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Toxic Symptoms Accompanied by Hemolysis During Transurethral Prostatectomy1
TOXIC SYMPTOMS ACCOMPANIED BY HEMOLYSIS DURING TRANSURETHRAL PROSTATECTOMY1 MILES GRIFFIN
Twenty per cent of the deaths following transurethral prostatectomy are due to renal failure characterized by varying degrees of oliguria to complete anuria. (Emmett.) Recently, Creevy reported a death apparently due to hemolysis and suggested that a hemolytic reaction might be the cause of uremia which may follow transurethral resection. How often does hemolysis follow transurethral prostatic resection? How often is it fatal? Will early recognition of this phenomenon and elimination of its cause affect the outcome of the patient? These questions are unanswered in the urologic literature and are of sufficient import to deserve our careful appraisal. Since February 1944, the clinical behavior of 5 patients undergoing transurethral removal of the prostate has suggested that the irrigating water was entering the prostatic veins and producing a toxic reaction. The toxic symptoms in each of these 5 cases were definitely correlated with attempts to control extensive venous hemorrhage. Systemic reactions from substances entering the blood stream in the region of the prostate have been recognized for a long time. Death has resulted from injecting local anesthetic agents into the posterior urethra, and argyrol injected into the posterior urethra has been detected in the patient's sputum. The toxic picture manifested by these patients was nausea and vomiting accompanied by a rise in blood pressure, not the fall which is often associated with spinal anesthesia. A mental review of our entire experience with transurethral prostatectomy recalls patients who exhibited a sensation of substernal constriction, lumbar backache, etc., and suggests that these symptoms may have been accompanied by hemolysis which was unrecognized at the time. Apprehensions, preoperative medication, anesthesia, hemorrhage, and surgical shock need only be mentioned to make it evident how numerous and· apparent are the etiological factors of fluctuations in blood pressure, nausea, vomiting and various subjective complaints noted sometimes during an operation. The multiplicity of factors involved and the fact that the clinical behavior of a patient even under standard conditions is variable explain to some degree the failure to correlate previously the occurrence of toxic symptoms and the infusion of irrigating water as its etiology. Laking of red blood cells as a primary intravascular effect of introducing water into the prostatic veins is an immediate thought in the search for the physiological explanation of the toxic symptoms. Following this reasoning, determinations were made for the presence of free hemoglobin in the patient's plasma. In each case the result was positive. Values for hemoglobin present in the plasma ranged from 35 to 650 mg. per cent. 1 Read at annual meeting, Western Section, American Urological Association, Yosemite Valley, Calif., May 21-23, 1947. 431
432
MILES GRIFFIN
Since tp.e first recognition of this toxic phenomenon due to irrigating water entering the prostatic veins, we have operated transurethrally upon 194 private patients for prostatic obstruction. (Charity cases are not included because of the inaccessibility and difficulty of analysing their clinical records.) The recognized occurrence of this toxic phenomenon in 5 cases represents an incidence of 2.5 per cent. The weight of the prostatic tissue removed in these 5 cases varied from 12 to 41 gm. It is interesting to note that the toxic reaction occurred in cases with small fibrous glands. No toxic clinical manifestations were noted on the operating table in other cases of the series when larger amounts of tissue were resected at a single sitting. The weight of the resected tissue in the 20 largest prostates varied between 70 and 142 gm. It is obvious that the site of operation can be extended into the prostatic veins more readily in the smaller glands. Also, fibrosis in the small obstructing glands is often the result of long standing infection. The more likely occurrence of a toxic bacterial agent and the degree of patients' susceptibility to the toxic agent are factors, in addition to the surgical rupture of prostatic veins, which must be considered in evaluating the occurrence of the toxic symptoms in patients with small obstructing prostates. With the exception of a few varied complaints of mild degree during the first 24 hours, the postoperative course of the patients who exhibited toxic symptoms on the operating table was essentially the same as those who did not. There was no permanent ill effect postoperatively. The presence of free hemoglobin disappeared from the plasma in approximately 24 hours. The details of case 1 are characteristic of the other 4 cases. Case 1. A. V., aged 60 years, complained of hesitance, nocturia and a weak urinary stream. His residual urine was 5 ounces and cystoscopic examination revealed tri-lobar prostatic enlargement and a trabeculated bladder. The patient's general appearance was that of a vigorous man appearing less than his stated age. Physical examination yielded normal findings, except for a minor degree of prostatic enlargement and an incipient left inguinal hernia. The blood pressure, an average of 4 separate preoperative readings, was 127 mm. of mercury systolic and 78 diastolic. On March 21, 1946, the hemoglobin was 16.0 gm. per cent. The white blood cells numbered 7,200 per cubic millimeter. The differential leucocyte count was normal. Bleeding and clotting times were normal. Fasting blood urea was 49 mg. per cent. Urinalysis revealed a spooific gravity 1.020; no albumin or sugar, and normal sediment. On March 22, 1946, thirty-seven grams of prostatic tissue were resected with the Thompson resectoscope. During the operation, difficulty was encountered with hemorrhage from two venous sinuses of the prostatic capsule. This was readily controlled after the resection by filling the hemostatic bag of ~n Emmett catheter to 60 cc and maintaining traction for 20 minutes. Nausea and vomiting occurred during the operation and there was a rise in the blood pressure to a level of 152 mm. of mercury systolic and 82 diastolic. The pulse was constant and regular. The presence of tetanic twitchings of the right arm was noted by the anesthetist. Upon return to his room, the patient was unusually tired and restless for several hours, was nauseated and vomited on several occasions.
TOXIC SYMPTOMS
433
Hourly blood pressure determinations during the period of the first 5 hours varied between 110 to 114 mm. of mercury systolic, and 60 to 72 diastolic. The pulse was constantly 62 beats per minute, regular and of good quality. Five hundred cubic centimeters of whole, citrated blood were given 6 hours postoperatively without adverse reaction. The presence of hemoglobin in the plasma was noted postoperatively in the following amounts: 2½ hours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 gm. per cent 6½ hours. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . .. . . . . . . . .35 gm. per cent 24 hours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . no hemoglobin
After the first 24 hours, the course was uneventful. On the second day following operation, the patient was allowed to be up, and the catheter was removed. He voided a good stream without discomfort. He was dismissed from the hospital on the third postoperative day. The pathologist's report on the resected tissue was benign prostatic hyperplasia. DISCUSSION
It is well known that small amounts of human hemoglobin solution may be injected intravenously in man without producing ill effects. (Gilligan, Altschule and Katersky; Otten.berg and Fox; Sellards and Minot.) Also, it has been shown that various amounts of distilled water may be injected intravenously without ill effects. One physiologist has taken, by continuous intravenous injection, 500 cc of distilled water without lowering the blood count below his own experimental err.or; there was mild hemoglobinuria but no subjective effects were noted. Routine determination for the presence of hemoglobin in the plasma of our patients who exhibited no untoward reaction to transurethral prostatectomy has proved that hemolysis of some degree is to be expected. One patient had as much as 650 mg. per cent of free plasma hemoglobin and had no toxic reaction to the hemolytic process. It is obvious that hemolysis per se is not sufficient to produce symptoms in the average case. On the other hand, severe abdominal cramps with vomiting and visible peristalsis, chills and fever, pain in the back and loins, and sensations of constriction in the chest have resulted from the injection of human hemoglobin. (De Cowin, Osterhagen and Andersch; Fairley; Gilligan, Altschule and Katersky; O'Shaughnessy, Mansell and Stone.) Solutions of rabbit hemoglobin laked by repeated freezing and thawing cause rapid death when injected into rabbits. However, if the solutions were sufficiently filtered, sudden death was avoided. (Baker and Dodds.) It appears that the toxic agent causing death in the rabbits was contained in the residue, not in the filterable hemoglobin. There has been no fatality among our cases in which hemolysis was proved to be present following transurethral prostatectomy. In the last 328 consecutive private cases of transurethral prostatic resection, there have been 3 deaths, a mortality rate of a little less than 1 per cent. One of these 3 patients died primarily as a result of renal failure, but did not exhibit toxic symptoms when he was on the operating table. Through oversight, his plasma was not studied specifically for the presence of hemolyisis. However, a cross match for blood transfusion was
434
MILES GRIFFIN
done shortly after operation and no record was made of hemoglobin being noted in the serum. Regarding the other 2 fatalities, one occurred in a 84 year old man with tertiary syphilis and complete vesical retention who died suddenly and unexpectedly on the second day following transurethral removal of 90 gm. of prostatic tissue. Autopsy was not permitted. The patient had had previous coronary accidents and the hospital resident who observed the patient's demise felt justified in attributing the death to coronary occlusion. The other fatality was a 73 year old man who had had gout and urinary symptoms typical of prostatic obstruction for 10 years. He died on the sixteenth day following transurethral resection of 20 gm. of prostatic tissue. His catheter had been removed, he was up, afebrile, and was voiding £reeling when he contracted gastro-enteritis. He died in coma and as a result of uncontrollable diarrhea. The cause of his death was confirmed by autopsy. This analysis indicates that a hemolytic reaction could not have been a fatal factor in more than ½of 1 per cent in our experience. Nausea, vomiting and rise in blood pressure occurring during transurethral prostatectomy, unexplained on a more obvious basis, could easily be explained by the intravascular introduction or production of an agent which caused contraction of smooth muscle. Gilligan et al. found that the intravenous administration of calcium chloride gave immediate relief of severe abdominal pain, vomiting and visible peristalsis when these symptoms occurred in patients following the intravenous injection of hemoglobin solutions. Their observations suggest that hemoglobin solutions may produce untoward symptoms as a result of marked spasm of the smooth muscle of the gastro-intestinal tract. Furthermore, it has been pointed out that the laking of red blood cells releases appreciable amounts of histamine-like substance and of potassium, either one of which may cause c0nstriction of smooth muscle. (Barsoum and Smirk; Mineev.) Although a rapid increase in the ratio of the total blood volume to the capacity of the vascular bed is a hemodynamic factor to be considered in any rise in blood pressure, it is unlikely that irrigating water passing into the prostatic veins is significant in this respect. Page has shown that blood pressure measurements made at 2 minute intervals during and after rapid intravenous infusion of glucose-saline (1000 cc) and blood or gum-saline (500 cc) show rises which rarely exceed 10 mm. of mercury and are only transient. (Page and Ogden.) If hemolysis is primarily responsible for the toxic symptoms manifested by our small series of cases there must be a great variance in patients' tolerance of hemoglobinemia. It has been pointed out previously that 1 patient with 35 mg. per cent of free hemoglobin in the plasma exhibited toxicity. Another patient had no untoward reaction to 650 mg. per cent, and the presence of hemoglobinemia would not have been detected if the test had not been made routinely. A possible answer, at least as regards renal tolerance, is found in the work of Yuile et al. They found, experimentally, that a standard amount of hemoglobin solution would cause hemoglobin precipitation in the tubules of damaged kidneys, but not in normal kidneys. The hemolytic reaction associated with renal failure has been observed clini-
TOXIC SYMPTOMS
435
cally in such varied cases as blackwater fever, blood transfusion reactions, severe burns, and transurethral prostatic resection. The importance of plasma hemoglobin concentrations and the pH of the urine has been repeatedly discussed in the literature. (Baker and Dodds; Flink; Maegraith.) The characteristic microscopic picture found at autopsy is degeneration of the renal tubular epithelium. Casts of cellular debris and substance containing iron pigment, probably hemoglobin, may or may not be present also. Whether renal insufficiency results from plugging of the renal tubules with precipitated hemoglobin or from the action of some toxic agent which produces renal ischemia and secondarily involves the tubular epithelium is a question of fundamental importance. Our observations indicate reaction from a toxic agent. The clinical application of either answer is early recognition and prevention of the hemolytic process and immediate institution of corrective measures. Although it is logical to assume that the complex of toxic symptoms discussed in this paper is a minor manifestation of the same process which may cause anuria and death, 5 cases is too small a series, and the nature of the observations are too debatable, to warrant hard and fast deductions. Nevertheless, an inconclll\Sive report seems justified in view of the fact that so little is found in urologic literature on the subject, and death from anuria in the hands of the experienced resectionists occur statistically only once in 500 cases. SUMMARY AND CONCLUSIONS
In a series of 194 cases of transurethral prostatectomy, the symptom complex of nausea, vomiting and rise in blood pressure was noted 5 times. The etiology of these symptoms was attributed to the entrance of irrigating water into the prostatic veins, because the occurrence of the symptoms in each instance was simultaneous with attempts to control venous hemorrhage and the patient's blood plasma, in each case, revealed hemolysis postoperatively. Hemolysis following transurethral resection was found by routine examination to have occurred frequently in other cases without subjective complaint or recognized symptoms. No permanent ill effect was noted in the 5 cases exhibiting toxic symptoms. The observations reported indicate that some poorly tolerated substance liberated in the process of hemolysis, or toxic agent introduced into the blood stream in the irrigating water, was responsible for the toxicity exhibited by the patient. The reactions of the patients did not vary in degree of toxicity with the amount of hemoglobin liberated in the plasma. The literature concerning hemoglobinemia, particularly as regards blackwater fever and blood transfusion reactions, indicates that renal failure as a result of tubular degeneration, with or without plugging of the nephron with hemoglobin casts, is often the primary cause of death in fatal cases. A series of 328 consecutive cases of transurethral prostatectomy is reported in which only 1 of the 3 deaths was due to renal failure. Postoperative shock resulting in renal ischemia, not a postoperative hemolytic reaction, was considered to be the cause of renal tubular degeneration in this case. The use of isotonic irrigating solution to prevent hemolysis during transure-
436
MILES GRIFFIN
thral prostatic resection must be carefully evaluated; else the remedy may be worse than the fault it is designed to correct. Normal saline solution can and has been used by the author while operating with the Thompson resectoscope, but the diffusion of the current through the electrolytic solution requires a stronger current for coagulation, and the electrode must be placed more accurately on the bleeder. The danger of upsetting the blood chemistry in poor surgical risks must be carefully evaluated in selecting a substitute for water as the irrigating medium. For this reason, glucose is preferred over sodium chloride in preparing irrigating fluid for patients with severe cardiovascular disease. At least for the present, the most important precautions to be taken in prevention of hemolysis during transurethral prostatectomy are: leaving a rim of prostatic tissue between the line of dissection and the prostatic capsule until the final moments of the operation, and using the irrigating water at the lowest workable pressure. 2900 Telegraph Ave., Berkeley 5, Calif. REFERENCES BAKER, S. L. AND DODDS, E. 0.: Obstruction of the renal tubules during the excretion of hemoglobin. Brit. J. Exper. Path., 6: 247, 1925. BARSOUN, G. S., AND SMIRK, F. H.: Observations on the histamine yielding substances in the plasma and red cells of normal human subjects and of patients with congestive heart failure, Olin. Sci., 2: 337, 1936. 0REEVY, 0. D. AND WEBB, E. A.: A fatal hemolytic reaction following transurethral resection of the prostate gland, Surgery, 21: 56, 1947. DAMESCHECK, w. AND SCHWARTZ, s. 0.: Acute hemolytic anemia (acquired hemolytic icterus, acute type), Medicine, 19: 231, 1940. DEGowIN, E. L., 0GTERHAGEN, H.F. AND ANDERSCH, M.: Renal insufficiency from blood transfusion-I. Relation to urinary acidity. Arch. Int. Med., 59: 432, 1937. EMMETT, J. L.: Personal communication. FAIRLEY, N. H.: The fate of extra corpuscular circulating hemoglobin. Brit. M. J., 2: 213, 1940. FLINK, E. B.: Blood transfusion studies. III. Relationship of hemoglobinemia and of the pH of the urine to renal damages produced by injection of hemoglobin solutions into dogs. J. Lab. & Olin. Med., 32: 223, 1947. GILLIGAN, D.R., ALTSCHULE, M. D. AND KATERSKY, E. M.: Studies of hemoglobinemia and hemoglobinuria produced in man by intravenous injection of hemoglobin solutions. J. Olin. Investigation, 20: 177, 1941. HAM, T. H.: Studies in destruction of red blood cells. I. Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria: An investigation of the mechanism of hemolysis, with observations on five cases, Arch. Int. Med., 64: 1271, 1939. Queries and Minor Notes. J. A. M. A., 129: 584, 1945. LICHTY, J. A., JR., HAVILL, W. H. AND WHIPPLE, G. H.: Renal thresholds for hemoglobin in dogs. Depression of threshold due to frequent hemoglobin injections and recovery during rest periods. J. Exper. Med., 55: 603, 1932. MAEGRAITH, B. G. AND HAVARD, R. E.: Dangers of intensive alkali treatments in Blackwater fever. Lancet, 2: 338, 1944. MASON, J.B. AND MANN, B. F.: Effect of hemoglobin on the volume of kidney. Am. J. Physiol., 98: 181, 1931. MINEV, A.: Quoted by Gilligan et al. O'SHAUGHNESSY, L. F., MANSELL, H. E. AND STOME, D.: Hemoglobin solution as a blood substitute. Lancet, 2: 1068, 1939. 0TTENBERG, R. AND Fox, D. L., JR.: The rate of removal of hemoglobin from the circulation and its renal threshold in human beings. Am. J. Physiol., 123: 516, 1938. PAGE, E.W. AND OGDEN, E.: The physiology of hypertension in eclampsia. Am. J. Obst. & Gynec., 38: 230, 1939. SELLARDS, A. W. AND MINOT, G. R.: Injection of hemoglobin in man and its relation to blood destruction, with especial reference to the anemias. J. Med. Research, 34: 469 1916. YUILE, 0. L., GOLD, N. A. AND MINDS, E. G.: Hemoglobin precipitation in renal tubules. J. Exper. Med. 82: 361, 1945.
Twenty per cent of the deaths following transurethral prostatectomy are due to renal failure characterized by varying degrees of oliguria to complete anuria. (Emmett.) Recently, Creevy reported a death apparently due to hemolysis and suggested that a hemolytic reaction might be the cause of uremia which may follow transurethral resection. How often does hemolysis follow transurethral prostatic resection? How often is it fatal? Will early recognition of this phenomenon and elimination of its cause affect the outcome of the patient? These questions are unanswered in the urologic literature and are of sufficient import to deserve our careful appraisal. Since February 1944, the clinical behavior of 5 patients undergoing transurethral removal of the prostate has suggested that the irrigating water was entering the prostatic veins and producing a toxic reaction. The toxic symptoms in each of these 5 cases were definitely correlated with attempts to control extensive venous hemorrhage. Systemic reactions from substances entering the blood stream in the region of the prostate have been recognized for a long time. Death has resulted from injecting local anesthetic agents into the posterior urethra, and argyrol injected into the posterior urethra has been detected in the patient's sputum. The toxic picture manifested by these patients was nausea and vomiting accompanied by a rise in blood pressure, not the fall which is often associated with spinal anesthesia. A mental review of our entire experience with transurethral prostatectomy recalls patients who exhibited a sensation of substernal constriction, lumbar backache, etc., and suggests that these symptoms may have been accompanied by hemolysis which was unrecognized at the time. Apprehensions, preoperative medication, anesthesia, hemorrhage, and surgical shock need only be mentioned to make it evident how numerous and· apparent are the etiological factors of fluctuations in blood pressure, nausea, vomiting and various subjective complaints noted sometimes during an operation. The multiplicity of factors involved and the fact that the clinical behavior of a patient even under standard conditions is variable explain to some degree the failure to correlate previously the occurrence of toxic symptoms and the infusion of irrigating water as its etiology. Laking of red blood cells as a primary intravascular effect of introducing water into the prostatic veins is an immediate thought in the search for the physiological explanation of the toxic symptoms. Following this reasoning, determinations were made for the presence of free hemoglobin in the patient's plasma. In each case the result was positive. Values for hemoglobin present in the plasma ranged from 35 to 650 mg. per cent. 1 Read at annual meeting, Western Section, American Urological Association, Yosemite Valley, Calif., May 21-23, 1947. 431
432
MILES GRIFFIN
Since tp.e first recognition of this toxic phenomenon due to irrigating water entering the prostatic veins, we have operated transurethrally upon 194 private patients for prostatic obstruction. (Charity cases are not included because of the inaccessibility and difficulty of analysing their clinical records.) The recognized occurrence of this toxic phenomenon in 5 cases represents an incidence of 2.5 per cent. The weight of the prostatic tissue removed in these 5 cases varied from 12 to 41 gm. It is interesting to note that the toxic reaction occurred in cases with small fibrous glands. No toxic clinical manifestations were noted on the operating table in other cases of the series when larger amounts of tissue were resected at a single sitting. The weight of the resected tissue in the 20 largest prostates varied between 70 and 142 gm. It is obvious that the site of operation can be extended into the prostatic veins more readily in the smaller glands. Also, fibrosis in the small obstructing glands is often the result of long standing infection. The more likely occurrence of a toxic bacterial agent and the degree of patients' susceptibility to the toxic agent are factors, in addition to the surgical rupture of prostatic veins, which must be considered in evaluating the occurrence of the toxic symptoms in patients with small obstructing prostates. With the exception of a few varied complaints of mild degree during the first 24 hours, the postoperative course of the patients who exhibited toxic symptoms on the operating table was essentially the same as those who did not. There was no permanent ill effect postoperatively. The presence of free hemoglobin disappeared from the plasma in approximately 24 hours. The details of case 1 are characteristic of the other 4 cases. Case 1. A. V., aged 60 years, complained of hesitance, nocturia and a weak urinary stream. His residual urine was 5 ounces and cystoscopic examination revealed tri-lobar prostatic enlargement and a trabeculated bladder. The patient's general appearance was that of a vigorous man appearing less than his stated age. Physical examination yielded normal findings, except for a minor degree of prostatic enlargement and an incipient left inguinal hernia. The blood pressure, an average of 4 separate preoperative readings, was 127 mm. of mercury systolic and 78 diastolic. On March 21, 1946, the hemoglobin was 16.0 gm. per cent. The white blood cells numbered 7,200 per cubic millimeter. The differential leucocyte count was normal. Bleeding and clotting times were normal. Fasting blood urea was 49 mg. per cent. Urinalysis revealed a spooific gravity 1.020; no albumin or sugar, and normal sediment. On March 22, 1946, thirty-seven grams of prostatic tissue were resected with the Thompson resectoscope. During the operation, difficulty was encountered with hemorrhage from two venous sinuses of the prostatic capsule. This was readily controlled after the resection by filling the hemostatic bag of ~n Emmett catheter to 60 cc and maintaining traction for 20 minutes. Nausea and vomiting occurred during the operation and there was a rise in the blood pressure to a level of 152 mm. of mercury systolic and 82 diastolic. The pulse was constant and regular. The presence of tetanic twitchings of the right arm was noted by the anesthetist. Upon return to his room, the patient was unusually tired and restless for several hours, was nauseated and vomited on several occasions.
TOXIC SYMPTOMS
433
Hourly blood pressure determinations during the period of the first 5 hours varied between 110 to 114 mm. of mercury systolic, and 60 to 72 diastolic. The pulse was constantly 62 beats per minute, regular and of good quality. Five hundred cubic centimeters of whole, citrated blood were given 6 hours postoperatively without adverse reaction. The presence of hemoglobin in the plasma was noted postoperatively in the following amounts: 2½ hours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6 gm. per cent 6½ hours. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . .. . . . . . . . .35 gm. per cent 24 hours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . no hemoglobin
After the first 24 hours, the course was uneventful. On the second day following operation, the patient was allowed to be up, and the catheter was removed. He voided a good stream without discomfort. He was dismissed from the hospital on the third postoperative day. The pathologist's report on the resected tissue was benign prostatic hyperplasia. DISCUSSION
It is well known that small amounts of human hemoglobin solution may be injected intravenously in man without producing ill effects. (Gilligan, Altschule and Katersky; Otten.berg and Fox; Sellards and Minot.) Also, it has been shown that various amounts of distilled water may be injected intravenously without ill effects. One physiologist has taken, by continuous intravenous injection, 500 cc of distilled water without lowering the blood count below his own experimental err.or; there was mild hemoglobinuria but no subjective effects were noted. Routine determination for the presence of hemoglobin in the plasma of our patients who exhibited no untoward reaction to transurethral prostatectomy has proved that hemolysis of some degree is to be expected. One patient had as much as 650 mg. per cent of free plasma hemoglobin and had no toxic reaction to the hemolytic process. It is obvious that hemolysis per se is not sufficient to produce symptoms in the average case. On the other hand, severe abdominal cramps with vomiting and visible peristalsis, chills and fever, pain in the back and loins, and sensations of constriction in the chest have resulted from the injection of human hemoglobin. (De Cowin, Osterhagen and Andersch; Fairley; Gilligan, Altschule and Katersky; O'Shaughnessy, Mansell and Stone.) Solutions of rabbit hemoglobin laked by repeated freezing and thawing cause rapid death when injected into rabbits. However, if the solutions were sufficiently filtered, sudden death was avoided. (Baker and Dodds.) It appears that the toxic agent causing death in the rabbits was contained in the residue, not in the filterable hemoglobin. There has been no fatality among our cases in which hemolysis was proved to be present following transurethral prostatectomy. In the last 328 consecutive private cases of transurethral prostatic resection, there have been 3 deaths, a mortality rate of a little less than 1 per cent. One of these 3 patients died primarily as a result of renal failure, but did not exhibit toxic symptoms when he was on the operating table. Through oversight, his plasma was not studied specifically for the presence of hemolyisis. However, a cross match for blood transfusion was
434
MILES GRIFFIN
done shortly after operation and no record was made of hemoglobin being noted in the serum. Regarding the other 2 fatalities, one occurred in a 84 year old man with tertiary syphilis and complete vesical retention who died suddenly and unexpectedly on the second day following transurethral removal of 90 gm. of prostatic tissue. Autopsy was not permitted. The patient had had previous coronary accidents and the hospital resident who observed the patient's demise felt justified in attributing the death to coronary occlusion. The other fatality was a 73 year old man who had had gout and urinary symptoms typical of prostatic obstruction for 10 years. He died on the sixteenth day following transurethral resection of 20 gm. of prostatic tissue. His catheter had been removed, he was up, afebrile, and was voiding £reeling when he contracted gastro-enteritis. He died in coma and as a result of uncontrollable diarrhea. The cause of his death was confirmed by autopsy. This analysis indicates that a hemolytic reaction could not have been a fatal factor in more than ½of 1 per cent in our experience. Nausea, vomiting and rise in blood pressure occurring during transurethral prostatectomy, unexplained on a more obvious basis, could easily be explained by the intravascular introduction or production of an agent which caused contraction of smooth muscle. Gilligan et al. found that the intravenous administration of calcium chloride gave immediate relief of severe abdominal pain, vomiting and visible peristalsis when these symptoms occurred in patients following the intravenous injection of hemoglobin solutions. Their observations suggest that hemoglobin solutions may produce untoward symptoms as a result of marked spasm of the smooth muscle of the gastro-intestinal tract. Furthermore, it has been pointed out that the laking of red blood cells releases appreciable amounts of histamine-like substance and of potassium, either one of which may cause c0nstriction of smooth muscle. (Barsoum and Smirk; Mineev.) Although a rapid increase in the ratio of the total blood volume to the capacity of the vascular bed is a hemodynamic factor to be considered in any rise in blood pressure, it is unlikely that irrigating water passing into the prostatic veins is significant in this respect. Page has shown that blood pressure measurements made at 2 minute intervals during and after rapid intravenous infusion of glucose-saline (1000 cc) and blood or gum-saline (500 cc) show rises which rarely exceed 10 mm. of mercury and are only transient. (Page and Ogden.) If hemolysis is primarily responsible for the toxic symptoms manifested by our small series of cases there must be a great variance in patients' tolerance of hemoglobinemia. It has been pointed out previously that 1 patient with 35 mg. per cent of free hemoglobin in the plasma exhibited toxicity. Another patient had no untoward reaction to 650 mg. per cent, and the presence of hemoglobinemia would not have been detected if the test had not been made routinely. A possible answer, at least as regards renal tolerance, is found in the work of Yuile et al. They found, experimentally, that a standard amount of hemoglobin solution would cause hemoglobin precipitation in the tubules of damaged kidneys, but not in normal kidneys. The hemolytic reaction associated with renal failure has been observed clini-
TOXIC SYMPTOMS
435
cally in such varied cases as blackwater fever, blood transfusion reactions, severe burns, and transurethral prostatic resection. The importance of plasma hemoglobin concentrations and the pH of the urine has been repeatedly discussed in the literature. (Baker and Dodds; Flink; Maegraith.) The characteristic microscopic picture found at autopsy is degeneration of the renal tubular epithelium. Casts of cellular debris and substance containing iron pigment, probably hemoglobin, may or may not be present also. Whether renal insufficiency results from plugging of the renal tubules with precipitated hemoglobin or from the action of some toxic agent which produces renal ischemia and secondarily involves the tubular epithelium is a question of fundamental importance. Our observations indicate reaction from a toxic agent. The clinical application of either answer is early recognition and prevention of the hemolytic process and immediate institution of corrective measures. Although it is logical to assume that the complex of toxic symptoms discussed in this paper is a minor manifestation of the same process which may cause anuria and death, 5 cases is too small a series, and the nature of the observations are too debatable, to warrant hard and fast deductions. Nevertheless, an inconclll\Sive report seems justified in view of the fact that so little is found in urologic literature on the subject, and death from anuria in the hands of the experienced resectionists occur statistically only once in 500 cases. SUMMARY AND CONCLUSIONS
In a series of 194 cases of transurethral prostatectomy, the symptom complex of nausea, vomiting and rise in blood pressure was noted 5 times. The etiology of these symptoms was attributed to the entrance of irrigating water into the prostatic veins, because the occurrence of the symptoms in each instance was simultaneous with attempts to control venous hemorrhage and the patient's blood plasma, in each case, revealed hemolysis postoperatively. Hemolysis following transurethral resection was found by routine examination to have occurred frequently in other cases without subjective complaint or recognized symptoms. No permanent ill effect was noted in the 5 cases exhibiting toxic symptoms. The observations reported indicate that some poorly tolerated substance liberated in the process of hemolysis, or toxic agent introduced into the blood stream in the irrigating water, was responsible for the toxicity exhibited by the patient. The reactions of the patients did not vary in degree of toxicity with the amount of hemoglobin liberated in the plasma. The literature concerning hemoglobinemia, particularly as regards blackwater fever and blood transfusion reactions, indicates that renal failure as a result of tubular degeneration, with or without plugging of the nephron with hemoglobin casts, is often the primary cause of death in fatal cases. A series of 328 consecutive cases of transurethral prostatectomy is reported in which only 1 of the 3 deaths was due to renal failure. Postoperative shock resulting in renal ischemia, not a postoperative hemolytic reaction, was considered to be the cause of renal tubular degeneration in this case. The use of isotonic irrigating solution to prevent hemolysis during transure-
436
MILES GRIFFIN
thral prostatic resection must be carefully evaluated; else the remedy may be worse than the fault it is designed to correct. Normal saline solution can and has been used by the author while operating with the Thompson resectoscope, but the diffusion of the current through the electrolytic solution requires a stronger current for coagulation, and the electrode must be placed more accurately on the bleeder. The danger of upsetting the blood chemistry in poor surgical risks must be carefully evaluated in selecting a substitute for water as the irrigating medium. For this reason, glucose is preferred over sodium chloride in preparing irrigating fluid for patients with severe cardiovascular disease. At least for the present, the most important precautions to be taken in prevention of hemolysis during transurethral prostatectomy are: leaving a rim of prostatic tissue between the line of dissection and the prostatic capsule until the final moments of the operation, and using the irrigating water at the lowest workable pressure. 2900 Telegraph Ave., Berkeley 5, Calif. REFERENCES BAKER, S. L. AND DODDS, E. 0.: Obstruction of the renal tubules during the excretion of hemoglobin. Brit. J. Exper. Path., 6: 247, 1925. BARSOUN, G. S., AND SMIRK, F. H.: Observations on the histamine yielding substances in the plasma and red cells of normal human subjects and of patients with congestive heart failure, Olin. Sci., 2: 337, 1936. 0REEVY, 0. D. AND WEBB, E. A.: A fatal hemolytic reaction following transurethral resection of the prostate gland, Surgery, 21: 56, 1947. DAMESCHECK, w. AND SCHWARTZ, s. 0.: Acute hemolytic anemia (acquired hemolytic icterus, acute type), Medicine, 19: 231, 1940. DEGowIN, E. L., 0GTERHAGEN, H.F. AND ANDERSCH, M.: Renal insufficiency from blood transfusion-I. Relation to urinary acidity. Arch. Int. Med., 59: 432, 1937. EMMETT, J. L.: Personal communication. FAIRLEY, N. H.: The fate of extra corpuscular circulating hemoglobin. Brit. M. J., 2: 213, 1940. FLINK, E. B.: Blood transfusion studies. III. Relationship of hemoglobinemia and of the pH of the urine to renal damages produced by injection of hemoglobin solutions into dogs. J. Lab. & Olin. Med., 32: 223, 1947. GILLIGAN, D.R., ALTSCHULE, M. D. AND KATERSKY, E. M.: Studies of hemoglobinemia and hemoglobinuria produced in man by intravenous injection of hemoglobin solutions. J. Olin. Investigation, 20: 177, 1941. HAM, T. H.: Studies in destruction of red blood cells. I. Chronic hemolytic anemia with paroxysmal nocturnal hemoglobinuria: An investigation of the mechanism of hemolysis, with observations on five cases, Arch. Int. Med., 64: 1271, 1939. Queries and Minor Notes. J. A. M. A., 129: 584, 1945. LICHTY, J. A., JR., HAVILL, W. H. AND WHIPPLE, G. H.: Renal thresholds for hemoglobin in dogs. Depression of threshold due to frequent hemoglobin injections and recovery during rest periods. J. Exper. Med., 55: 603, 1932. MAEGRAITH, B. G. AND HAVARD, R. E.: Dangers of intensive alkali treatments in Blackwater fever. Lancet, 2: 338, 1944. MASON, J.B. AND MANN, B. F.: Effect of hemoglobin on the volume of kidney. Am. J. Physiol., 98: 181, 1931. MINEV, A.: Quoted by Gilligan et al. O'SHAUGHNESSY, L. F., MANSELL, H. E. AND STOME, D.: Hemoglobin solution as a blood substitute. Lancet, 2: 1068, 1939. 0TTENBERG, R. AND Fox, D. L., JR.: The rate of removal of hemoglobin from the circulation and its renal threshold in human beings. Am. J. Physiol., 123: 516, 1938. PAGE, E.W. AND OGDEN, E.: The physiology of hypertension in eclampsia. Am. J. Obst. & Gynec., 38: 230, 1939. SELLARDS, A. W. AND MINOT, G. R.: Injection of hemoglobin in man and its relation to blood destruction, with especial reference to the anemias. J. Med. Research, 34: 469 1916. YUILE, 0. L., GOLD, N. A. AND MINDS, E. G.: Hemoglobin precipitation in renal tubules. J. Exper. Med. 82: 361, 1945.