Curr Urol Rep (2015) 16: 25 DOI 10.1007/s11934-015-0499-5

UROTHELIAL CANCER (A SAGALOWSKY, SECTION EDITOR)

Postoperative Changes in Serum CO2 as an Indicator of Postoperative Complications After Radical Cystectomy Mark D. Tyson & Eric S. Wisenbaugh & Michael Patton & Daniel Salevitz & Erik P. Castle

Published online: 17 March 2015 # Springer Science+Business Media New York 2015

Abstract The purpose of this article was to review the relationship of postoperative CO2 levels to the risk of complications after radical cystectomy. In this review, we summarize the existing body of literature on the topic as well as metabolic complications after urinary diversion. Currently, there are no studies that specifically examine CO2 levels in the context of complications after radical cystectomy; therefore, we also present our own institutional data which demonstrate that a drop in postoperative CO2 levels is highly predictive of complications, the most common of which is failure to thrive. These data indicate that significant changes in CO2 levels prior to discharge after a radical cystectomy may be a harbinger of forthcoming complications. Keywords Cystectomy . Readmission . Failure to thrive . Acidosis . Complications

Introduction Radical cystectomy is the gold standard for the treatment of clinically localized muscle invasive bladder cancer. However, this is a complex operation with significant perioperative morbidity with a complication rate as high as 60 % and a mortality This article is part of the Topical Collection on Urothelial Cancer

M. D. Tyson (*) : E. S. Wisenbaugh : M. Patton : D. Salevitz : E. P. Castle Department of Urology, Mayo Clinic Hospital, 5777 E. Mayo Blvd, Phoenix, AZ 85054, USA e-mail: [email protected] E. S. Wisenbaugh e-mail: [email protected] E. P. Castle e-mail: [email protected]

rate as high as 3 % [1–5]. Efforts to reduce this morbidity would undoubtedly not only improve outcomes and patient satisfaction but also could be valuable to the institution from a cost standpoint. While there are many factors that influence postoperative morbidity after radical cystectomy, many of these complications are related to the metabolic disturbances that occur after urinary diversion. In our experience, a substantial number of patients are readmitted for a failure to thrive syndrome which is characterized by poor oral intake, dehydration, fatigue, malaise, and weakness. Anecdotally, we have noted that many of these patients are acidotic at the time of discharge from the index hospitalization leading us to hypothesize that correction of CO2 levels prior to discharge may prevent readmissions for this common syndrome. However, virtually no published data exists on the relationship between CO2 levels and complications after radical cystectomy or after any major abdominal surgery for that matter. In this review, we examine the relationship of postoperative CO2 levels to complications after radical cystectomy and present institutional data which demonstrates this relationship.

A Brief Primer on the Metabolic Disturbances After Urinary Diversion Metabolic abnormalities after urinary diversion are well documented. The most common metabolic complications result from electrolyte abnormalities which are a consequence of altered reabsorption of solutes across the intestinal mucosa. The type of metabolic complication is highly dependent upon the type of urinary diversion that is employed, the surface area of the segment used, the dwell time of urine, and the renal function. The most common forms of urinary diversion use segments of the ileum in their formation. The classic teaching is that

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ileal segments used in diversion can lead to hyperchloremic metabolic acidosis, which occurs in only about 25 % of patients [6]. The physiologic mechanism of this metabolic disturbance pertains to the ionized transport of ammonium as ammonium substitutes for sodium in the sodium hydrogen antiport [7]. Due to the fact that the exchange of ammonia for a proton is coupled with the exchange of bicarbonate for chloride, ammonium chloride is reabsorbed in exchange for carbonic acid (CO2 and H2O), resulting in hyperchloremic metabolic acidosis. The bowel segments that most commonly result in metabolic acidosis are the ileum or ileocolic reservoirs, colon, and jejunum. The latter segment most commonly results in a hyponatremic, hypochloremic, hyperkalemic metabolic acidosis [7]. Gastric segments most commonly result in hypokalemic, hypochloremic metabolic alkalosis [7]. Other electrolyte abnormalities that have been described after urinary diversion also include hypomagnesemia, hypocalcemia, hypoammonemia, as well as deterioration of renal function as evidenced by elevations in the blood urea nitrogen and creatinine levels. Regardless of the segment used, these abnormalities can lead to severe symptoms such as dehydration, fatigue, anorexia, lethargy, weakness, and nausea, often leading to a readmission for failure to thrive. As an aside, nutritional abnormalities are also common after urinary diversion and may lead to metabolic disturbances as well. Resection of a segment of the ileum may also result in the malabsorption of bile salts and vitamin B12 which are essential for the absorption of lipids in the terminal ileum [8]. This may in turn lead to gallstone formation, megaloblastic anemia, or neurologic symptoms.

Treatment of Metabolic Abnormalities The mainstay in the treatment of metabolic abnormalities after urinary diversion, more specifically hyperchloremic metabolic acidosis, involves the administration of oral alkalizing agents or blockers of chloride transport. There are three primary buffer systems in normal plasma: total phosphate, anionic protein, and total carbon dioxide (CO2, H2CO3, and HCO3−). The acid-base balance is nearly completely dependent upon the total carbon dioxide and hydrogen concentrations which is precisely what makes sodium bicarbonate so effective in restoring normal acid-base balance [9••]. Sodium bicarbonate increases the plasma bicarbonate levels which buffers excess hydrogen ion concentration, raises the blood pH, and reverses the clinical manifestations of acidosis described above [9••]. Sodium bicarbonate should be used with caution in patients with chloride loss from vomiting or from continuous gastrointestinal suction, hypocalcemia, a history of seizures, and congestive heart failure and patients with renal insufficiency [10]. Chloride transport inhibitors, such as

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chlorpromazine and nicotinic acid, can be used as well. These medications work by impeding chloride transport by inhibiting cyclic adenosine monophosphate.

Relationship of Metabolic Disturbances to Increased Readmission Rates After Radical Cystectomy As previously mentioned, no published data on the relationship of CO2 levels and complications after radical cystectomy or any other intra-abdominal surgery for that matter exist. Therefore, we performed a recent retrospective review of our institutional cystectomy database in an effort to elucidate the relationship of postoperative CO2 levels with complications after radical cystectomy (unpublished work: Tyson, Castle, et al. 2014). Our institutional cystectomy data set was queried for patients who underwent cystectomy from 1998 to 2013 (N = 643). Table 1 summarizes the clinical and demographic

Table 1

Patient demographics and clinical characteristics n (%) or median (IQR)

Median age (IQR) Female sex Robotic approach Continent diversion Median OR time (IQR) Median BMI Median LN yield (IQR) Median LOS (IQR) Median EBL (IQR) Blood transfusion ASA score 2 3 4 90-day readmission 90-day readmission for FTT

71 (64, 77) 129 (20.1 %) 152 (23.6 %) 133 (20.7 %) 265 (218, 327) 27 (25, 31) 10 (6, 16) 8 (6, 10) 400 (250, 650) 308 (47.9 %) 231 (37.0 %) 372 (59.6 %) 20 (3.2 %) 144 (22.9 %) 37 (6.9 %)

Pathologic stage T0 T1 T2 T3 T4 CIS only Other tumor type Benign pathology

64 (10.4 %) 94 (15.3 %) 205 (33.4 %) 76 (12.4 %) 43 (7.0 %) 26 (4.2 %) 59 (9.6 %) 46 (7.5 %)

IQR interquartile range, OR operating room, BMI body mass index, ASA American Society of Anesthesiology, FTT failure to thrive, CIS carcinoma in situ

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characteristics of the cohort. Of these, 22 % were readmitted to institution within 90 days of discharge. Of these, 26 % were readmitted for failure to thrive. To determine the predictors of failure to thrive, a logistic regression analysis was performed. On univariate analysis, age greater than 75 years and mean change in CO2 levels were associated with failure to thrive. Approximately 11 % of patients over the age of 75 years were readmitted for failure to thrive compared to only 4 % of patients under the age of 75 (p = 0.001). The mean change in CO2 levels for patients readmitted for failure to thrive was −2.40 mmol/l compared to −0.77 mmol/l among patients that were not readmitted (p=0.02). On multivariate logistic regression analysis (Table 2), both age greater than 75 years (OR 3.4, 95 % CI: 1.6–7.5, p=0.002) and a drop in CO2 levels greater than 6 mmol/l (OR 3.1, 95 % CI: 1.4–7.0, p=0.007) retain their significant association with readmission for failure to thrive. Notably, continent forms of diversion were also associated with readmission for failure to thrive (OR 2.6, 95 % CI: 1.1–6.1, p=0.04). There was no interaction between postoperative CO 2 levels and postoperative creatinine values (p = 0.20). Taken together, these data suggest that among patients undergoing radical cystectomy, the risk of readmission for failure to thrive is highest among patients over the age of 75 years who undergo continent forms of diversion and experience a drop in CO2 levels greater than or equal to 6 mmol/l. Given the above explanation, metabolic acidosis after radical cystectomy may be an easy target for quality improvement. Whether the acidosis shares a causative relationship with the failure to thrive syndrome or is merely associated with it remains to be determined. In the case of the former, efforts to correct the acidosis prior to discharge from the index hospitalization may prevent readmissions for failure to thrive after radical cystectomy. In the case of the latter, recognition of large drops in CO2 levels postoperatively may serve as a warning sign to regard that patient as high risk of readmission for failure to thrive, especially if they are over the age of 75 years and have undergone a continent form of diversion. As no study to date has examined Table 2 Multivariable logistic regression model of predictors of 90-day readmission for failure to thrive

Age ≥75 years Change in CO2 ≥6 mmol/l Continent diversion ASA score

Odds ratio

95 % confidence interval

p

3.40 3.07 2.55 1.35

1.55–7.47 1.36–6.95 1.07–6.09 0.71–2.60

0.002 0.007 0.035 0.36

the relationship of CO 2 levels to complications after radical cystectomy, these data are uniquely informative.

Future Directions Since no prospective data on the topic exist, the next obvious step in the understanding of this relationship is a clinical trial. While anecdotal experience is useful for hypothesis generation, these unpublished data are limited by their generalizability as well as lack of peer review. We are currently in the design phases of this study and will report the results accordingly.

Conclusion Metabolic abnormalities after radical cystectomy and urinary diversion are a common complication. These disturbances are related to electrolyte abnormalities which result from altered transport of solutes. Anecdotal experience suggests that these disturbances are correctable with oral medical therapy and may result in lower complication rates and readmission rates after this very complex operation. Prospective data from clinical trials are needed to confirm this but the initial results appear promising. Efforts to reduce complications after radical cystectomy are important both for patient satisfaction and cost-effectiveness after this highly complex operation. Acknowledgments Mark D. Tyson, MD, had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. We would like to thank Desert Mountain’s Cancer Awareness Through Research and Education (C.A.R.E.) organization for its generous support of the genitourinary research program at Mayo Clinic, Scottsdale, Arizona. Compliance with Ethics Guidelines Conflict of Interest Dr. Mark D. Tyson, Dr. Eric S. Wisenbaugh, Dr. Michael Patton, Dr. Daniel Salevitz, and Dr. Erik P. Castle each declare no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References Papers of particular interest, published recently, have been highlighted as: •• Of major importance 1.

Chang SS, Cookson MS, Baumgartner RG, Wells N, Smith Jr JA. Analysis of early complications after radical cystectomy: results of a collaborative care pathway. J Urol. 2002;167(5):2012.

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Cookson MS, Chang SS, Wells N, Parekh DJ, Smith Jr JA. Complications of radical cystectomy for nonmuscle invasive disease: comparison with muscle invasive disease. J Urol. 2003;169(1):101. 3. Hollenbeck BK, Miller DC, Taub D, Dunn RL, Khuri SF, Henderson WG, et al. Identifying risk factors for potentially avoidable complications following radical cystectomy. J Urol. 2005;174(4 Pt 1):1231. 4. Konety BR, Allareddy V, Herr H. Complications after radical cystectomy: analysis of population-based data. Urology. 2006;68(1):58. 5. Novotny V, Hakenberg OW, Wiessner D, Heberling U, Litz RJ, Oehlschlaeger S, et al. Perioperative complications of radical cystectomy in a contemporary series. Eur Urol. 2007;51(2):397.

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Studer UE, Burkland FC, Schumacher TM, et al. Twenty years experience with an ileal orthotopic low pressure bladder substitute—lessons to be learned. J Urol. 2006;176:161–6. 7. Dahl DM, Mcdougal WS. Use of intestinal segments in urinary diversion. Cambell-Walsh Urology. 2014 8. Mills RD, Studer UE. Metabolic consequences of continent urinary diversion. J Urol. 1999;161(4):1057. 9.•• Adeva-Andany MM, Fernández-Fernández C, Mouriño-Bayolo D, Castro-Quintela E, Domínguez-Montero A. Sodium bicarbonate therapy in patients with metabolic acidosis. Sci World J. 2014;2014, 627673. This reference is important because it contains a nice review of the use of Sodium Bicarb in the treatment of metabolic acidosis. 10. Physician Desk Reference 2014.

Postoperative changes in serum CO2 as an indicator of postoperative complications after radical cystectomy.

The purpose of this article was to review the relationship of postoperative CO2 levels to the risk of complications after radical cystectomy. In this ...
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