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Increased Serum Total Creatine Kinase and Creatine Kinase Isoenzyme MB After Cryosurgical Ablation of the Prostate
0022-j347/97/15751723$03.00/0 Val. 157,1723-1726. May 1997 Printed in U S A
JI)URNAI. OF UROLOGY
Copyright 0 1997 by
AMERICAN U R O ~ I C A L ASSOCIATION,INC.
INCREASED SERUM TOTAL CREATINE KINASE AND CREATINE KINASE ISOENZYME MB AFTER CRYOSURGICAL ABLATION OF THE PROSTATE JOHN P. LONG, MARK L. FALLICK AND WILLIAM RAND From the Tufts University School of Medicine and New England Medical Center Hospitals, Boston, Massachusetts
ABSTRACT
Purpose: Several reports have documented that the MB isoenzyme of creatine kinase is present in prostatic tissue. However, since it has been shown that lower urinary tract manipulations, including transurethral prostatectomy, do not significantly increase serum creatine kinase isoenzyme MB levels, such elevations, which are found in patients after prostatic surgery, are believed to be specific for myocardial infarction. We examined whether cryosurgical ablation of the prostate altered serum creatine kinase or isoenzyme MB levels. Materials and Methods: In 81 consecutive patients undergoing routine cryosurgical ablation of the prostate serum levels of creatine kinase and creatine kinase isoenzyme MB were measured from peripheral blood specimens drawn preoperatively, in the recovery room and at 8 and 24 hours postoperatively. Postoperative electrocardiograms were compared to the preoperative study. Results: In 72 of 81patients (89%) significant elevations in creatine kinase and creatine kinase isoenzyme MB levels were noted a t all time points after cryosurgical ablation of the prostate and appeared to reach a peak a t 16 hours postoperatively. The mean increases within the first 8 hours after cryosurgical ablation of the prostate were 1,355 units per 1. for creatine kinase and 46.6 ng./ml. for creatine kinase isoenzyme MB. No patient had any si@cant changes on the postoperative electrocardiogram. All 9 patients (11%) who did not have significant creatine kinase or creatine b a s e isoenzyme MB levels aRer cryosurgery had undergone prior cryosurgery or combined radiation and hormonal therapy. Conclusions: Cryosurgical ablation of the prostate appears to produce elevations in serum creatine kinase and creatine kinase isoenzyme MB, which are specific to the procedure. Assays for creatine kinase isoenzyme MB are unreliable to render a diagnosis of myocardial infarction after cryosurgical ablation of the prostate. KEYWORDS: prostatic neoplasms, cryosurgery,isoenzymes, creatine kinase The enzyme creatine kinase is a dimer composed of 2 subunits, that is M (muscle) and B (brain). Therefore, this molecule can exist in 3 isoenzyme forms, MM, MB and BB. Cardiac muscle has a reported total creatine b a s e activity of 400 to 600 international units per gm.with 80 to 100 international units per gm.being accounted for by the creatine kinase isoenzyme MB.1 These are believed to be the highest tissue levels of creatine b a s e isoenzyme MB in the body, although low levels of this isoenzyme have been found in tissue homogenates of smooth muscle, bladder and prostate.s-4 Because of this unique tissue distribution serum assays of creatine kinase isoenzyme MB have been widely corroborated as accurate and specific tests for myocardial infarction.'. 5 Creatine kinase isoenzyme MB has also been shown to be present in prostatic tissue in small but detectable amounts.2.6 This finding has led to several reports examining the possible role of prostatic surgery and/or lower urinary tract surgical manipulation in producing artifactual elevations of serum creatine kinase isoenzyme MB. However, significant elevations of this enzyme after transurethral resection or open prostatectomy were found to occur at a low rate6 or not at all.7 These studies confirmed that serum creatine kinase isoenzyme MB activity following conventional prostatic surgery was minimal, and that the assay still funcAccepted for publication October 18,1996.
tioned as a reliable and specific indicator of cardiac damage &r these procedures. Cryosurgical ablation of the prostate in patients with proatatic carcinoma attempts to destroy carcinomatous tissue by the direct application of low temperatures. Contemporary technique involves the transperineal placement of 3 mm. cryoprobes under continuous real-time transrectal ultrasound guidance into target areas of the prostate. In an ongoing program we evaluated the efficacy of this approach in patients with prostatic carcinoma within the last 36 months. As part of our investigation, we discovered that use of this procedure in patients with varying stages of prostate carcinoma routinely produces dramatic postoperative elevations in total creatine kinase activity and specifically in creatine kinase isoenzyme MB activity. In particular, creatine b a s e isoenzyme MB levels 1 and 24 hours after cryoablation consistently were well above the minimal criteria we used to establish a myocardial infarction. However, none of our patients had any other evidence of significant cardiac disease. We reviewed the current status of our results with this phenomenon. MATERIALS AND METHODS
Data were gathered on 81 consecutive patients with clinical stages Tlto3NOtolMO adenocarcinoma of the prostate. All patients provided informed consent to participate in an institutional review board approved pilot study ~xaminiq~
1723
1724
ALTERED SERUM CREATINE KINASE ISOENZYME MB AFTER PROSTATE ABLATION
the efficacy of cryosurgicaI ablation of the prostate in treating prostatic carcinoma. Electrocardiograms were performed on all patients as part of the routine preoperative evaluations. Intraoperative serum specimens were drawn before any prostatic manipulation but afier induction of spinal or general anesthesia. In addition, postoperative serum specimens were collected in the recovery room, and a t 8 and 24 hours postoperatively. Before each cryoablation but after the peripheral blood draw each patient underwent cystoscopy with placement of a 10.4F pigtail nephrostorny catheter into the bladder under direct endoscopic vision through a small midline suprapubic stab wound. This suprapubic tube was kept to gravity drainage during the postoperative period. No other urinary tract manipulations, that is urethral catheterizations, bladder irrigations and so forth, were done on any patient during the procedure. Each patient underwent standard cryoablation of the entire prostate with at least 5 probes used. Occasionally, depending on the anatomical dictates of the individual tumor burden, additional probes were used to ablate extraprostatic areas during cryoablation. Electrocardiograms were obtained for each patient on postoperative morning 1and were compared to the preoperative study. Total serum creatine kinase isoenzyme MB was quantitated by a standard double antibody chemoluminescence method using the manufacturer recommended methods and reagents. Total serum creatine kinase was measured by conventional enzymatic analysis using a Beckman CX7 analyzer* with Beckman reagents. Upper limits of normal for total creatine kinase and creatine kinase isoenzyme MB were 292 units per 1. and 5.9 ng./ml., respectively. Creatine kinase isoenzyme MB values greater than 12 ng./ml. were considered by the manufacturer to be highly specific for acute myocardial infarction. Statistical analysis was based on the natural logarithm of creatine kinase and isoenzyme MB because of the skewed distributions involved. Recovery room, and 8 and 24-hour levels were compared to preoperative levels using paired Student's t tests. The relationship among patient age, prostate volume, and creatine kinase and isoenzyme MB levels were measured with correlation analysis. Differences between creatine kinase and isoenzyme MB levels for those with and without prior hormonal or radiation therapy were analyzed with 2 sample t tests. Because of the multiple statistical tests run the Bonferroni correction was applied to determine statistical significance. The activities of creatine kinase and creatine kinase isoenzyme MB are expressed as mean plus or minus standard error. A value of p <0.05 was considered statistically significant. RESULTS
Patient age ranged from 46 to 82 years (mean age 65.9 ? 7.9). Mean prostatic volume (height X width x length X 0.523) before cryosurgical ablation of the prostate was 38.3 cc 2 16.1 (range 17 to 90). Of the patients 40 (49%) underwent cryosurgical ablation of the prostate with no prior treatment, while 1 had undergone prior attempts at cure with '%dine brachytherapy and 10 with external beam radiotherapy (6,800 to 7,100 cGy.1. Neoadjuvant hormonal ablation (luteinizing hormone-releasing hormone agonists with or without flutamide) was done in 21 patients (26%)for 3 ta 4 months before cryosurgical ablation of the prostate. Five patients (6.1%) had undergone prior cryosurgery and were being re-treated because of a positive biopsy on random sampling 6 months &r the original procedure. Four patients (5%)were initially treated with external beam radiotherapy with curative intent. Disease subsequently recurred and they were placed on hormonal therapy. Salvage cryosurgical ablation of the prostate was attempted after subsequent disease recurrence. Beckman Instruments, Inc., Fullerton, California.
Mean preoperative enzyme levels for total serum creatine kinase and creatine kinase isoenzyme MB were 120.1 units per 1. and 3.8 ng./ml., respectively, which were within normal limits in 78 and 74 of 81 patients, respectively. All 7 patients in the latter group with elevated creatine kinase isoenzyme MB levels before cryosurgical ablation of the prostate had isoenzyme MB-to-total creatine kinase ratios of less than 5%, which is considered to be inconsistent with myocardial injury a t our laboratory. Only 1 of 7 patients had a history of coronary artery disease and none complained of chest pain, palpitations, shortness of breath, or other clinical signs of angina or myocardial ischemia before or after surgery. In all patients the preoperative electrocardiogram was unremarkable or revealed no significant change from a prior study. In no patient did the postoperative electrocardiogram reveal any new findings suggestive of myocardial injury, that is new Q waves, S-T elevations or T wave inversions. Two patients complained of mild substernal chest pain in the recovery room, which responded to sublingual nitroglycerin. One of these patients also had a brief synocopal episode believed to be vasovagal in origin. All patients were discharged home on postoperative day 1 with no cardiac sequelae occurring during subsequent followup. Enzyme levels &r cryosurgical ablation of the prostate are listed in the table. Postoperative elevations in creatine kinase and creatine kinase isoenzyme MB levels above the upper limits of normal for each enzyme were noted in 73 of 81 patients (90%).For total serum creatine kinase and creatine kinase isoenzyme MB the enzyme levels a t each time point postoperatively differed significantly from preoperative levels (p <0.001). Mean creatine kinase values in the recovery room, and 8 and 24 hours were 811.8, 1,473.9 and 1,081.7 units per I., respectively, while mean creatine kinase isoenzyme MB values were 28.7, 50.0 and 15.5 ng./ml., respectively. There were no statistically significant correlations between patient age and postoperative levels of creatine kinase or creatine kinase isoenzyme MB at any time point. Likewise no correlations were noted between prostate volume before cryosurgical ablation of the prostate and postoperative creatine kinase or creatine kinase isoenzyme MB levels. Patients treated with prior radiation alone or neoadjuvant hormonal therapy had no significant differences in enzyme levels from those of patients with no prior therapy. Minimal changes, that is postoperative elevations of 0 to 10% versus preoperative levels, in creatine kinase and creatine kinase isoenzyme MB after cryosurgical ablation of the prostate were noted in 8 patients. These patients included 4 of 5 who had undergone prior cryosurgery and all 4 who had been previously irradiated and placed on total androgen ablation, that is not simply neoadjuvant hormonal therapy, before cryosurgery. The patient who did have significant enzyme elevations after secondary cryosurgical ablation of the prostate had a gland volume of 100 cc at the original procedure and circumferential extension of the ice ball to the capsule of the prostate could not be achieved technically during the original cryosurgery. Changes in serum creatine kinase and creatine kinase isoenzyme M B values after cryosurgery of the prostate Mean
Preop. Recovery morn* 8 Hrs. postop.* 24 Hrs. postop.' First 8-hr. change * p <0.01.
120.1 2 83.8 811.8 2 550.2 1,473.9t 894.8 1,081.7 2 658.5 1.355.7 2 917.3
z SD
3.8 2 2.5 28.7 ? 23.5 50.0 2 25.7 15.5 -C 9.4 46.6 2 26.1
ALTERED SERUM CREATINE KINASE ISOENZYME MB AFTER PROSTATE ABLATION DISCUSSION
1725
these data suggest that most patients will have an increase Creatine kinase catalyzes the conversion of adenosine in total serum creatine kinase activity after transurethral &phosphate to adenosine triphosphate, providing 1 of the prostatectomy but in nearly all cases this increase is acchief sources of energy for muscle tissue. The highest levels of counted for by an increase in the creatine kinase isoenzyme this enzyme in tissue homogenates are recorded in skeletal MM fraction. The authors concluded that significant inmuscle with 3,000units per gm.,nearly all of which consist of creases in creatine kinase isoenzyme MB activity following the MM f r a ~ t i o nThe . ~ highest concentrations of the BB frac- transurethral prostatectomy must continue to be considered tion exist in brain tissue, at 150 units per gm., and the specific for myocardial infarction, and cannot reliably be athighest fractions of the MB form exist in cardiac muscle with tributed to a potential artifact caused by transurethral prostissue homogenates yielding 80 to 100 units per gm.1.3.7.8 tatectomy per se. We demonstrated that cryoablation of the prostate proIncreases in serum creatine kinase have been associated with a variety of invasive interventions, including use of general duces dramatic increases in the creatine kinase and creatine anesthesia, intraoperative cautery and muscle splitting inci- kinase isoenzyme MB activities in the serum. This phenomMost elevations are believed to be primarily due enon appears to reach a peak at approximately 16 hours after sions.1..=~9.10 cryosurgery and then begins to subside. The degree of ento the MM fraction of the enzyme. Several investigators have examined homogenates of pros- zyme elevation appears to be independent of the pretreattate tissue to determine the levels of each specific creatine ment prostate volume, and neither prior radiation alone nor kinase isoenzyme. Tsung reported that the mean creatine short-term hormonal therapy appears to have any mitigating b a s e activity was 8 to 10 units per gm.yet he only tested 2 effect. However, this phenomenon seems to be muted by prior specimens.3 Others have reported that mean creatine kinme cryosurgical ablation of the prostate or previous treatment activity was 100 units per gm. but the number of samples with combinations of definitive radiation plus long-tern hortested was not stated.1.9-13 More recent studies suggested monal ablation. During cryosurgical ablation of the prostate that mean creatine b a s e activity is 48 units per gm. pros- some degree of cryosurgical injury to the pelvic floor or urotatic tissue6 or 0.81 international units per mg. total protein genital diaphragm may occur but this is not likely to cause in tissue homogenates.2 In these and other studies the pre- serum elevations in creatine kinase isoenzyme MB since this isoenzyme is nearly absent in skeletal m ~ s c l eAlso, . ~ benign dominant creatine kinase isoenzyme has been demonstrated prostatic hyperplasia and prostate carcinoma tissue have to be the BB fraction, ranging from 77 to 100% of the total been shown previously to have similar distributions of creacreatine kinase activity in prostate hornogenates.2.6.13.14 tine kinase isoenzymes.2 Therefore, it is unlikely that our Kimler and Sandhu reported that the second highest levels findingscompared to those reported after transurethralproswere due to the MB fraction at 14.8% with the lowest due to tatectomy can be explained by intrinsic differences in isoenthe MM fraction a t 7.2%.6 Truong et al found no significant zyme distributions between transitional zone and peripheral difference in this isoenzyme distribution between benign zone tissues. Thus, given the low serum levels of total creaprostatic hyperplasia and carcinoma tissue.2 tine kinase and creatine b a s e isoenzyme MB following Following a report of high serum creatine kinase isoen- transurethral prostatectomy noted previously, it would apzyme BB activity in a patient with disseminated prostate pear that the enzyme elevations noted after cryosurgical carcinoma,12 several studies in the urological literature have ablation of the prostate in our report result from a phenomexamined the possible relationship between this enzyme and enon that is not specific to prostate tissue injury per se but prostatic surgery as well as other types of pelvic urological rather is cryosurgery specific. The creation of extracellular surgery. However, significant increases in total creatine ki- and particularly intracellular ice via rapid tissue freezing is nase activity in the serum did not occur after routine cystos- well described as being extremely c y t ~ t o x i c .The ~ ~ cellular copy, transurethral resections of bladder tumors and ure- disruption caused by cryosurgical ablation of the prostate thral dilations.7 In addition, particular interest has been may well be much more severe and extensive than that directed toward changes in total creatine kinase activity caused by electrocautery and coagulation, resulting in masl5 These studafter transurethral resection of the pro~tate.~. sive releases of intracellular contents from prostatic epitheies reported that 65 to 100%of patients undergoing trans- lial and stromal cells into the systemic circulation. urethral resection of the prostate will exhibit increases in total serum creatine kinase activity postoperatively comCONCLUSIONS pared to preoperative levels. However, to our knowledge the Unlike data previously reported for transurethral prostapercentage of patients with increased serum creatine b a s e activity above normal levels after transurethral prostatec- tectomy, cryosurgical ablation of the prostate appears to protomy has been determined only once and only 37% of patients duce significantly elevated serum levels of creatine kinase had creatine kinase levels greater than normal postopera- isoenzyme MB in nearly all cases. This phenomenon usually persists for as long as 24 hours, and may be attenuated in tively.7 For patients with an increase in total serum creatine ki- patients previously treated with cryosurgery or combined nase activity following transurethral prostatectomy this in- radiation and hormonal therapy. Therefore, for patients uncrease appears to be predominantly due to elevations in the dergoing cryosurgical ablation of the prostate the finding of creatine kinase isoenzyme MM fraction in nearly all cases. elevated serum levels of creatine kinase isoenzyme MB may The mean percentage of the total post-transurethral prosta- not be specific for myocardial infarction. Other diagnostic tectomy creatine kinase activity accounted for by the MB tools, such as changes in the postoperative electrocardiofraction has been reported to be 1 to 7%.6.7 Furthermore, the gram, continuing clinical condition and possibly persistence percentage of patients with increased creatine kinase isoen- of the creatine kinase isoenzyme MB fraction beyond 24 zyme MB after transurethral prostatectomy significant hours, may have to be relied on to establish the diagnosis of enough to be considered diagnostic of a myocardial infarction myocardial injury in these patients. has been reported to be 07 and 9.6 In both studies, even among patients with a slight increase in the creatine kinase REFERENCES isoenzyme MB fraction at 2 to 4 hours after transurethral 1. Roberts, R., Gowda, K S., Ludbrook, P. A. and Sobel, B. E.: Prostatectomy, none had detectable levels at 24 hours. In Specificity of elevated aerum MB creatine phospholrinase acaddition the levels of total creatine kinase serum activity or tivity in the diagnosis of acute myocardial infarction.h e r . specific isoenzyme activities did not appear to have any reJ. Cardiol.. 38:433, 1975. 2. Truong, T., Carmel, M.,E l h h h M.,Cloutier, D. and L ~ ~ O U X * lationship to the volume of resection.7 Thus, in the aggregate
1726
ALTERED SERUM CREATINE KINASE ISOENZYME MB AFTER PROSTATE ABLATION
J. G.: Creatine phosphokinase isoenzymes in human prostatic tissues: a eomparison between benign hyperplasia and adenocarcinoma. Prostate, ?: 143,1985. 3. Tsung, S. H.: Creatine kinase isoenzyme patterns in human tissue obtained at surgery. Clin. Chem., 2 2 173, 1976. 4. Wong, R.and Swallen, T. 0.:Cellulose acetate electrophoresis of creatine phosphokinase isoenzymes in the diagnosis of myocardial infarction. Amer. J. Clin. Path., Sa: 209, 1975. 5. Grenadier, E., Alpan, G. and Palant, A,: Sensitivity and specificity of diagnostic tests:III CPK and CPK-MB in myocardial infarction and ischemia. Pract. Cardiol., 6 107,1980. 6.Kimler, S.C. and Sandhu, R. S.: Circulating CK-MB and CK-BB isoenzymes after prostate resection. Clin. Chem., 26.55.1980. 7. Clayman, R.V.,Ortlip, S. A. and Eckfeldt, J. H.: The diagnostic specificity of creatine kinase isoenzymes after transurethral operations. J. Urol., 130 279. 1983. 8. Smith, A. F.: Separation of tissue and serum creatine kinase isoenzymes on polyacrylamide gel slabs. Clin. Chem. Acta, 39: 351, 1972. 9.Mostert. J. W.: Electrocautery makes CPK levels rise: technique may lead to a false diagnosis of myocardial infarction, study indicates. J.A.M.A., 2 1 2 712, 1970.
10. Roberts, R. and Sobel, B. E.: Elevated plasma MB creatine phosphokinase activity. A specific marker for myocardial infarction in perioperative patients. Arch. Intern. Med., 136 421, 1976. 11. Long, J. P.: Does cryoablation have a role in the management of localized prostate carcinoma? Urol. Clin. N. Amer., in press. 12. Sandhu, R. S. and Conover, R. E.: Unusually high creatine kinase BB isoenzyme and study of lactate dehydrogenase pattern in metastatic adenocarcinoma of the prostate. Clin. Biochem., 13 30, 1980. 13. Shain, S.A,, Boesel, R. W., Klipper, R. W. and Lancaster, C. M.: Creatine kinase and lactate dehydrogenase: stability of isoenzymes and their activity in stored human plasma and prostatic tissue extracts and effect of sample dilution. Clin. Chem., 2 9 832,1983. 14. Fair, W. R., Heston, W. D. W., Kadmon, D., Crane, D. B., Catalona, W. J., Ladenson, J. H., McDonald, J. M., Noll, B. W. and Harvey, G.: Prostatic cancer, acid phosphatase, creatine kinase-BB and race: a prospective study. J. Urol., 128: 735, 1982. 15. Liang, D. S.: Value of enzyme studies after prostatic surgery. Rhode Island Med. J., 5 9 457, 1976.
JI)URNAI. OF UROLOGY
Copyright 0 1997 by
AMERICAN U R O ~ I C A L ASSOCIATION,INC.
INCREASED SERUM TOTAL CREATINE KINASE AND CREATINE KINASE ISOENZYME MB AFTER CRYOSURGICAL ABLATION OF THE PROSTATE JOHN P. LONG, MARK L. FALLICK AND WILLIAM RAND From the Tufts University School of Medicine and New England Medical Center Hospitals, Boston, Massachusetts
ABSTRACT
Purpose: Several reports have documented that the MB isoenzyme of creatine kinase is present in prostatic tissue. However, since it has been shown that lower urinary tract manipulations, including transurethral prostatectomy, do not significantly increase serum creatine kinase isoenzyme MB levels, such elevations, which are found in patients after prostatic surgery, are believed to be specific for myocardial infarction. We examined whether cryosurgical ablation of the prostate altered serum creatine kinase or isoenzyme MB levels. Materials and Methods: In 81 consecutive patients undergoing routine cryosurgical ablation of the prostate serum levels of creatine kinase and creatine kinase isoenzyme MB were measured from peripheral blood specimens drawn preoperatively, in the recovery room and at 8 and 24 hours postoperatively. Postoperative electrocardiograms were compared to the preoperative study. Results: In 72 of 81patients (89%) significant elevations in creatine kinase and creatine kinase isoenzyme MB levels were noted a t all time points after cryosurgical ablation of the prostate and appeared to reach a peak a t 16 hours postoperatively. The mean increases within the first 8 hours after cryosurgical ablation of the prostate were 1,355 units per 1. for creatine kinase and 46.6 ng./ml. for creatine kinase isoenzyme MB. No patient had any si@cant changes on the postoperative electrocardiogram. All 9 patients (11%) who did not have significant creatine kinase or creatine b a s e isoenzyme MB levels aRer cryosurgery had undergone prior cryosurgery or combined radiation and hormonal therapy. Conclusions: Cryosurgical ablation of the prostate appears to produce elevations in serum creatine kinase and creatine kinase isoenzyme MB, which are specific to the procedure. Assays for creatine kinase isoenzyme MB are unreliable to render a diagnosis of myocardial infarction after cryosurgical ablation of the prostate. KEYWORDS: prostatic neoplasms, cryosurgery,isoenzymes, creatine kinase The enzyme creatine kinase is a dimer composed of 2 subunits, that is M (muscle) and B (brain). Therefore, this molecule can exist in 3 isoenzyme forms, MM, MB and BB. Cardiac muscle has a reported total creatine b a s e activity of 400 to 600 international units per gm.with 80 to 100 international units per gm.being accounted for by the creatine kinase isoenzyme MB.1 These are believed to be the highest tissue levels of creatine b a s e isoenzyme MB in the body, although low levels of this isoenzyme have been found in tissue homogenates of smooth muscle, bladder and prostate.s-4 Because of this unique tissue distribution serum assays of creatine kinase isoenzyme MB have been widely corroborated as accurate and specific tests for myocardial infarction.'. 5 Creatine kinase isoenzyme MB has also been shown to be present in prostatic tissue in small but detectable amounts.2.6 This finding has led to several reports examining the possible role of prostatic surgery and/or lower urinary tract surgical manipulation in producing artifactual elevations of serum creatine kinase isoenzyme MB. However, significant elevations of this enzyme after transurethral resection or open prostatectomy were found to occur at a low rate6 or not at all.7 These studies confirmed that serum creatine kinase isoenzyme MB activity following conventional prostatic surgery was minimal, and that the assay still funcAccepted for publication October 18,1996.
tioned as a reliable and specific indicator of cardiac damage &r these procedures. Cryosurgical ablation of the prostate in patients with proatatic carcinoma attempts to destroy carcinomatous tissue by the direct application of low temperatures. Contemporary technique involves the transperineal placement of 3 mm. cryoprobes under continuous real-time transrectal ultrasound guidance into target areas of the prostate. In an ongoing program we evaluated the efficacy of this approach in patients with prostatic carcinoma within the last 36 months. As part of our investigation, we discovered that use of this procedure in patients with varying stages of prostate carcinoma routinely produces dramatic postoperative elevations in total creatine kinase activity and specifically in creatine kinase isoenzyme MB activity. In particular, creatine b a s e isoenzyme MB levels 1 and 24 hours after cryoablation consistently were well above the minimal criteria we used to establish a myocardial infarction. However, none of our patients had any other evidence of significant cardiac disease. We reviewed the current status of our results with this phenomenon. MATERIALS AND METHODS
Data were gathered on 81 consecutive patients with clinical stages Tlto3NOtolMO adenocarcinoma of the prostate. All patients provided informed consent to participate in an institutional review board approved pilot study ~xaminiq~
1723
1724
ALTERED SERUM CREATINE KINASE ISOENZYME MB AFTER PROSTATE ABLATION
the efficacy of cryosurgicaI ablation of the prostate in treating prostatic carcinoma. Electrocardiograms were performed on all patients as part of the routine preoperative evaluations. Intraoperative serum specimens were drawn before any prostatic manipulation but afier induction of spinal or general anesthesia. In addition, postoperative serum specimens were collected in the recovery room, and a t 8 and 24 hours postoperatively. Before each cryoablation but after the peripheral blood draw each patient underwent cystoscopy with placement of a 10.4F pigtail nephrostorny catheter into the bladder under direct endoscopic vision through a small midline suprapubic stab wound. This suprapubic tube was kept to gravity drainage during the postoperative period. No other urinary tract manipulations, that is urethral catheterizations, bladder irrigations and so forth, were done on any patient during the procedure. Each patient underwent standard cryoablation of the entire prostate with at least 5 probes used. Occasionally, depending on the anatomical dictates of the individual tumor burden, additional probes were used to ablate extraprostatic areas during cryoablation. Electrocardiograms were obtained for each patient on postoperative morning 1and were compared to the preoperative study. Total serum creatine kinase isoenzyme MB was quantitated by a standard double antibody chemoluminescence method using the manufacturer recommended methods and reagents. Total serum creatine kinase was measured by conventional enzymatic analysis using a Beckman CX7 analyzer* with Beckman reagents. Upper limits of normal for total creatine kinase and creatine kinase isoenzyme MB were 292 units per 1. and 5.9 ng./ml., respectively. Creatine kinase isoenzyme MB values greater than 12 ng./ml. were considered by the manufacturer to be highly specific for acute myocardial infarction. Statistical analysis was based on the natural logarithm of creatine kinase and isoenzyme MB because of the skewed distributions involved. Recovery room, and 8 and 24-hour levels were compared to preoperative levels using paired Student's t tests. The relationship among patient age, prostate volume, and creatine kinase and isoenzyme MB levels were measured with correlation analysis. Differences between creatine kinase and isoenzyme MB levels for those with and without prior hormonal or radiation therapy were analyzed with 2 sample t tests. Because of the multiple statistical tests run the Bonferroni correction was applied to determine statistical significance. The activities of creatine kinase and creatine kinase isoenzyme MB are expressed as mean plus or minus standard error. A value of p <0.05 was considered statistically significant. RESULTS
Patient age ranged from 46 to 82 years (mean age 65.9 ? 7.9). Mean prostatic volume (height X width x length X 0.523) before cryosurgical ablation of the prostate was 38.3 cc 2 16.1 (range 17 to 90). Of the patients 40 (49%) underwent cryosurgical ablation of the prostate with no prior treatment, while 1 had undergone prior attempts at cure with '%dine brachytherapy and 10 with external beam radiotherapy (6,800 to 7,100 cGy.1. Neoadjuvant hormonal ablation (luteinizing hormone-releasing hormone agonists with or without flutamide) was done in 21 patients (26%)for 3 ta 4 months before cryosurgical ablation of the prostate. Five patients (6.1%) had undergone prior cryosurgery and were being re-treated because of a positive biopsy on random sampling 6 months &r the original procedure. Four patients (5%)were initially treated with external beam radiotherapy with curative intent. Disease subsequently recurred and they were placed on hormonal therapy. Salvage cryosurgical ablation of the prostate was attempted after subsequent disease recurrence. Beckman Instruments, Inc., Fullerton, California.
Mean preoperative enzyme levels for total serum creatine kinase and creatine kinase isoenzyme MB were 120.1 units per 1. and 3.8 ng./ml., respectively, which were within normal limits in 78 and 74 of 81 patients, respectively. All 7 patients in the latter group with elevated creatine kinase isoenzyme MB levels before cryosurgical ablation of the prostate had isoenzyme MB-to-total creatine kinase ratios of less than 5%, which is considered to be inconsistent with myocardial injury a t our laboratory. Only 1 of 7 patients had a history of coronary artery disease and none complained of chest pain, palpitations, shortness of breath, or other clinical signs of angina or myocardial ischemia before or after surgery. In all patients the preoperative electrocardiogram was unremarkable or revealed no significant change from a prior study. In no patient did the postoperative electrocardiogram reveal any new findings suggestive of myocardial injury, that is new Q waves, S-T elevations or T wave inversions. Two patients complained of mild substernal chest pain in the recovery room, which responded to sublingual nitroglycerin. One of these patients also had a brief synocopal episode believed to be vasovagal in origin. All patients were discharged home on postoperative day 1 with no cardiac sequelae occurring during subsequent followup. Enzyme levels &r cryosurgical ablation of the prostate are listed in the table. Postoperative elevations in creatine kinase and creatine kinase isoenzyme MB levels above the upper limits of normal for each enzyme were noted in 73 of 81 patients (90%).For total serum creatine kinase and creatine kinase isoenzyme MB the enzyme levels a t each time point postoperatively differed significantly from preoperative levels (p <0.001). Mean creatine kinase values in the recovery room, and 8 and 24 hours were 811.8, 1,473.9 and 1,081.7 units per I., respectively, while mean creatine kinase isoenzyme MB values were 28.7, 50.0 and 15.5 ng./ml., respectively. There were no statistically significant correlations between patient age and postoperative levels of creatine kinase or creatine kinase isoenzyme MB at any time point. Likewise no correlations were noted between prostate volume before cryosurgical ablation of the prostate and postoperative creatine kinase or creatine kinase isoenzyme MB levels. Patients treated with prior radiation alone or neoadjuvant hormonal therapy had no significant differences in enzyme levels from those of patients with no prior therapy. Minimal changes, that is postoperative elevations of 0 to 10% versus preoperative levels, in creatine kinase and creatine kinase isoenzyme MB after cryosurgical ablation of the prostate were noted in 8 patients. These patients included 4 of 5 who had undergone prior cryosurgery and all 4 who had been previously irradiated and placed on total androgen ablation, that is not simply neoadjuvant hormonal therapy, before cryosurgery. The patient who did have significant enzyme elevations after secondary cryosurgical ablation of the prostate had a gland volume of 100 cc at the original procedure and circumferential extension of the ice ball to the capsule of the prostate could not be achieved technically during the original cryosurgery. Changes in serum creatine kinase and creatine kinase isoenzyme M B values after cryosurgery of the prostate Mean
Preop. Recovery morn* 8 Hrs. postop.* 24 Hrs. postop.' First 8-hr. change * p <0.01.
120.1 2 83.8 811.8 2 550.2 1,473.9t 894.8 1,081.7 2 658.5 1.355.7 2 917.3
z SD
3.8 2 2.5 28.7 ? 23.5 50.0 2 25.7 15.5 -C 9.4 46.6 2 26.1
ALTERED SERUM CREATINE KINASE ISOENZYME MB AFTER PROSTATE ABLATION DISCUSSION
1725
these data suggest that most patients will have an increase Creatine kinase catalyzes the conversion of adenosine in total serum creatine kinase activity after transurethral &phosphate to adenosine triphosphate, providing 1 of the prostatectomy but in nearly all cases this increase is acchief sources of energy for muscle tissue. The highest levels of counted for by an increase in the creatine kinase isoenzyme this enzyme in tissue homogenates are recorded in skeletal MM fraction. The authors concluded that significant inmuscle with 3,000units per gm.,nearly all of which consist of creases in creatine kinase isoenzyme MB activity following the MM f r a ~ t i o nThe . ~ highest concentrations of the BB frac- transurethral prostatectomy must continue to be considered tion exist in brain tissue, at 150 units per gm., and the specific for myocardial infarction, and cannot reliably be athighest fractions of the MB form exist in cardiac muscle with tributed to a potential artifact caused by transurethral prostissue homogenates yielding 80 to 100 units per gm.1.3.7.8 tatectomy per se. We demonstrated that cryoablation of the prostate proIncreases in serum creatine kinase have been associated with a variety of invasive interventions, including use of general duces dramatic increases in the creatine kinase and creatine anesthesia, intraoperative cautery and muscle splitting inci- kinase isoenzyme MB activities in the serum. This phenomMost elevations are believed to be primarily due enon appears to reach a peak at approximately 16 hours after sions.1..=~9.10 cryosurgery and then begins to subside. The degree of ento the MM fraction of the enzyme. Several investigators have examined homogenates of pros- zyme elevation appears to be independent of the pretreattate tissue to determine the levels of each specific creatine ment prostate volume, and neither prior radiation alone nor kinase isoenzyme. Tsung reported that the mean creatine short-term hormonal therapy appears to have any mitigating b a s e activity was 8 to 10 units per gm.yet he only tested 2 effect. However, this phenomenon seems to be muted by prior specimens.3 Others have reported that mean creatine kinme cryosurgical ablation of the prostate or previous treatment activity was 100 units per gm. but the number of samples with combinations of definitive radiation plus long-tern hortested was not stated.1.9-13 More recent studies suggested monal ablation. During cryosurgical ablation of the prostate that mean creatine b a s e activity is 48 units per gm. pros- some degree of cryosurgical injury to the pelvic floor or urotatic tissue6 or 0.81 international units per mg. total protein genital diaphragm may occur but this is not likely to cause in tissue homogenates.2 In these and other studies the pre- serum elevations in creatine kinase isoenzyme MB since this isoenzyme is nearly absent in skeletal m ~ s c l eAlso, . ~ benign dominant creatine kinase isoenzyme has been demonstrated prostatic hyperplasia and prostate carcinoma tissue have to be the BB fraction, ranging from 77 to 100% of the total been shown previously to have similar distributions of creacreatine kinase activity in prostate hornogenates.2.6.13.14 tine kinase isoenzymes.2 Therefore, it is unlikely that our Kimler and Sandhu reported that the second highest levels findingscompared to those reported after transurethralproswere due to the MB fraction at 14.8% with the lowest due to tatectomy can be explained by intrinsic differences in isoenthe MM fraction a t 7.2%.6 Truong et al found no significant zyme distributions between transitional zone and peripheral difference in this isoenzyme distribution between benign zone tissues. Thus, given the low serum levels of total creaprostatic hyperplasia and carcinoma tissue.2 tine kinase and creatine b a s e isoenzyme MB following Following a report of high serum creatine kinase isoen- transurethral prostatectomy noted previously, it would apzyme BB activity in a patient with disseminated prostate pear that the enzyme elevations noted after cryosurgical carcinoma,12 several studies in the urological literature have ablation of the prostate in our report result from a phenomexamined the possible relationship between this enzyme and enon that is not specific to prostate tissue injury per se but prostatic surgery as well as other types of pelvic urological rather is cryosurgery specific. The creation of extracellular surgery. However, significant increases in total creatine ki- and particularly intracellular ice via rapid tissue freezing is nase activity in the serum did not occur after routine cystos- well described as being extremely c y t ~ t o x i c .The ~ ~ cellular copy, transurethral resections of bladder tumors and ure- disruption caused by cryosurgical ablation of the prostate thral dilations.7 In addition, particular interest has been may well be much more severe and extensive than that directed toward changes in total creatine kinase activity caused by electrocautery and coagulation, resulting in masl5 These studafter transurethral resection of the pro~tate.~. sive releases of intracellular contents from prostatic epitheies reported that 65 to 100%of patients undergoing trans- lial and stromal cells into the systemic circulation. urethral resection of the prostate will exhibit increases in total serum creatine kinase activity postoperatively comCONCLUSIONS pared to preoperative levels. However, to our knowledge the Unlike data previously reported for transurethral prostapercentage of patients with increased serum creatine b a s e activity above normal levels after transurethral prostatec- tectomy, cryosurgical ablation of the prostate appears to protomy has been determined only once and only 37% of patients duce significantly elevated serum levels of creatine kinase had creatine kinase levels greater than normal postopera- isoenzyme MB in nearly all cases. This phenomenon usually persists for as long as 24 hours, and may be attenuated in tively.7 For patients with an increase in total serum creatine ki- patients previously treated with cryosurgery or combined nase activity following transurethral prostatectomy this in- radiation and hormonal therapy. Therefore, for patients uncrease appears to be predominantly due to elevations in the dergoing cryosurgical ablation of the prostate the finding of creatine kinase isoenzyme MM fraction in nearly all cases. elevated serum levels of creatine kinase isoenzyme MB may The mean percentage of the total post-transurethral prosta- not be specific for myocardial infarction. Other diagnostic tectomy creatine kinase activity accounted for by the MB tools, such as changes in the postoperative electrocardiofraction has been reported to be 1 to 7%.6.7 Furthermore, the gram, continuing clinical condition and possibly persistence percentage of patients with increased creatine kinase isoen- of the creatine kinase isoenzyme MB fraction beyond 24 zyme MB after transurethral prostatectomy significant hours, may have to be relied on to establish the diagnosis of enough to be considered diagnostic of a myocardial infarction myocardial injury in these patients. has been reported to be 07 and 9.6 In both studies, even among patients with a slight increase in the creatine kinase REFERENCES isoenzyme MB fraction at 2 to 4 hours after transurethral 1. Roberts, R., Gowda, K S., Ludbrook, P. A. and Sobel, B. E.: Prostatectomy, none had detectable levels at 24 hours. In Specificity of elevated aerum MB creatine phospholrinase acaddition the levels of total creatine kinase serum activity or tivity in the diagnosis of acute myocardial infarction.h e r . specific isoenzyme activities did not appear to have any reJ. Cardiol.. 38:433, 1975. 2. Truong, T., Carmel, M.,E l h h h M.,Cloutier, D. and L ~ ~ O U X * lationship to the volume of resection.7 Thus, in the aggregate
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ALTERED SERUM CREATINE KINASE ISOENZYME MB AFTER PROSTATE ABLATION
J. G.: Creatine phosphokinase isoenzymes in human prostatic tissues: a eomparison between benign hyperplasia and adenocarcinoma. Prostate, ?: 143,1985. 3. Tsung, S. H.: Creatine kinase isoenzyme patterns in human tissue obtained at surgery. Clin. Chem., 2 2 173, 1976. 4. Wong, R.and Swallen, T. 0.:Cellulose acetate electrophoresis of creatine phosphokinase isoenzymes in the diagnosis of myocardial infarction. Amer. J. Clin. Path., Sa: 209, 1975. 5. Grenadier, E., Alpan, G. and Palant, A,: Sensitivity and specificity of diagnostic tests:III CPK and CPK-MB in myocardial infarction and ischemia. Pract. Cardiol., 6 107,1980. 6.Kimler, S.C. and Sandhu, R. S.: Circulating CK-MB and CK-BB isoenzymes after prostate resection. Clin. Chem., 26.55.1980. 7. Clayman, R.V.,Ortlip, S. A. and Eckfeldt, J. H.: The diagnostic specificity of creatine kinase isoenzymes after transurethral operations. J. Urol., 130 279. 1983. 8. Smith, A. F.: Separation of tissue and serum creatine kinase isoenzymes on polyacrylamide gel slabs. Clin. Chem. Acta, 39: 351, 1972. 9.Mostert. J. W.: Electrocautery makes CPK levels rise: technique may lead to a false diagnosis of myocardial infarction, study indicates. J.A.M.A., 2 1 2 712, 1970.
10. Roberts, R. and Sobel, B. E.: Elevated plasma MB creatine phosphokinase activity. A specific marker for myocardial infarction in perioperative patients. Arch. Intern. Med., 136 421, 1976. 11. Long, J. P.: Does cryoablation have a role in the management of localized prostate carcinoma? Urol. Clin. N. Amer., in press. 12. Sandhu, R. S. and Conover, R. E.: Unusually high creatine kinase BB isoenzyme and study of lactate dehydrogenase pattern in metastatic adenocarcinoma of the prostate. Clin. Biochem., 13 30, 1980. 13. Shain, S.A,, Boesel, R. W., Klipper, R. W. and Lancaster, C. M.: Creatine kinase and lactate dehydrogenase: stability of isoenzymes and their activity in stored human plasma and prostatic tissue extracts and effect of sample dilution. Clin. Chem., 2 9 832,1983. 14. Fair, W. R., Heston, W. D. W., Kadmon, D., Crane, D. B., Catalona, W. J., Ladenson, J. H., McDonald, J. M., Noll, B. W. and Harvey, G.: Prostatic cancer, acid phosphatase, creatine kinase-BB and race: a prospective study. J. Urol., 128: 735, 1982. 15. Liang, D. S.: Value of enzyme studies after prostatic surgery. Rhode Island Med. J., 5 9 457, 1976.