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Regional Hypothermia in Acute Renal Ischemia
THE JOURNAL OF UROLOGY
Vol. 79, No.!5, May 1958
Printed in U.S.A.
REGIONAL HYPOTHERMIA IN ACUTE RENAL ISCHEMIA PAUL J. STUEBER, JR., STEVEN KOVACS, SIMON KOLETSKY AND LESTER PERSKY
From the Department of Surgery, Urological and Anesthesiology Services, and the Institute of Pathology, Western Reserve University School of Medicine and the University Hospitals of Cleveland, Ohio
In recent years, during the course of extensive renal and vascular surgery, the renal blood flow has been frequently interrupted for more protracted periods than heretofore. At the present time, sufficient laboratory data are available to suggest that there is a limit to the period of temporary renal anoxia compatible with survival.1• 2 • 3 This limit, which varies from species to species, may be measured by survival of an animal or histological examination of the organ when anoxia has been unilateral. Litten, 4 in 1880 demonstrated that the renal pedicle could be occluded for one hour before microscopic damage could be observed upon subsequent section. Eisendrath and Strauss5 in 1910 studied the changes in the kidneys of rabbits and found residual evidence of injury occurring four weeks after a period of fifteen minutes of temporary anoxia. George Prather 6 has suggested the clinical use of a rubber-shod pedicle clamp to occlude the renal hilar vessels during the removal of large branching calculi, but cautioned that such should be released at eight to ten minute intervals. Longer periods of anoxia were recently studied by Van Slyke and associates, 1 using previously unilateral nephrectomized dogs. In their experiments, occlusion of the renal artery and vein for three hours resulted in a brief period of anuria followed in two to three days by a gradual rise of the blood urea nitrogen to approximately 150 mg. per 100 ml. By the fourth day however, a gradual return to normal levels was noted. Survival in this group was close to 100 per cent. If the period of anoxia was extended to four hours 50 per cent of the animals died, and if extended to six hours, the mortality was 100 per cent. There is little doubt that occlusion of both artery and vein appears to be better tolerated than occlusion of the vein alone, as demonstrated by C. W. Vermeulen. 7 It is possible that pre-existing renal damage enhances the likelihood of increased injury by anoxia, and a relatively brief period of anoxia in an already diseased kidney may be equivalent to a much longer period in the normal organ. ThereSupported in part by the Beaumont Fund, Cleveland, Ohio. Read at annual meeting of North Central Section of American Urological Association, Mackinac Island, Mich., August 29-31, 1957. 1 Van Slyke, D.: Effects of shock on the kidneys. Tr. A. Am. Phys., 58: 119, 1944. 2 Koletsky, S. and Gustafson, G. E.: The effects of temporary cessation of renal blood flow in rats. J. Clin. Investig., 26: 1072, 1947. 3 Koletsky, S.: Effects of temporary interruption of renal circulation in rats. Arch. Path., 58: 592, 1954. 4 Litten, M.: Untersuchungen uber den haemorrhagischen Infarct und uber die Einwirkung arterieller Anaemie auf lebende Gewebe. Ztschr. f. klin Med., 1: 131, 1880. 5 Eisendrath, E. and Stauss, D. C.: The effect on the kidney of temporary compression of its vessels. J.A.M.A., 55: 2286, 1910. 6 Prather, G. C. : Method of hemostasis during nephrostomy. J. U rol., 32: 578, 1934. 7 Scheibe, J. R., Giraldi, E. and Vermeulen, C. W.: The effect of temporary renal vascular occlusion on kidney function. Surgery, 25: 724-729, 1949. 793
794
STUEBER, KOVACS, KOLETSKY AND PERSKY
fore, an attempt was made to utilize the effect of regional hypothermia to decrease tissue oxygen demands during periods of renal ischemia. Generalized hypothermia, while desirable in some situations, carries with it certain side effects which are significant and which may be avoided by localized cooling. It is technically difficult to produce generalized hypothermia. Even with moderate degrees of cooling, cardiac irregularities are common. To produce temperatures adequate to protect the kidney from anoxic damage, as found necessary in our experiments, fibrillation and cardiac standstill would result. The rewarming of the entire body is a tedious process and several complications may arise at this point again; the complete derangement of the temperature regulating mechanisms has been frequently observed. Although the literature concerning generalized hypothermia is abundant, only recently attention has been paid to the effects of hypothermia on renal function. 8 A few reports deal with the survival and late effects of hypothermia during the periods of renal pedicle occlusion. Utilizing generalized hypothermia Harsing, Jellinek and associates 9 in Budapest, Hungary in 1956 reported a 100 per cent survival following a four-hour period of renal pedicle occlusion when the rectal temperature of dogs had been lowered to 22 to 24 degrees centigrade. The same group reported a 30 per cent survival in non-cooled animals. Localized hypothermia has been applied to renal autografts in sheep by Mitchell and W oodruff10 in New Zealand with interesting results. In these transplanted kidneys, when the renal temperature was above 25 degrees centigrade, all the animals died after a two-hour period of ischemia. All the animals survived however, if the kidney was locally cooled to between 10 and 20 degrees centigrade. The purpose of our study was to re-define the period of renal anoxia that is compatible with survival in the dog. Secondly, the effects of regional cooling of the kidney during prolonged periods of acute renal ischemia were followed and correlated with the survival of the animals, the histological changes found in the kidney, and with the course of the blood urea nitrogen. Thirdly, an attempt was made to pinpoint the optimum temperature for kidney survival during and following the anoxic period. PROCEDURE
Adult mongrel dogs underwent right nephrectomy at least two weeks prior to the experimental period. Under general intravenous sodium pentobarbital anesthesia the remaining left kidney was delivered through a muscle-splitting left lumbar incision. The perirenal fat was stripped from the capsule, and any communicating capsular vessels tied. The ureter was dissected free from the pedicle, and then the artery and vein were stripped of some, but not all, of the fat nerves. To combat intrarenal thrombosis, 1 cc heparin diluted with 4 cc of 8 Moyer, J. H., Morris, G. and DeBakey, M. E.: Hypothermia-effect on renal hemodynamics and on excretion of water and electrolytes in dog and man. Ann. Surg., 145: 26-40, 1957. 9 Harsing, L., Jellinek, H., Kover, G., Laszlo, K., Veghelyi, P., and Fony6di, S.: The effect of ischemic changes in the kidney. Acta Physiol., 4: 429-436, 1956. 10 Mitchell, R. M. and Woodruff, M. F. A.: The effects of local hypothermia in increasing tolerance of kidney to ischeTUia. Transplantation Bull., 4: 15, 1957.
HYPOTHERMIA IN ACUTE RENAL ISCHEMIA
795
Heparin Injection Prior to clamping the Blood Supply
Fm. 1. Technique of injection of renal artery with heparin solution with clamp in position for immediate application.
normal saline was injected into the renal artery immediately before a "bulldog" rubber-shod clamp was closed on both artery and vein (fig. 1). An additional clamp secured the tips of the "bulldog" to insure complete occlusion of the pedicle. Temperature of the kidney was recorded by means of a small glass thermometer inserted through a stab wound into the renal substance. Room temperature and rectal temperature were recorded continuously throughout the procedure. Each animal received 500 cc of 5 per cent glucose in distilled water intravenously during the period of occlusion which lasted six hours in every instance. At the end of the six-hour period, the "bulldog" clamp was released; pulsation was palpated in the segment of the artery distal to the clamp and filling of the vein was observed. The kidney was then replaced in the renal fossa, the wound closed and the dogs followed until death or sacrifice. At this time, the renal size was measured and compared with measurements obtained prior to the period of acute anoxia. The kidneys were then fixed and submitted for pathological study. In the control group of 10 dogs, the kidney was left exposed to room temperature covered only by a gauze sponge and protected from the warmth of the animal by an asbestos pad. In the experimental group of 10 dogs, the kidney was cooled during the period of anoxia by a plastic jacket* surrounding the kidney but similarly insulated from the animal (fig. 2, A). By means of a contiimous flow of cold water regulated by rate and temperature, we were able to keep the temperature between 20 and 25 degrees centigrade during the period (fig. 2, B). The kidneys of the third group of animals underwent additional lowering of the temperature to 10 to 15 degrees centigrade by circulation of a salt and water mixture through the plastic jacket. * Plastic Dispoza Bag (C.R. Bard, Inc., Summit, N. J.)
796
STUEBER, KOVACS, KOLETSKY AND PERSKY
A
KIDNEY SURROUNDED BY PLASTIC WATER JACKET
!\REPARATION
COMPLETE
Inflow Cooling
~-.
\ FIG. 2. A, experimental kidney surrounded. by plastic jacket through which cooling solution flows. B, experimental animal with thermometer in kidney, rectum and with cooling solution flowing through plastic jacket. Longest and shortest days of survival for control and experimental groups.
Blood urea nitrogen was used to follow renal function during the procedure and subsequent days. A blood urea nitrogen was drawn at the start and end of the acute period of anoxia and daily for the next four days. Subsequent readings were taken at three to seven-day intervals. RESUL'l'S
In the control series, at the end of a six-hour period of anoxia, the kidney appeared dark-blue, mottled and devitalized. After release of the pedicle clamp, the general appearance improved with oozing from the surface vessels and the site of the temperature recording incision. This bleeding was easily controlled ,vith mattress hemostatic sutures in all caees before the kidney was replaced in the wound. The dogs of this group usually went through a period of anuria of one to two days' duration followed by a gradually increased urinary output. The animals appeared lethargic and frequently refused to eat. Usually by the third day they would take a small amount of milk or water. Nevertheless, there was
797
HYPOTHERMIA IN ACUTE RENAL ISCHEMIA
a 100 per cent mortality with death usually occurring in four to five days. In the experimental group where the renal temperature was reduced to 20 to 25 degrees centigrade, 30 per cent of the animals survived and were sacrificed after eight weeks. In group three, in which the kidney temperature was dropped even lower to between 10 and 15 degrees centigrade, a 75 per cent survival was found. A remarkable difference in gross appearance of the kidney at the end of the sixhour period of ischemia was noticed after cooling at either level. Instead of being dark-blue and mottled, the kidney appeared rather pale, smaller than normal and pinked up upon release of the pedicle much more rapidly than in the control group. After a few minutes, the kidney returned to its preoperative size, and at the time of sacrifice, the kidney's gross measurements were equal TABLE
1. Longest and shortest days of survival for control and experimental groups
Group 1 .... . Group 2 ... . Group 3 ..
Shortest Day Survival
Longest Day Survival
2
15 60+ 60+
5 12
BUN 240 ·230
220 210 200 190 180 1 70
160
!50 12---Q
CONTROL ROOM TEMP. U-38U-46 COOLING 20°- 25°C U-27U-61 COOLING I 0°- I 5°C U-75U-77
2
10 ldaw2
3
4
5
6
7
B
9 10 II
12 13 2wk1
3
4
5
6
7
8
I
Fw. 3. Typical curves of blood urea nitrogen changes in each group. Blood urea nitrogen of control animals shows rapid rise until death. Curve for experimental group demonstrates gradual recovery until normal values are obtained.
798
STUEBER, KOVACS, KOLETSKY AND PERSKY
to the size postoperatively. Survival periods in terms of the shortest and longest duration of survival for each group are shown in table 1. The blood urea nitrogen in the control group showed a rapid elevation which usually continued to rise until death. In the 20 to 25 degrees centigrade kidneys there was also a rapid rise, which usually declined slowly after four days. In the last group, the rise was more gradual, the peak was lower and the normal levels were again obtained after two weeks. In figure 3 two representative curves are shown for each group. PATHOLOGICAL OBSERVATIONS
All but two of the control animals were autopsied within one week after the six-hour period of complete renal ischemia. The kidneys presented a bulging cortex with indistinct architectural pattern. The medulla was usually dark red in its entirety or in the outer juxtacortical portion. The kidneys of the experimental dogs, most of which were examined within twelve days after the period of ischemia, were either pale throughout and slightly enlarged or within normal
Fm. 4. A, massive tubular necrosis in control dogs 3 days after a 6-hour period of complete renal ischemia. B, marked tubular necrosis in control dog 3 days after a 6-hour period of complete renal ischemia. H & E X 126.
HYI'OTI-rnmVIL\. IN ACUTE RE;\TAL ISCI-IEMIA
799
limits in gross appearance and size. An oe:casionnl animal in both control and treated groups showed small recent cortical infarcts. ;\ifie:roscopie:ally, in all animals which died the principal lesion coagulation necrosis of the proximal convoluted tubules. There Yms tion of the lining loss of nuclei, and blockage of lumens by coarse acidophilic debric1. Supcrimprn,e:d e:alcific deposit wm; frequently observed. The glomeruli ,vere intact and neither the loops of Henle nor the distal convoluted segmentt, of the nephron participated in the necro~is. pink-staining eastc: were m1merous, especially in the collecting tubules. There were focal regions of interstitial lymphocytie: exudate in the Yicinity of necrotic tubules. afte1 In the control almost all of which died within a fe11· to several circulation ,Yas restored, the tubular necrosis ,Yai:i widespread and nuiss1ye (fig. 4, il). The entire proximal tubule ,rns involved, including the or spiral segments, and repair was usually minimal or slight (fig '1, B). The necrotic lesion in the experiment,al animals was ,;imilarly but, less
:Fm, 5. Kidney of experimental dog 7 days after inierrupLion of renal eirculation for G hours. Slight necrosis of tllhules. large!)· repaired, and focal ealcific deposit. B, kidney experimental dog 8 days after interruption of renal eircnlation for 6 honrn. Slight tubular necrosis ,Yith repair. H & EX 126.
800
STUEBER, KOVACS, KOLETSKY AND PERSKY
severe in extent and distribution. In fact, in most instances the renal damage was comparatively slight or minimal and consisted merely of focal degeneration or necrosis of the proximal tubules (fig. 5, A). Widespread massive tubular destruction did not occur in any of the animals. Repair was fairly rapid and within one or two weeks debris was cleared and new cells lined the dilated tubules. There was focal calcific deposit. Dogs sacrificed eight weeks after renewal of the rena.l circulation showed practically normal kidneys (fig. 5, B). DISCUSSION
These studies therefore demonstrate conclusively that localized cooling offers protection in the face of a severe, protracted period of renal anoxia. The percentage of survival of these animals, the less severe elevation of the blood urea nitrogen with hypothermia, and the microscopic evidence of less severe injury are consistent throughout. Although this is a preliminary report, and further levels of cooling are to be explored, these data to date suggest that temperatures from 10 to 15 degrees offer the maximum protection. This degree of cooling, -which could not be attained by generalized hypothermia without derangeinent of the body temperature control centers, or the development of cardiac arrhythmias, could easily be attained at surgery. In the large aortic aneurysms involving the renal vessels or in dissecting aneurysms its application might prove efficacious in avoiding the oliguria and anuria seen subsequently.10 The urologist, in the case of large branching calculi, where extensive nephrotomy is indicated, or in the segmental replacement of renal arteries, similarly might find it effective. It is possible that in certain situations combined generalized and regional hypothermia may be used concomitantly. This might be especially applicable in the case of the previously mentioned large abdominal aneurysms when separation of the kidney from its blood supply is necessary during aortic replacement. It seems unlikely that its use can successfully be extended to the clinical situation::, of anuria, the so-called acute tubular necroses, where the microscopic picture is so similar. Here the difficulty of achieving regional cooling in a critically ill patient would prohibit its usefulness. If renal homotransplantation becomes a clinical reality, cooling the graft may aid in its survival. Prolonged studies are contemplated to determine if ultimate renal dysfunction and hypertension will develop. Also, it is hoped to ascertain if cooling will protect the already damaged kidney during various manipulative procedures. In general, we feel that regional hypothermia is a potentially valuable tool for the urological surgeon. SUMMARY
A six-hour period of acute renal ischemia at room temperatures results in 100 per cent mortality in the dog. In experimental groups, with applied regional hypothermia (20° and 10°C) 30 per cent and 75 per cent survival was achieved. Histological studies showed proximal tubular damage with less severe degrees of injury in the cooled group. Renal function measured by blood urea nitrogen levels showed a significant protection afforded by hypothermia during the period of anoxia.
Vol. 79, No.!5, May 1958
Printed in U.S.A.
REGIONAL HYPOTHERMIA IN ACUTE RENAL ISCHEMIA PAUL J. STUEBER, JR., STEVEN KOVACS, SIMON KOLETSKY AND LESTER PERSKY
From the Department of Surgery, Urological and Anesthesiology Services, and the Institute of Pathology, Western Reserve University School of Medicine and the University Hospitals of Cleveland, Ohio
In recent years, during the course of extensive renal and vascular surgery, the renal blood flow has been frequently interrupted for more protracted periods than heretofore. At the present time, sufficient laboratory data are available to suggest that there is a limit to the period of temporary renal anoxia compatible with survival.1• 2 • 3 This limit, which varies from species to species, may be measured by survival of an animal or histological examination of the organ when anoxia has been unilateral. Litten, 4 in 1880 demonstrated that the renal pedicle could be occluded for one hour before microscopic damage could be observed upon subsequent section. Eisendrath and Strauss5 in 1910 studied the changes in the kidneys of rabbits and found residual evidence of injury occurring four weeks after a period of fifteen minutes of temporary anoxia. George Prather 6 has suggested the clinical use of a rubber-shod pedicle clamp to occlude the renal hilar vessels during the removal of large branching calculi, but cautioned that such should be released at eight to ten minute intervals. Longer periods of anoxia were recently studied by Van Slyke and associates, 1 using previously unilateral nephrectomized dogs. In their experiments, occlusion of the renal artery and vein for three hours resulted in a brief period of anuria followed in two to three days by a gradual rise of the blood urea nitrogen to approximately 150 mg. per 100 ml. By the fourth day however, a gradual return to normal levels was noted. Survival in this group was close to 100 per cent. If the period of anoxia was extended to four hours 50 per cent of the animals died, and if extended to six hours, the mortality was 100 per cent. There is little doubt that occlusion of both artery and vein appears to be better tolerated than occlusion of the vein alone, as demonstrated by C. W. Vermeulen. 7 It is possible that pre-existing renal damage enhances the likelihood of increased injury by anoxia, and a relatively brief period of anoxia in an already diseased kidney may be equivalent to a much longer period in the normal organ. ThereSupported in part by the Beaumont Fund, Cleveland, Ohio. Read at annual meeting of North Central Section of American Urological Association, Mackinac Island, Mich., August 29-31, 1957. 1 Van Slyke, D.: Effects of shock on the kidneys. Tr. A. Am. Phys., 58: 119, 1944. 2 Koletsky, S. and Gustafson, G. E.: The effects of temporary cessation of renal blood flow in rats. J. Clin. Investig., 26: 1072, 1947. 3 Koletsky, S.: Effects of temporary interruption of renal circulation in rats. Arch. Path., 58: 592, 1954. 4 Litten, M.: Untersuchungen uber den haemorrhagischen Infarct und uber die Einwirkung arterieller Anaemie auf lebende Gewebe. Ztschr. f. klin Med., 1: 131, 1880. 5 Eisendrath, E. and Stauss, D. C.: The effect on the kidney of temporary compression of its vessels. J.A.M.A., 55: 2286, 1910. 6 Prather, G. C. : Method of hemostasis during nephrostomy. J. U rol., 32: 578, 1934. 7 Scheibe, J. R., Giraldi, E. and Vermeulen, C. W.: The effect of temporary renal vascular occlusion on kidney function. Surgery, 25: 724-729, 1949. 793
794
STUEBER, KOVACS, KOLETSKY AND PERSKY
fore, an attempt was made to utilize the effect of regional hypothermia to decrease tissue oxygen demands during periods of renal ischemia. Generalized hypothermia, while desirable in some situations, carries with it certain side effects which are significant and which may be avoided by localized cooling. It is technically difficult to produce generalized hypothermia. Even with moderate degrees of cooling, cardiac irregularities are common. To produce temperatures adequate to protect the kidney from anoxic damage, as found necessary in our experiments, fibrillation and cardiac standstill would result. The rewarming of the entire body is a tedious process and several complications may arise at this point again; the complete derangement of the temperature regulating mechanisms has been frequently observed. Although the literature concerning generalized hypothermia is abundant, only recently attention has been paid to the effects of hypothermia on renal function. 8 A few reports deal with the survival and late effects of hypothermia during the periods of renal pedicle occlusion. Utilizing generalized hypothermia Harsing, Jellinek and associates 9 in Budapest, Hungary in 1956 reported a 100 per cent survival following a four-hour period of renal pedicle occlusion when the rectal temperature of dogs had been lowered to 22 to 24 degrees centigrade. The same group reported a 30 per cent survival in non-cooled animals. Localized hypothermia has been applied to renal autografts in sheep by Mitchell and W oodruff10 in New Zealand with interesting results. In these transplanted kidneys, when the renal temperature was above 25 degrees centigrade, all the animals died after a two-hour period of ischemia. All the animals survived however, if the kidney was locally cooled to between 10 and 20 degrees centigrade. The purpose of our study was to re-define the period of renal anoxia that is compatible with survival in the dog. Secondly, the effects of regional cooling of the kidney during prolonged periods of acute renal ischemia were followed and correlated with the survival of the animals, the histological changes found in the kidney, and with the course of the blood urea nitrogen. Thirdly, an attempt was made to pinpoint the optimum temperature for kidney survival during and following the anoxic period. PROCEDURE
Adult mongrel dogs underwent right nephrectomy at least two weeks prior to the experimental period. Under general intravenous sodium pentobarbital anesthesia the remaining left kidney was delivered through a muscle-splitting left lumbar incision. The perirenal fat was stripped from the capsule, and any communicating capsular vessels tied. The ureter was dissected free from the pedicle, and then the artery and vein were stripped of some, but not all, of the fat nerves. To combat intrarenal thrombosis, 1 cc heparin diluted with 4 cc of 8 Moyer, J. H., Morris, G. and DeBakey, M. E.: Hypothermia-effect on renal hemodynamics and on excretion of water and electrolytes in dog and man. Ann. Surg., 145: 26-40, 1957. 9 Harsing, L., Jellinek, H., Kover, G., Laszlo, K., Veghelyi, P., and Fony6di, S.: The effect of ischemic changes in the kidney. Acta Physiol., 4: 429-436, 1956. 10 Mitchell, R. M. and Woodruff, M. F. A.: The effects of local hypothermia in increasing tolerance of kidney to ischeTUia. Transplantation Bull., 4: 15, 1957.
HYPOTHERMIA IN ACUTE RENAL ISCHEMIA
795
Heparin Injection Prior to clamping the Blood Supply
Fm. 1. Technique of injection of renal artery with heparin solution with clamp in position for immediate application.
normal saline was injected into the renal artery immediately before a "bulldog" rubber-shod clamp was closed on both artery and vein (fig. 1). An additional clamp secured the tips of the "bulldog" to insure complete occlusion of the pedicle. Temperature of the kidney was recorded by means of a small glass thermometer inserted through a stab wound into the renal substance. Room temperature and rectal temperature were recorded continuously throughout the procedure. Each animal received 500 cc of 5 per cent glucose in distilled water intravenously during the period of occlusion which lasted six hours in every instance. At the end of the six-hour period, the "bulldog" clamp was released; pulsation was palpated in the segment of the artery distal to the clamp and filling of the vein was observed. The kidney was then replaced in the renal fossa, the wound closed and the dogs followed until death or sacrifice. At this time, the renal size was measured and compared with measurements obtained prior to the period of acute anoxia. The kidneys were then fixed and submitted for pathological study. In the control group of 10 dogs, the kidney was left exposed to room temperature covered only by a gauze sponge and protected from the warmth of the animal by an asbestos pad. In the experimental group of 10 dogs, the kidney was cooled during the period of anoxia by a plastic jacket* surrounding the kidney but similarly insulated from the animal (fig. 2, A). By means of a contiimous flow of cold water regulated by rate and temperature, we were able to keep the temperature between 20 and 25 degrees centigrade during the period (fig. 2, B). The kidneys of the third group of animals underwent additional lowering of the temperature to 10 to 15 degrees centigrade by circulation of a salt and water mixture through the plastic jacket. * Plastic Dispoza Bag (C.R. Bard, Inc., Summit, N. J.)
796
STUEBER, KOVACS, KOLETSKY AND PERSKY
A
KIDNEY SURROUNDED BY PLASTIC WATER JACKET
!\REPARATION
COMPLETE
Inflow Cooling
~-.
\ FIG. 2. A, experimental kidney surrounded. by plastic jacket through which cooling solution flows. B, experimental animal with thermometer in kidney, rectum and with cooling solution flowing through plastic jacket. Longest and shortest days of survival for control and experimental groups.
Blood urea nitrogen was used to follow renal function during the procedure and subsequent days. A blood urea nitrogen was drawn at the start and end of the acute period of anoxia and daily for the next four days. Subsequent readings were taken at three to seven-day intervals. RESUL'l'S
In the control series, at the end of a six-hour period of anoxia, the kidney appeared dark-blue, mottled and devitalized. After release of the pedicle clamp, the general appearance improved with oozing from the surface vessels and the site of the temperature recording incision. This bleeding was easily controlled ,vith mattress hemostatic sutures in all caees before the kidney was replaced in the wound. The dogs of this group usually went through a period of anuria of one to two days' duration followed by a gradually increased urinary output. The animals appeared lethargic and frequently refused to eat. Usually by the third day they would take a small amount of milk or water. Nevertheless, there was
797
HYPOTHERMIA IN ACUTE RENAL ISCHEMIA
a 100 per cent mortality with death usually occurring in four to five days. In the experimental group where the renal temperature was reduced to 20 to 25 degrees centigrade, 30 per cent of the animals survived and were sacrificed after eight weeks. In group three, in which the kidney temperature was dropped even lower to between 10 and 15 degrees centigrade, a 75 per cent survival was found. A remarkable difference in gross appearance of the kidney at the end of the sixhour period of ischemia was noticed after cooling at either level. Instead of being dark-blue and mottled, the kidney appeared rather pale, smaller than normal and pinked up upon release of the pedicle much more rapidly than in the control group. After a few minutes, the kidney returned to its preoperative size, and at the time of sacrifice, the kidney's gross measurements were equal TABLE
1. Longest and shortest days of survival for control and experimental groups
Group 1 .... . Group 2 ... . Group 3 ..
Shortest Day Survival
Longest Day Survival
2
15 60+ 60+
5 12
BUN 240 ·230
220 210 200 190 180 1 70
160
!50 12---Q
CONTROL ROOM TEMP. U-38U-46 COOLING 20°- 25°C U-27U-61 COOLING I 0°- I 5°C U-75U-77
2
10 ldaw2
3
4
5
6
7
B
9 10 II
12 13 2wk1
3
4
5
6
7
8
I
Fw. 3. Typical curves of blood urea nitrogen changes in each group. Blood urea nitrogen of control animals shows rapid rise until death. Curve for experimental group demonstrates gradual recovery until normal values are obtained.
798
STUEBER, KOVACS, KOLETSKY AND PERSKY
to the size postoperatively. Survival periods in terms of the shortest and longest duration of survival for each group are shown in table 1. The blood urea nitrogen in the control group showed a rapid elevation which usually continued to rise until death. In the 20 to 25 degrees centigrade kidneys there was also a rapid rise, which usually declined slowly after four days. In the last group, the rise was more gradual, the peak was lower and the normal levels were again obtained after two weeks. In figure 3 two representative curves are shown for each group. PATHOLOGICAL OBSERVATIONS
All but two of the control animals were autopsied within one week after the six-hour period of complete renal ischemia. The kidneys presented a bulging cortex with indistinct architectural pattern. The medulla was usually dark red in its entirety or in the outer juxtacortical portion. The kidneys of the experimental dogs, most of which were examined within twelve days after the period of ischemia, were either pale throughout and slightly enlarged or within normal
Fm. 4. A, massive tubular necrosis in control dogs 3 days after a 6-hour period of complete renal ischemia. B, marked tubular necrosis in control dog 3 days after a 6-hour period of complete renal ischemia. H & E X 126.
HYI'OTI-rnmVIL\. IN ACUTE RE;\TAL ISCI-IEMIA
799
limits in gross appearance and size. An oe:casionnl animal in both control and treated groups showed small recent cortical infarcts. ;\ifie:roscopie:ally, in all animals which died the principal lesion coagulation necrosis of the proximal convoluted tubules. There Yms tion of the lining loss of nuclei, and blockage of lumens by coarse acidophilic debric1. Supcrimprn,e:d e:alcific deposit wm; frequently observed. The glomeruli ,vere intact and neither the loops of Henle nor the distal convoluted segmentt, of the nephron participated in the necro~is. pink-staining eastc: were m1merous, especially in the collecting tubules. There were focal regions of interstitial lymphocytie: exudate in the Yicinity of necrotic tubules. afte1 In the control almost all of which died within a fe11· to several circulation ,Yas restored, the tubular necrosis ,Yai:i widespread and nuiss1ye (fig. 4, il). The entire proximal tubule ,rns involved, including the or spiral segments, and repair was usually minimal or slight (fig '1, B). The necrotic lesion in the experiment,al animals was ,;imilarly but, less
:Fm, 5. Kidney of experimental dog 7 days after inierrupLion of renal eirculation for G hours. Slight necrosis of tllhules. large!)· repaired, and focal ealcific deposit. B, kidney experimental dog 8 days after interruption of renal eircnlation for 6 honrn. Slight tubular necrosis ,Yith repair. H & EX 126.
800
STUEBER, KOVACS, KOLETSKY AND PERSKY
severe in extent and distribution. In fact, in most instances the renal damage was comparatively slight or minimal and consisted merely of focal degeneration or necrosis of the proximal tubules (fig. 5, A). Widespread massive tubular destruction did not occur in any of the animals. Repair was fairly rapid and within one or two weeks debris was cleared and new cells lined the dilated tubules. There was focal calcific deposit. Dogs sacrificed eight weeks after renewal of the rena.l circulation showed practically normal kidneys (fig. 5, B). DISCUSSION
These studies therefore demonstrate conclusively that localized cooling offers protection in the face of a severe, protracted period of renal anoxia. The percentage of survival of these animals, the less severe elevation of the blood urea nitrogen with hypothermia, and the microscopic evidence of less severe injury are consistent throughout. Although this is a preliminary report, and further levels of cooling are to be explored, these data to date suggest that temperatures from 10 to 15 degrees offer the maximum protection. This degree of cooling, -which could not be attained by generalized hypothermia without derangeinent of the body temperature control centers, or the development of cardiac arrhythmias, could easily be attained at surgery. In the large aortic aneurysms involving the renal vessels or in dissecting aneurysms its application might prove efficacious in avoiding the oliguria and anuria seen subsequently.10 The urologist, in the case of large branching calculi, where extensive nephrotomy is indicated, or in the segmental replacement of renal arteries, similarly might find it effective. It is possible that in certain situations combined generalized and regional hypothermia may be used concomitantly. This might be especially applicable in the case of the previously mentioned large abdominal aneurysms when separation of the kidney from its blood supply is necessary during aortic replacement. It seems unlikely that its use can successfully be extended to the clinical situation::, of anuria, the so-called acute tubular necroses, where the microscopic picture is so similar. Here the difficulty of achieving regional cooling in a critically ill patient would prohibit its usefulness. If renal homotransplantation becomes a clinical reality, cooling the graft may aid in its survival. Prolonged studies are contemplated to determine if ultimate renal dysfunction and hypertension will develop. Also, it is hoped to ascertain if cooling will protect the already damaged kidney during various manipulative procedures. In general, we feel that regional hypothermia is a potentially valuable tool for the urological surgeon. SUMMARY
A six-hour period of acute renal ischemia at room temperatures results in 100 per cent mortality in the dog. In experimental groups, with applied regional hypothermia (20° and 10°C) 30 per cent and 75 per cent survival was achieved. Histological studies showed proximal tubular damage with less severe degrees of injury in the cooled group. Renal function measured by blood urea nitrogen levels showed a significant protection afforded by hypothermia during the period of anoxia.