, and 247 hours, respectively, after implantation. The causes of death were as follows: 80 hour survivor, breakage of the left ventricle; 120 hour survivor, tear of the natural aorta with massive hemorrhage; 190 hour survivor, tear of the left ventricle; 220 hour survivor, sepsis and asphyxiation; 247 hour survivor, sepsis. The 80 and 120 hour survivors died very shortly after the respective technical complications occurred. However, the 190, 220, and 247 hour survivors were generally normal until approximately 24 hours prior to death. At that time, each animal developed a "shocklike" state which became profound and irreversible. Details of the clinical course of these animals were given in an earlier report. 6 Pathological studies. At necropsy the calf which survived for 80 hours grossly showed minor pleural effusion and marked congestion of both lungs. There were no ascites, minimal congestion of the gastrointestinal tract, and no intraluminal hemorrhage. The liver and gallbladder were moderately congested but otherwise unremarkable. The kidneys had a pale, swollen cortex but were otherwise grossly unremarkable. The spleen was markedly contracted but otherwise un-
remarkable. The other organs studied were generally unremarkable. Microscopic observations of the tissues from the 80 hour survivor showed the lungs to have severe congestion, interstitial edema, mild focal hemorrhage, mild interstitial pneumonitis, and moderate atelectasis. However, the most marked alteration in the lungs was the presence of multiple microthromboemboli, primarily in the alveolar capillaries. The kidneys exhibited marked edema and focal necrosis of the proximal tubules. Distal tubules and collecting ducts in the above focal areas were filled with red blood cells and casts. Certain focal areas revealed hemorrhage of the glomerular capillaries, with numerous red blood cells in the lumens of adjacent tubules. The liver showed moderate fat accumulation in the hepatocytes, early focal central lobular necrosis, marked congestion, and edema. Alterations in the other organs were generally unremarkable, except for the presence of moderate congestion and edema. The animals which survived for longer than 100 hours (i.e., 120, 190, 220, and 247 hours) showed moderate pleural effusion and most showed marked ascites. The lungs generally showed moderate amounts of viscous bloody fluid in the tracheobronchial tree. The lungs also showed marked to severe consolidation with varying degrees of hemorrhage and infarction. The gastrointestinal tract showed moderate to severe congestion, edema, and intraluminal hemorrhage. The livers of these animals generally showed moderate to severe congestion and edema. Two of the animals (i.e., the 220 and 247 hour survivors) showed multiple focal areas of infarction of the liver, which varied in size from 0.5 to 3 em. in diameter, and diffuse softening with early signs of necrosis. The 247 hour survivor was grossly markedly jaundiced. The other animals showed marked softening of the liver, suggestive of early diffuse necrosis, without focal areas of frank advanced necrosis. The kidneys of the animals which survived longer than 100 hours showed focal areas of frank cortical infarction. These areas varied in
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Akutsu total artificial heart
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July, 1973
Fig. 1. Section of lung from calf that survived 220 hours after cardiac implantation. Note con gestion, hemorrhage, interstitial edema, and atelectasis . There is also mild bronchial pneumonitis . (Hematoxylin and eosin; original magnification x 100.)
size from approximately 0.2 em. in diameter to those which included as much as one third of the surface area of the cortex. On cut section, these infarcts were found to extend for variable distances into the medulla. Cut sections also revealed significant thickening of the cortex of all kidneys, suggestive of marked edema. The other organs studied exhibited varied degrees of congestion but were otherwise grossly unremarkable. Microscopic examination of the animals which survived more than 100 hours showed the lungs to have moderate to severe diffuse congestion, focal hemorrhage, interstitial and alveolar edema , atelectasis , and bronchial pneumonia (Fig. I) . In addition there were focal areas of infarction. The
Fig. 2. High magnification of lung from calf that survived 220 hours, showing thrombosis of pulmonary alveolar capillary. (Hematoxylin and eosin; original magnification x l ,OOO. )
animals which survived for 120 and 220 hours showed an abundance of microthromboemboli in the pulmonary alveolar capillaries (Fig. 2) . The 190 hour survivor showed minimal amounts of microthromboemboli in the lungs; none was seen in the lungs of the 247 hour survivor. The gastrointestinal tracts in the above 4 animals showed marked congestion, edema, and varying degrees of sloughing of the mucosal epithelium , as well as focal areas of hemorrhage into the lumen of the stomach and intestines. The livers showed changes which varied from congestion only to severe diffuse central lobular necrosis (Fig. 3) . All animals studied showed marked to severe changes in hepatic parenchymal cells which varied from marked accumulation of fat to frank necrosis. The kidneys of all four of the latter animals showed marked tubular ne-
1
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Henson et at.
Fig. 3. Section of liver from animal that survived 247 hours after implantation . Note necrosis of hepatic parenchymal cells in central portion of lobule with viable parenchymal cells near periphery of lobule. (Hematoxylin and eosin ; original magnification x IOO.)
crosis (Fig. 4) with focal areas of cortical infarction. The other organs studied primarily showed congestion and edema. Even though there were extensive changes in the lungs, livers, and kidneys of the above animals, the most important contributing cause of death in the 190, 220, and 247 hour survivors was irreversible hypotension, attributable to gram-negative sepsis. Escherichia coli and Pseudomonas aeruginosa were isolated from the blood of the above animals. Extreme stress factors resulting from implantation of the device were also thought to contribute to the terminal stages of extreme hypotension. Discussion
Previous studies showed that sheep in which a total artificial heart had been im-
The Journol of Thorocic ond Cordiovosculor Surgery
Fig. 4. Section of kidney from calf that survived 247 hours. Note diffuse tubular necrosis. (Hematoxylin and eosin ; original magnification x100.)
planted develop an irreversible "shocklike" state, generally within 18 to 24 hours, with death occurring at a mean time of 25.8 hours. " At necropsy, the latter animals showed massive hemorrhage and segmental infarction throughout the gastrointestinal tract. Other changes included marked ascites, pleural effusion, extreme congestion of the lungs, and multiple infarcts of the kidneys. Microscopic examination revealed severe alterations in the lungs, consisting of extreme congestion, edema, hemorrhage, atelectasis, and interstitial pneumonitis. In addition, many bronchioles were plugged with mucus . The kidneys showed marked tubular necrosis and focal infarctions. The causes of death were presumed to be irreversible shock and respiratory failure . In the above previous studies , a second group of sheep was given antishock therapy beginning at the time of implantation. This
Volume 66 Number 1
Akutsu total artificial heart
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July, 1973
treatment increased the survival time to a mean of 35.4 hours, with a maximum of 60 hours. The treated group at necropsy showed much less severe changes in all organs except the lungs, which showed extreme congestion grossly. Microscopic studies showed the same changes in the lungs as those seen in the nontreated animals. However, there was minimal hemorrhage in the gastrointestinal tract and other morphological signs of profound shock were much less pronounced. Here, too, the causes of death were thought to be irreversible shock and respiratory failure. In the present studies, calves in which a total artificial heart had been implanted showed a much longer survival time than that seen earlier in sheep. The shortest survival time for a calf (i.e., 80 hours) was greater than the longest survival time for a sheep (i.e., 60 hours) in our earlier studies. The latter calf, which survived for only 80 hours, died from a broken left ventricle. One calf survived for 120 hours before dying from hemorrhage due to a tear in the ascending aorta. The calves surviving the longest times (i.e., 190, 220, and 247 hours) showed extensive alterations in the lungs, liver, and kidneys. The terminal phase in the latter animals resulted from gramnegative sepsis with irreversible hypotension. In contrast to the sheep studied, the calves generally showed less severe changes in the lungs and gastrointestinal tract. However, the livers of the longer surviving calves were much more severely altered than those of the sheep. The manifestations of renal injury were generally the same in both species. The changes seen in both species reflect the extreme degree of hypotension present in these animals. The main cause of the hypotension in the calves was gramnegative septic "shock." Extreme physical and psychological stresses produced by implantation of the total heart were also thought to play a role in the production of hypotension. However, the importance of the latter mechanism is unknown at this time. At present, the main problem influencing survival in calves in our laboratory is de-
velopment of irreversible hypotension due to gram-negative sepsis. Technical complications in operations and in the device itself have both played a role in preventing longterm survival. The influence of stress on the development of irreversible hypotension is presently under investigation. Other workers have emphasized the importance of microthromboembolism and disseminated intravascular coagulation in causing death after implantation of total artificial hearts.' However, these findings were not seen in the sheep in our earlier studies. In the present studies, extensive microthromboernbo!ism occurred in the 80, 120, and 220 hour survivors, but only minimal amounts were seen in the 190 hour survivor, and none were seen in the 247 hour survivor. Although microthromboembolism was present in the above animals, the main cause of death in our studies is thought to be gramnegative sepsis with resulting irreversible hypotension.
Summary Calves in which the Akutsu total artificial heart had been implanted survived for 80, 120, 190, 220, and 247 hours, respectively. The 80 hour survivor died as a result of breakage of the left ventricle in the device. The 120 hour survivor died from hemorrhage due to a tear of the aorta. The 190, 220, and 247 hour survivors died as a result of gram-negative sepsis with irreversible hypotension. The lungs consistently showed the most severe alterations, consisting of diffuse congestion, edema, focal hemorrhage, infarction, atelectasis, and pneumonitis. Three of the animals showed numerous microthromboemboli; 2 showed little or none. Hepatic changes varied from marked congestion in some animals to severe diffuse central lobular necrosis with infarction in others. Renal changes varied from focal tubular necrosis in some to diffuse tubular necrosis with infarction in others. The authors wish to thank Judy Fenter for technical assistance and Brenda Watts and Kathy Windham for assistance in the preparation of the manuscript.
The Journal of
10 4
Henson et al.
Thoracic and Cardiovascular Surgery
REFERENCES
2
3
4
5
Akutsu, T., and Kolff, W. J.: Permanent Substitutes for Valves and Hearts, Trans. Am. Soc. Artif. Int. Organs 4: 230, 1958. Atsumi, K., Hori, M., Ikedo, S., Sakurai, Y., Fujimori, Y., and Kimoto, S.: Artificial Heart Incorporated in the Chest, Trans. Am. Soc. Artif. Int. Organs 9: 292, 1963. Cooley, D. A., Liotta, D., Hallman, G. L., Bloodwell, R. D., Leachmen, R. D., and Milam, J. D.: First Human Implantation of Cardiac Prosthesis for Staged Total Replacement of the Heart, Trans. Am. Soc. Artif. Int. Organs 15: 252, 1969. Takano, T., Takagi, H., Turner, M. D., Henson, E. C., Crowell, J. W., and Akutsu, T.: Problems in Total Artificial Heart, Trans. Am. Soc. Artif. Int. Organs 27: 449, 1971. Henson, E. C., Weaver, D. Q., Lockard, V. G.,
Takano, H., Takagi, H., Akutsu, T., Arhelger, R. B., and Brunson, J. G.: Morphologic Alterations in Sheep After Implantation of the Akutsu Total Artificial Heart, Am. J. Pathol. 66: 331, 1972. 6 Akutsu, T., Takano, H., Takagic, H., Turner, M. D., Henson, E. C., and Crowell, J. W.: Pathophysiology and New Problems in Total Artificial Heart, J. THoRAc. CARDIOVASC. SURG. 64: 762, 1972. 7 Kwan-Gett, c, Bakeman, D. K., Donovan, Jr., F. M., Eastwood, N., Foote, J. L., Kawai, J., Kessler, T. R., Kralios, A. c, Peters, J. L., Van Kampen, K. R., Wong, H. K., Zwart, H. H. J., and Kolff, W. J.: Artificial Heart With Hemispherical Ventricles and Disseminated Intravascular Coagulation, Trans. Am. Soc. Artif. Int. Organs 17: 474, 1971.
The first report concerning implantation of a total artificial heart was by Akutsu and Kolff" in 1958. At that time such a device was implanted into a dog which survived for 2 hours. In 1963, Atsumi and associates" attained a maximum of 51;2 hours' survival in dogs in which a two-chambered waterdriven plastic heart was implanted. The latter animals at necropsy showed marked pulmonary edema and hemorrhage, with marked pooling of blood in the abdominal organs. In 1969, Cooley and associates" reported results of implanting separate left and right ventricular units into a human subject. That patient was maintained on these devices for 64 hours and then given a cardiac allograft, but he died 32 hours later. Autopsy revealed necrotizing confluent bronchopneumonia throughout both lungs. Moreover, both kidneys showed marked edema, tubular necrosis, and multiple fibrin thrombi in the glomeruli. It has taken a long while to achieve longterm survival in experimental animals in which a total artificial heart has been imFrom the Departments of Pathology (Drs. Henson and Brunson) and Surgery (Drs. Takagi, Takano, and Akutsu ) , The University of Mississippi Medical Center, Jackson, Miss. 39216. Supported by Contract NIH-69-2185 and Grant HE-06943 and Grant HL-14733-01Al from the U.S. Public Health Service. Received for publication Dec. 5, 1972.
planted. Takano and associates: in 1971 reported a maximum survival time of 60 hours in sheep with such a device, but the mean survival time was approximately one half the maximum. A separate report described in detail the pathological alterations produced in sheep, none of which survived for more than 60 hours after implantation." In the latter studies, sheep given minimal therapy showed a rapid onset of a profound "shocklike" state with a short survival time after implantation. At necropsy, these animals showed extensive changes in almost all major organ systems. Other sheep were given specific antishock therapy after implantation and showed a longer survival time than the untreated group. The pathological changes in the group given antishock therapy were generally less severe than in the nontreated group, but the lungs of both groups showed marked generalized alterations. Death in both groups was due to irreversible hypotension and respiratory failure. Recently, two separate groups of workers reported survival times of longer than 100 hours in calves in which a total artificial heart had been implanted." 7 The present report represents the first detailed study of pathological alterations in animals most of which survived for longer than 100 hours after implantation of a total artificial heart. 99
The Journal of
1 00
Henson et al.
Thoracic and Cardiovascular Surgery
Materials and methods
Five calves, some male and some female, which weighed from 70 to 90 kilograms, were implanted with the Akutsu four-chambered total artificial heart according to methods previously described.' Postoperative care was performed by methods given in the latter report." At the time of death, as determined by the absence of pupillary reflexes, the animals were studied by gross examination, and tissue sections were taken for studies by conventional light microscopy. These tissues were processed and stained with hematoxylin and eosin in the usual fashion. The organs and tissues studied were lungs, kidneys, adrenal glands, gastrointestinal tract, liver, pancreas, spleen, and lymph nodes. Results Clinical course. The five calves studied showed survival times of 80, 120, 190, 220, and 247 hours, respectively, after implantation. The causes of death were as follows: 80 hour survivor, breakage of the left ventricle; 120 hour survivor, tear of the natural aorta with massive hemorrhage; 190 hour survivor, tear of the left ventricle; 220 hour survivor, sepsis and asphyxiation; 247 hour survivor, sepsis. The 80 and 120 hour survivors died very shortly after the respective technical complications occurred. However, the 190, 220, and 247 hour survivors were generally normal until approximately 24 hours prior to death. At that time, each animal developed a "shocklike" state which became profound and irreversible. Details of the clinical course of these animals were given in an earlier report. 6 Pathological studies. At necropsy the calf which survived for 80 hours grossly showed minor pleural effusion and marked congestion of both lungs. There were no ascites, minimal congestion of the gastrointestinal tract, and no intraluminal hemorrhage. The liver and gallbladder were moderately congested but otherwise unremarkable. The kidneys had a pale, swollen cortex but were otherwise grossly unremarkable. The spleen was markedly contracted but otherwise un-
remarkable. The other organs studied were generally unremarkable. Microscopic observations of the tissues from the 80 hour survivor showed the lungs to have severe congestion, interstitial edema, mild focal hemorrhage, mild interstitial pneumonitis, and moderate atelectasis. However, the most marked alteration in the lungs was the presence of multiple microthromboemboli, primarily in the alveolar capillaries. The kidneys exhibited marked edema and focal necrosis of the proximal tubules. Distal tubules and collecting ducts in the above focal areas were filled with red blood cells and casts. Certain focal areas revealed hemorrhage of the glomerular capillaries, with numerous red blood cells in the lumens of adjacent tubules. The liver showed moderate fat accumulation in the hepatocytes, early focal central lobular necrosis, marked congestion, and edema. Alterations in the other organs were generally unremarkable, except for the presence of moderate congestion and edema. The animals which survived for longer than 100 hours (i.e., 120, 190, 220, and 247 hours) showed moderate pleural effusion and most showed marked ascites. The lungs generally showed moderate amounts of viscous bloody fluid in the tracheobronchial tree. The lungs also showed marked to severe consolidation with varying degrees of hemorrhage and infarction. The gastrointestinal tract showed moderate to severe congestion, edema, and intraluminal hemorrhage. The livers of these animals generally showed moderate to severe congestion and edema. Two of the animals (i.e., the 220 and 247 hour survivors) showed multiple focal areas of infarction of the liver, which varied in size from 0.5 to 3 em. in diameter, and diffuse softening with early signs of necrosis. The 247 hour survivor was grossly markedly jaundiced. The other animals showed marked softening of the liver, suggestive of early diffuse necrosis, without focal areas of frank advanced necrosis. The kidneys of the animals which survived longer than 100 hours showed focal areas of frank cortical infarction. These areas varied in
Volume 66 Number 1
Akutsu total artificial heart
10 1
July, 1973
Fig. 1. Section of lung from calf that survived 220 hours after cardiac implantation. Note con gestion, hemorrhage, interstitial edema, and atelectasis . There is also mild bronchial pneumonitis . (Hematoxylin and eosin; original magnification x 100.)
size from approximately 0.2 em. in diameter to those which included as much as one third of the surface area of the cortex. On cut section, these infarcts were found to extend for variable distances into the medulla. Cut sections also revealed significant thickening of the cortex of all kidneys, suggestive of marked edema. The other organs studied exhibited varied degrees of congestion but were otherwise grossly unremarkable. Microscopic examination of the animals which survived more than 100 hours showed the lungs to have moderate to severe diffuse congestion, focal hemorrhage, interstitial and alveolar edema , atelectasis , and bronchial pneumonia (Fig. I) . In addition there were focal areas of infarction. The
Fig. 2. High magnification of lung from calf that survived 220 hours, showing thrombosis of pulmonary alveolar capillary. (Hematoxylin and eosin; original magnification x l ,OOO. )
animals which survived for 120 and 220 hours showed an abundance of microthromboemboli in the pulmonary alveolar capillaries (Fig. 2) . The 190 hour survivor showed minimal amounts of microthromboemboli in the lungs; none was seen in the lungs of the 247 hour survivor. The gastrointestinal tracts in the above 4 animals showed marked congestion, edema, and varying degrees of sloughing of the mucosal epithelium , as well as focal areas of hemorrhage into the lumen of the stomach and intestines. The livers showed changes which varied from congestion only to severe diffuse central lobular necrosis (Fig. 3) . All animals studied showed marked to severe changes in hepatic parenchymal cells which varied from marked accumulation of fat to frank necrosis. The kidneys of all four of the latter animals showed marked tubular ne-
1
°
2
Henson et at.
Fig. 3. Section of liver from animal that survived 247 hours after implantation . Note necrosis of hepatic parenchymal cells in central portion of lobule with viable parenchymal cells near periphery of lobule. (Hematoxylin and eosin ; original magnification x IOO.)
crosis (Fig. 4) with focal areas of cortical infarction. The other organs studied primarily showed congestion and edema. Even though there were extensive changes in the lungs, livers, and kidneys of the above animals, the most important contributing cause of death in the 190, 220, and 247 hour survivors was irreversible hypotension, attributable to gram-negative sepsis. Escherichia coli and Pseudomonas aeruginosa were isolated from the blood of the above animals. Extreme stress factors resulting from implantation of the device were also thought to contribute to the terminal stages of extreme hypotension. Discussion
Previous studies showed that sheep in which a total artificial heart had been im-
The Journol of Thorocic ond Cordiovosculor Surgery
Fig. 4. Section of kidney from calf that survived 247 hours. Note diffuse tubular necrosis. (Hematoxylin and eosin ; original magnification x100.)
planted develop an irreversible "shocklike" state, generally within 18 to 24 hours, with death occurring at a mean time of 25.8 hours. " At necropsy, the latter animals showed massive hemorrhage and segmental infarction throughout the gastrointestinal tract. Other changes included marked ascites, pleural effusion, extreme congestion of the lungs, and multiple infarcts of the kidneys. Microscopic examination revealed severe alterations in the lungs, consisting of extreme congestion, edema, hemorrhage, atelectasis, and interstitial pneumonitis. In addition, many bronchioles were plugged with mucus . The kidneys showed marked tubular necrosis and focal infarctions. The causes of death were presumed to be irreversible shock and respiratory failure . In the above previous studies , a second group of sheep was given antishock therapy beginning at the time of implantation. This
Volume 66 Number 1
Akutsu total artificial heart
10 3
July, 1973
treatment increased the survival time to a mean of 35.4 hours, with a maximum of 60 hours. The treated group at necropsy showed much less severe changes in all organs except the lungs, which showed extreme congestion grossly. Microscopic studies showed the same changes in the lungs as those seen in the nontreated animals. However, there was minimal hemorrhage in the gastrointestinal tract and other morphological signs of profound shock were much less pronounced. Here, too, the causes of death were thought to be irreversible shock and respiratory failure. In the present studies, calves in which a total artificial heart had been implanted showed a much longer survival time than that seen earlier in sheep. The shortest survival time for a calf (i.e., 80 hours) was greater than the longest survival time for a sheep (i.e., 60 hours) in our earlier studies. The latter calf, which survived for only 80 hours, died from a broken left ventricle. One calf survived for 120 hours before dying from hemorrhage due to a tear in the ascending aorta. The calves surviving the longest times (i.e., 190, 220, and 247 hours) showed extensive alterations in the lungs, liver, and kidneys. The terminal phase in the latter animals resulted from gramnegative sepsis with irreversible hypotension. In contrast to the sheep studied, the calves generally showed less severe changes in the lungs and gastrointestinal tract. However, the livers of the longer surviving calves were much more severely altered than those of the sheep. The manifestations of renal injury were generally the same in both species. The changes seen in both species reflect the extreme degree of hypotension present in these animals. The main cause of the hypotension in the calves was gramnegative septic "shock." Extreme physical and psychological stresses produced by implantation of the total heart were also thought to play a role in the production of hypotension. However, the importance of the latter mechanism is unknown at this time. At present, the main problem influencing survival in calves in our laboratory is de-
velopment of irreversible hypotension due to gram-negative sepsis. Technical complications in operations and in the device itself have both played a role in preventing longterm survival. The influence of stress on the development of irreversible hypotension is presently under investigation. Other workers have emphasized the importance of microthromboembolism and disseminated intravascular coagulation in causing death after implantation of total artificial hearts.' However, these findings were not seen in the sheep in our earlier studies. In the present studies, extensive microthromboernbo!ism occurred in the 80, 120, and 220 hour survivors, but only minimal amounts were seen in the 190 hour survivor, and none were seen in the 247 hour survivor. Although microthromboembolism was present in the above animals, the main cause of death in our studies is thought to be gramnegative sepsis with resulting irreversible hypotension.
Summary Calves in which the Akutsu total artificial heart had been implanted survived for 80, 120, 190, 220, and 247 hours, respectively. The 80 hour survivor died as a result of breakage of the left ventricle in the device. The 120 hour survivor died from hemorrhage due to a tear of the aorta. The 190, 220, and 247 hour survivors died as a result of gram-negative sepsis with irreversible hypotension. The lungs consistently showed the most severe alterations, consisting of diffuse congestion, edema, focal hemorrhage, infarction, atelectasis, and pneumonitis. Three of the animals showed numerous microthromboemboli; 2 showed little or none. Hepatic changes varied from marked congestion in some animals to severe diffuse central lobular necrosis with infarction in others. Renal changes varied from focal tubular necrosis in some to diffuse tubular necrosis with infarction in others. The authors wish to thank Judy Fenter for technical assistance and Brenda Watts and Kathy Windham for assistance in the preparation of the manuscript.
The Journal of
10 4
Henson et al.
Thoracic and Cardiovascular Surgery
REFERENCES
2
3
4
5
Akutsu, T., and Kolff, W. J.: Permanent Substitutes for Valves and Hearts, Trans. Am. Soc. Artif. Int. Organs 4: 230, 1958. Atsumi, K., Hori, M., Ikedo, S., Sakurai, Y., Fujimori, Y., and Kimoto, S.: Artificial Heart Incorporated in the Chest, Trans. Am. Soc. Artif. Int. Organs 9: 292, 1963. Cooley, D. A., Liotta, D., Hallman, G. L., Bloodwell, R. D., Leachmen, R. D., and Milam, J. D.: First Human Implantation of Cardiac Prosthesis for Staged Total Replacement of the Heart, Trans. Am. Soc. Artif. Int. Organs 15: 252, 1969. Takano, T., Takagi, H., Turner, M. D., Henson, E. C., Crowell, J. W., and Akutsu, T.: Problems in Total Artificial Heart, Trans. Am. Soc. Artif. Int. Organs 27: 449, 1971. Henson, E. C., Weaver, D. Q., Lockard, V. G.,
Takano, H., Takagi, H., Akutsu, T., Arhelger, R. B., and Brunson, J. G.: Morphologic Alterations in Sheep After Implantation of the Akutsu Total Artificial Heart, Am. J. Pathol. 66: 331, 1972. 6 Akutsu, T., Takano, H., Takagic, H., Turner, M. D., Henson, E. C., and Crowell, J. W.: Pathophysiology and New Problems in Total Artificial Heart, J. THoRAc. CARDIOVASC. SURG. 64: 762, 1972. 7 Kwan-Gett, c, Bakeman, D. K., Donovan, Jr., F. M., Eastwood, N., Foote, J. L., Kawai, J., Kessler, T. R., Kralios, A. c, Peters, J. L., Van Kampen, K. R., Wong, H. K., Zwart, H. H. J., and Kolff, W. J.: Artificial Heart With Hemispherical Ventricles and Disseminated Intravascular Coagulation, Trans. Am. Soc. Artif. Int. Organs 17: 474, 1971.