Blood Transfusion Requirement and Not Preoperative Anemia Are Associated with Perioperative Complications Following Intracorporeal Robot-Assisted Radical Cystectomy

Abstract

Objectives:

To assess the prevalence of preoperative anemia and the impact of preoperative anemia and blood transfusion requirement on 30- and 90-day complications in a cohort of patients undergoing robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC).

Patients and Methods:

IRARC was performed on 166 patients between June 2011 and March 2016. Prospective data were collected for patient demographics, clinical and pathologic characteristics, perioperative variables, transfusion requirements, and hospital length of stay. Thirty- and 90-day complications were classified according to the modified Memorial Sloan Kettering Cancer Center Clavien–Dindo system.

Results:

Preoperative anemia was common (43.4%) and greatest in patients receiving neoadjuvant chemotherapy (48.6%) (p < 0.001). Patients with preoperative anemia were significantly more likely to have an Ileal conduit (p = 0.033), higher cystectomy stage (≥pT3) (p = 0.028), and a lower lymph node yield (p = 0.031). Preoperative anemia was not associated with increased perioperative morbidity but was associated with the requirement for blood transfusion (p = 0.001).

Blood transfusion required in 20.4% of patients with intraoperative and postoperative blood transfusion rate was 10.2% and 13.9%, respectively. The 30-day all complication rate and 30-day major complication rate were 55.4% and 15.7%, respectively, while 90-day all complication rate and 90-day major complication rate were 65.7% and 19.3%, respectively. Intraoperative blood transfusion was not associated with increased complications, but postoperative blood transfusion requirement was independently associated with perioperative morbidity: all 30-day complications (p = 0.003), all 90-day complications (p = 0.009), and 90-day major complications (p = 0.004).

Conclusion:

The presence of preoperative anemia in patients undergoing iRARC is not associated with increased surgical risk, although preoperative anemic patients were significantly more likely to require blood transfusion. Blood transfusion requirement and specifically postoperative blood transfusion are independently associated with perioperative morbidity and are an important factor for the optimization of postoperative outcomes.

Introduction

Bladder cancer is a disease affecting predominantly elderly patients often with associated comorbidity such as cardiovascular and respiratory disease secondary to tobacco smoking and exposure to environmental carcinogens. Radical cystectomy with urinary diversion is the gold-standard treatment for muscle invasive and highest risk bladder cancer but carries a risk of significant perioperative complications.

Preoperative anemia and blood transfusion have been shown to be associated with higher 30-day morbidity and mortality rate following major noncardiac surgery.^1
–3 While preoperative anemia in patients undergoing radical cystectomy has been associated with worse oncologic outcomes,⁴ the relationship between preoperative anemia and postoperative complications has not been investigated in the setting of radical cystectomy.

Efforts to minimize perioperative complications by means of a minimally invasive approach using a robotic platform have shown limited benefits according to data from randomized controlled trials^5

–8 and this has been confirmed in a meta-analysis.⁹ However, these trials were feasibility studies, trials that were closed early before planned recruitment, or were measuring surrogate endpoints. One advantage of a robotic approach that is consistently reported is the reduction in operative blood loss and blood transfusion requirement. Open radical cystectomy (ORC) has a reported perioperative transfusion rate of 24% to 83%, which is significantly lower than the 0% to 39% reported for RARC.¹⁰

In this study, we report the prevalence of preoperative anemia in patients undergoing radical cystectomy and investigate whether preoperative anemia is associated with 30- and 90-day morbidity in patients undergoing robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC). A secondary aim is to explore the interplay between blood transfusion requirement, preoperative anemia, and perioperative morbidity.

Patients and Methods

Patient population

Data for patients treated by iRARC were prospectively recorded to an institutional approved database. Patients included in this analysis were treated between June 2011 and March 2016. During this period, 166 patients underwent iRARC and were included in the analysis. Urinary diversion was either ileal conduit or continent diversion (neobladder or Mitrofanoff), and all cases were performed by one of two surgeons. This study was registered with our institutional department and is part of an ongoing quality assurance program (Urology2015.2).

Surgical technique

Our technique for iRARC has previously been described.¹¹ Briefly, iRARC was performed through a standard 6-port transperitoneal approach in 27° Trendelenburg. Extent of pelvic lymph node dissection included external, internal, common iliac, and obturator fossa lymph nodes. An Endo Catch bag (Covidien, Dublin, Ireland) was used to retrieve specimens either from the vagina if possible in females or an iliac fossa incision in other cases. Ileal conduit formation was performed using a 15 cm segment of terminal ileum from the ileocecal valve, which was isolated by a laparoscopic 60 mm intestinal stapler (Endo-GIA; Covidien Corp, Dublin, Ireland). Continent diversion was constructed using a 50 cm segment of terminal ileum. Ureteroileal anastomosis was constructed using either a Bricker or Wallace anastomosis depending on surgeon preference with 6 Fr infant feeding tubes/Bander stents, which were externalized as ureteral stents.

Data collected

Patient demographics, clinical and pathologic characteristics, perioperative variables, blood transfusion requirement, hospital length of stay (LOS), and standardized complication data were prospectively recorded. Preoperative cardiopulmonary exercise testing (CPET) was performed on 115 patients (69.3%) to determine the following results: anaerobic threshold (AT), peak oxygen consumption (Peak VO₂), and minute ventilation–carbon dioxide production (VE/VCO₂). All patients were followed up for a minimum of 90 days postsurgery.

Study outcomes measured

Thirty and 90-day complications were classified according to the modified Memorial Sloan-Kettering Cancer Center (MSKCC) Clavien–Dindo (CD) system.¹² CD I-II and CD III-V were defined as minor and major complications, respectively. Preoperative anemia status was defined as hemoglobin <13 g/dL in men and hemoglobin <12.0 g/dL in women in accordance with the WHO criteria.¹³ Anemia severity was classified as mild (men: 11.0–12.9 g/dL, women: 11.0–11.9 g/dL), moderate (men and women: 8.0–10.9 g/dL), and severe (men and women: <8.0 g/dL).

Medical complications were defined as cardiovascular, neurologic, noninfective pulmonary, prerenal failure, nonsurgical-related gastrointestinal (GI) complications. Infective complications were defined as the development of pyrexia (38°C) often with an attributable cause such as genitourinary, pulmonary, or intra-abdominal collection.

Statistic methods

For continuous data, the following descriptive statistics were used: mean, median, interquartile range, standard deviation, and confidence interval (95% CI). Chi square test and t-test were used for categoric and continuous variables, respectively. Multivariable logistic regression was performed on variables with significance in univariate analysis. For the primary analysis, all cases were included (n = 166); propensity score matching was performed as a subanalysis for 121 cases. Propensity score was derived from a multivariable logistic regression model taking into account the following variables: use of neoadjuvant chemotherapy (NAC), type of urinary diversion, cystectomy stage, and lymph node dissection yield. Statistic significance was set at p ≤ 0.05. Statistic analysis was performed using SPSS v22 (IBM, New York).

Results

Patient demographics, type of urinary diversion, physiologic status, prior therapy, and histopathologic outcomes for 166 cases stratified according to preoperative anemia status are shown in Table 1 and blood transfusion requirement in Table 2. Overall, 43.4% (72/166) of patients were anemic preoperatively and 20.5% (34/166) received a blood transfusion. Patients who had NAC (p < 0.001), ileal conduit reconstruction (p = 0.033), cystectomy stage ≥pT3 (p = 0.028), and lower lymph node yield (p = 0.031) were more likely to be anemic preoperatively. The results following propensity score matching are shown in Supplementary Table S1 (Supplementary Data are available at www.liebertpub.com/end) and confirm that preoperative anemia was not associated with perioperative morbidity. Preoperative blood transfusion was administered in 5.4% (9/166) of patients while intraoperative and postoperative blood transfusion was performed in 10.2% (17/166) and in 13.9% (23/166) of patients, respectively. Preoperative anemic patients were significantly more likely to require intraoperative blood transfusion (p = 0.004).

Table 1.

Patient Demographics, Preoperative, and Pathologic Variables Stratified According to Preoperative Anemia Status

Variable	All patients (n = 166)	Anemia ^a (n = 72)	No anemia (n = 94)	p
Sex				0.312
Male	125 (75.3)	57 (77.0)	68 (73.9)
Female	41 (24.7)	15 (36.6)	26 (63.4)
Age group				0.349
<65 years	83 (50.0)	33 (45.8)	50 (53.2)
≥65 years	83 (50.0)	29 (54.2)	44 (46.8)
Type of urinary diversion				0.020
Ileal conduit	126(75.9)	61 (84.7)	65 (69.1)
Continent diversion	40 (24.1)	11 (15.3)	29 (30.9)
ASA				0.796
I and II	101 (60.8)	43 (59.7)	58 (61.7)
≥III	65 (39.2)	29 (40.3)	36 (38.3)
BMI, mean ± SD	27.40 ± 4.73	27.03 ± 4.68	27.66 ± 4.78	0.454
CPET
AT, mean ± SD	10.29 ± 2.03	10.19 ± 1.65	10.36 ± 2.25	0.639
Peak VO₂, mean ± SD	15.60 ± 4.82	15.04 ± 4.41	15.99 ± 5.07	0.261
VE/VCO₂, mean ± SD	34.06 ± 5.33	34.64 ± 5.80	33.67 ± 4.98	0.304
Neoadjuvant chemotherapy	51 (30.7)	35 (48.6)	16 (17.0)	<0.001
Previous pelvic radiotherapy	14 (8.4)	6 (8.1)	8 (8.7)	0.968
Cystectomy stage				0.028
≤pT2	102 (62.2)	38 (52.8)	64 (69.6)
≥pT3	62 (37.8)	34 (47.2)	28 (31.1)
Lymph node yield, mean ± SD	14.54 ± 9.26	12.80 ± 7.68	15.85 ± 10.14	0.031
Transfusion requirement	34 (20.5)	24 (33.3)	10 (10.6)	<0.001
Intraoperative	17 (10.2)	13 (18.1)	4 (4.3)	0.004
Postoperative	23 (13.9)	14 (19.4)	9 (9.6)	0.068
Blood units transfused, mean ± SD	1.03 ± 4.32	1.57 ± 5.66	0.60 ± 2.81	0.152

Normal reference range for CPET variables: AT ≥11 mL/kg/min; Peak VO₂ ≥15 ml/kg/min; VE/VCO₂ ≤32.

Men: hemoglobin <13 g/dL, women: hemoglobin <12.0 g/dL.

ASA = American Society of Anesthesiologist score; AT = anaerobic threshold; BMI = body mass index; CPET = cardiopulmonary exercise testing; Peak VO₂ = maximal oxygen consumption; VE/VCO₂ = minute ventilation–carbon dioxide production.

Table 2.

Patient Demographics, Preoperative, And Pathologic Variables Stratified According to Blood Transfusion Requirement

Variable	All patients (n = 166)	Blood transfusion (n = 34)	No blood transfusion (n = 132)	p
Male sex	125 (75.3)	23 (67.6)	102 (77.3)	0.246
Age group				0.249
<65 years	83 (50.0)	20 (58.8)	63 (47.7)
≥65 years	83 (50.0)	14 (41.2)	69 (52.3)
Type of urinary diversion				0.151
Ileal conduit	126(75.9)	629 (85.3)	97 (73.5)
Neobladder	40 (24.1)	5 (14.7)	35 (26.5)
ASA				0.290
I and II	101 (60.8)	18 (52.9)	83 (62.9)
≥III	65 (39.2)	16 (47.1)	49 (37.1)
BMI, mean ± SD	27.40 ± 4.73	28.06 ± 5.71	27.28 ± 4.57	0.512
CPET
AT, mean ± SD	10.29 ± 2.03	10.00 ± 1.29	10.34 ± 2.1	0.503
Peak VO₂, mean ± SD	15.60 ± 4.82	14.00 ± 3.54	15.88 ± 4.97	0.108
VE/VCO₂, mean ± SD	34.06 ± 5.33	35.09 ± 6.53	33.88 ± 5.10	0.349
Neoadjuvant chemotherapy	51 (30.7)	20 (58.8)	14 (51.2)	0.138
Previous pelvic radiotherapy	14 (8.4)	4 (28.6)	10 (71.4)	0.433
Cystectomy stage				0.211
≤pT2	102 (62.2)	18 (52.9)	84 (64.6)
≥pT3	62 (37.8)	16 (47.1)	46 (35.4)
Lymph node yield, mean ± SD	14.54 ± 9.26	14.30 ± 8.72	14.60 ± 9.43	0.869

Normal reference range for CPET variables: AT ≥11 ml/kg/min; Peak VO₂ ≥15 mL/kg/min; VE/VCO₂ ≤32.

The 30-day all complication and 30-day major complication rate was 55.4% and 15.7%, respectively, while the 90-day all complication and 90-day major complication rate was 65.7% and 19.3%, respectively. GI and infective adverse events were the two most common complications affecting 43.4% and 33.7% of the patient cohort, respectively. There was no relation between GI or infective events and anemia or transfusion, however, postoperative ileus, which developed in 24.1% (40/166) of patients, was associated with blood transfusion requirement (p = 0.031). The 90-day mortality rate was 2.4%, and deaths were attributed to cardiac arrest in two patients, significant postoperative bleeding resulting in disseminated intravascular coagulation and ischemic bowel in one patient, and one patient died from carcinomatosis secondary to a pT4 N0 transitional cell carcinoma.

Preoperative anemia was not associated with 30-day or 90-day morbidity, 90-day readmission rate, and median LOS (Table 3A). No relationship was identified between severity of anemia and complications when anemia was further classified as mild or moderate anemia (only one patient had severe anemia) (Supplementary Table S2). In addition, the propensity score-matched cohort confirmed that preoperative anemia was not associated with perioperative morbidity (Table 3B).

Table 3.

(A) Perioperative Morbidity of Patients Stratified According to Preoperative Anemia Status, (B) Propensity Score-Matched Perioperative Morbidity of Patients Stratified According to Preoperative Anemia Status

(A)
Variable	All patients (n = 166)	Anemia ^a (n = 72)	No anemia (n = 94)	p
30-day complication rate	92 (55.4)	37 (51.4)	55 (58.5)	0.360
30-day major complication rate	26 (15.7)	10 (13.9)	16 (17.0)	0.582
30-day infective complications	40 (24.1)	19 (26.4)	21 (22.3)	0.546
30-day medical complications	22 (13.3)	9 (12.5)	13 (13.8)	0.802
90-day complication rate	109 (65.7)	46 (63.9)	63 (67.0)	0.674
90-day major complication rate	32 (19.3)	15 (20.8)	17 (18.1)	0.656
90-day infective complications	56 (33.7)	24 (33.3)	32 (34.0)	0.924
90-day medical complications	30 (18.1)	14 (19.4)	16 (17.0)	0.688
90-day readmission rate	35 (21.1)	11 (15.3)	24 (25.5)	0.108
LOS, median (IQR)	10.0 (8.0–15.0)	10.0 (8.0–16.0)	10.0 (8.0–14.8)	0.299
90-day mortality rate	4 (2.4)	1 (1.4)	3 (3.3)	0.453

(B)
Variable	All patients (n = 121)	Anemia ^a (n = 49)	No anemia (n = 72)	p
30-day complication rate	64 (52.9)	25 (51.0)	39 (54.2)	0.734
30-day major complication rate	14 (11.6)	4 (8.2)	10 (13.9)	0.334
30-day infective complications	28 (23.1)	11 (22.4)	17 (23.6)	0.882
30-day medical complications	14 (11.6)	4 (8.2)	10 (13.9)	0.334
90-day complication rate	77 (63.6)	32 (41.6)	45 (62.5)	0.753
90-day major complication rate	20 (16.5)	9 (18.4)	11 (15.3)	0.653
90-day infective complications	39 (32.3)	15 (30.6)	24 (33.3)	0.753
90-day medical complications	21 (17.4)	8 (16.3)	13 (18.1)	0.805
90 day readmission rate	28 (23.1)	9 (18.4)	19 (26.4)	0.304
LOS, median (IQR)	10.0 (8.0–15.0)	11.0 (8.0–16.0)	10.0 (8.0–14.0)	0.330
90-day mortality rate	2 (1.7)	1 (2.0)	1 (1.4)	0.782

Men: hemoglobin <13 g/dL, women: hemoglobin <12.0 g/dL.

LOS = length of stay.

In contrast, blood transfusion requirement was associated with 30-day all (p = 0.002) and major (0.003) complications as well as 90-day major complications (p = 0.008) but not 90-day all complications (Table 4). Median LOS was significantly longer in patients requiring blood transfusion (p < 0.001), but no difference was observed for the 90-day readmission rate. Patients who received blood transfusion were more than twofold more likely to develop a 90-day complication and three times more likely to develop a major 90-day complication (Table 4). Of interest, intraoperative blood transfusion was not associated with perioperative morbidity; however, postoperative blood transfusion was significantly associated with both 30-day and 90-day all and major complications (Table 5). When analyzed according to complication type, postoperative blood transfusion was significantly associated with infection (52.2% vs 30.8%; p = 0.044) and medical complications (43.5% vs 14.0%; p = 0.001). Furthermore, postoperative blood transfusion was the only factor associated with 30-day and 90-day all and major complications in a multivariate analysis (Table 6).

Table 4.

Perioperative Morbidity of Patients Stratified According to Blood Transfusion Requirement

Variable	All patients (n = 166)	Blood transfusion (n = 34)	No blood transfusion (n = 132)	p-value
30-day complication rate	92 (55.4)	27 (79.4)	65 (49.2)	0.002
30-day major complication rate	26 (15.7)	11 (32.4)	15 (11.4)	0.003
30-day infective complications	40 (24.1)	12 (35.3)	28 (21.2)	0.087
30-day medical complications	22 (13.3)	9 (26.5)	13 (59.1)	0.011
90-day complication rate	109 (65.7)	27 (79.4)	82 (62.1)	0.058
90-day major complication rate	32 (19.3)	12 (35.3)	20 (15.2)	0.008
90-day infective complications	56 (33.7)	15 (44.1)	41 (31.1)	0.151
90-day medical complications	30 (18.1)	12 (35.3)	18 (13.6)	0.003
90-day readmission rate	35 (21.1)	8 (23.5)	27 (20.5)	0.695
LOS, median (IQR)	10.0 (8.0–15.0)	14.0 (8.3–25.0)	10.0 (8.0–14.0)	<0.001
90-day mortality rate	4 (2.4)	1 (2.9)	3 (2.3)	0.821

Table 5.

Univariate Analysis to Evaluate 30-Day and 90-Day Complications

	All 30-day complications		30-day major complications		All 90-day complications		90-day major complications
Variable Preoperative	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p	OR (95% CI)	p
Gender: male vs female	1.38 (0.68, 2.80)	0.371	2.86 (0.81, 10.06)	0.090	1.31 (0.63, 2.72)	0.466	3.83 (1.10, 13.31)	0.025
Age <65 vs ≥ 65 yrs	1.05 (0.57, 1.94)	0.876	0.47 (0.20, 1.13)	0.088	0.69 (0.36, 1.31)	0.253	0.53 (0.24, 1.18)	0.115
BMI <25 vs ≥25	1.54 (0.74, 3.21)	0.244	1.06 (0.37, 3.00)	0.920	0.60 (0.27, 1.32)	0.199	0.89 (0.34, 2.29)	0.804
ASA: I and II vs ≥III	1.90 (1.00, 3.60)	0.048	1.42 (0.61, 3.31)	0.410	1.02 (0.53, 1.97)	0.950	1.28 (0.59, 2.80)	0.533
AT	0.95 (0.80, 1.12)	0.553	1.00 (0.79, 1.26)	0.990	0.93 (0.78, 1.10)	0.375	1.02 (0.83, 1.26)	0.850
Peak VO₂	1.01 (0.94, 1.08)	0.824	1.05 (0.96, 1.14)	0.320	1.03 (0.95, 1.11)	0.507	1.06 (0.97, 1.15)	0.192
VE/VCO₂	0.98 (0.92, 1.05)	0.582	0.99 (0.90, 1.08)	0.765	0.96 (0.90, 1.03)	0.213	0.98 (0.90, 1.06)	0.591
NAC: yes vs no	0.64 (0.33, 1.24)	0.181	1.83 (0.78, 4.33)	0.163	1.07 (0.53, 2.14)	0.856	1.73 (0.78, 3.84)	0.177
Preoperative anemia: yes vs no^a	0.75 (0.40, 1.39)	0.360	0.79 (0.33, 1.85)	0.582	0.87 (0.46, 1.66)	0.674	1.19 (0.55, 2.59)	0.656
Intraoperative
Transfusion: yes vs no	5.11 (1.99, 13.16)	<0.001	3.73 (1.52, 9.15)	0.003	2.35 (0.95, 5.80)	0.058	3.06 (1.31, 7.14)	0.008
Intraoperative transfusion	2.13 (0.71, 6.34)	0.168	1.78 (0.53, 5.95)	0.346	1.29 (0.43, 3.85)	0.652	1.33 (0.40, 4.39)	0.639
Postoperative transfusion	23.6 (3.1, 179.77)	<0.001	4.77 (1.79, 12.68)	0.001	6.56 (1.48, 29.01)	0.005	4.23 (1.65, 10.85)	0.002
Type of diversion: IC vs continent	1.51 (0.73, 3.14)	0.263	1.20 (0.46, 3.09)	0.714	3.10 (1.27, 7.56)	0.010	1.30 (0.55, 3.10)	0.553
Previous pelvic radiotherapy: yes vs no	0.81 (0.27, 2.42)	0.705	1.53 (0.40, 5.91)	0.535	0.36 (0.12, 1.09)	0.060	0.68 (0.144, 3.19)	0.621
Cystectomy stage: ≤pT2 vs ≥pT3	0.81 (0.43, 1.53)	0.512	0.69 (0.28, 1.70)	0.420	0.62 (0.32, 1.20)	0.151	1.16 (0.53, 2.55)	0.714

Men: hemoglobin <13 g/dL, women: hemoglobin <12.0 g/dL.

IC = ileal conduit; NAC = neoadjuvant chemotherapy.

Table 6.

Multivariate Analysis to Evaluate Perioperative Morbidity

	OR (95% CI)	p
All 30-day complications
ASA: I and II vs ≥III	1.49 (0.77, 2.88)	0.233
Postoperative transfusion: yes vs no	9.46 (2.13, 42.00)	0.003
90-day all complications
Type of diversion: IC vs continent	3.43 (1.40, 8.44)	0.007
Postoperative transfusion: yes vs no	7.39 (1.65, 33.1)	0.009
90-day major complications
Gender: male vs female	0.45 (0.17, 1.23)	0.121
Postoperative transfusion: yes vs no	4.2 (1.62, 10.97)	0.004

Discussion

This is the first study to report the relationship between preoperative anemia, blood transfusion requirement, and perioperative morbidity following radical cystectomy. The prevalence of preoperative anemia in this contemporary cohort was 43.4%, and we report that anemia alone is not associated with a higher complication rate. In contrast, we show that that requirement for blood transfusion, specifically postoperative blood transfusion, is significantly associated with an increase in complications at 30 and 90 days, as well as longer hospital LOS.

The WHO defines preoperative anemia as hemoglobin <13 g/dL in men and hemoglobin <12.0 g/dL in women.¹³ Anemia can be further stratified according to severity and this has also not shown any association with perioperative complications. These results were confirmed in a propensity score-matched cohort of patients. Our results are in contrast to other reports in which the relationship between preoperative anemia and complications is established in general, vascular, and orthopedic surgery.¹ In the study by Musallam et al., preoperative anemia was associated with 30-day morbidity and mortality rate. This analysis was performed using a large registry data set, and such data are not available for radical cystectomy; hence, we cannot discount type II error in our study. In addition, our cohort of patients was treated with a robotic approach with intracorporeal urinary diversion, which represents an evolution from conventional ORC.¹⁴ However, to date there is little evidence to support any advantage for iRARC in terms of perioperative outcomes,⁸ although early oncologic outcomes for iRARC and ORC are comparable.¹⁵ It is interesting to postulate that the relationship between anemia and perioperative outcomes for iRARC will be different for ORC and well-designed prospective randomized controlled trials will be necessary to understand this.

As reported herein, patients with bladder cancer are often anemic, and, as shown by others, anemia is a poor prognostic indicator for cancer-specific survival (CSS).¹⁶ This study did not access CSS, but we report that patients treated with NAC are significantly more likely to have preoperative anemia. The survival benefit for NAC is established and it may be relevant to differentiate between iatrogenic (NAC induced) anemia and the anemia attributed to cancer (impaired erythropoietin production or hematuria). However, even when all 37 NAC cases were excluded from analysis, there remained no significant difference between preoperative anemia and perioperative morbidity.

Although preoperative anemia itself is not associated with perioperative morbidity, it is associated with blood transfusion requirement. Intraoperative blood transfusion specifically was associated with preoperative anemia, and there was a trend toward significance with postoperative blood transfusion. This is expected, given intraoperative blood loss during cystectomy can be significant, and patients with a lower preoperative hemoglobin are more likely to require blood transfusion.

The current study supports that unlike preoperative anemia, blood transfusion requirement is significantly associated with the development of postoperative complications. All blood transfusion and, specifically, postoperative blood transfusion requirement were significantly associated with 90-day medical and infective complications. This confirms a recent report by Sui et al., in which analysis of a radical cystectomy registry data set showed that blood transfusion requirement was associated with postoperative infection and morbidity.¹⁷ Blood transfusion, particularly transfusion of nonleukocyte depleted blood has an effect on immunomodulation.¹⁸ In patients with bladder cancer undergoing radical cystectomy, and receiving blood transfusion, there is a reduced overall survival (HR: 1.65; 95% CI: 1.08, 2.52) and CSS (HR: 1.68; 95% CI: 1.04, 2.70).¹⁹ Blood transfusion has been shown to increase the risk of cancer recurrence in other solid organ tumors²⁰ and is associated with postoperative infection in trauma patients.²¹ Immunologic studies suggest that it is a reduction in natural killer cells following blood transfusion that can influence the host immune response and may be a factor responsible for the increase in postoperative bacterial infections.²² Similarly, blood transfusion is reported to be associated with organ dysfunction in intensive care-treated patients.²³ In orthopedic surgery, nontransfusion optimization of preoperative hemoglobin has been shown to reduce the requirements for blood transfusion as well as reduce postoperative infection rates.²⁴ In our study, we found a significant linear association between number of units of blood transfused (1, 2, or ≥3 units) and both 30- and 90-day all and major complications (p < 0.05).

We can postulate several hypotheses why postoperative blood transfusion but not intraoperative blood transfusion is associated with increased morbidity. The number of units transfused intraoperatively is lower than in the postoperative setting and may be a factor for the lack of association observed. Our intraoperative transfusion rate of 10.2% may also be too low to detect any significant difference in perioperative complications. It is not possible to determine if postoperative transfusion is a harbinger of a pending complication or that blood transfusion itself may predispose patients to perioperative morbidity. While a preoperative prognostic factor provides an opportunity to address the risk factor, we feel that patients requiring postoperative blood transfusion should be investigated and monitored closely due to the high risk of complications.

Randomized controlled trials comparing ORC with robotic cystectomy consistently show a lower operative blood loss favoring robotic cystectomy. Following multivariate analysis, we show blood requirement transfusion is the most significant factor associated with perioperative complications. It is attractive to postulate that a robotic approach that is known to have lower estimated blood loss and requirement for blood transfusion may compensate for the increased perioperative risk attributed to preoperative anemia.⁸ Similarly, other reports have suggested that impaired cardiopulmonary function measured by CPET is associated with hospital LOS and postoperative morbidity in patients treated with ORC²⁵ but not in iRARC-treated patients.²⁶

The results of this study should be interpreted taking into account its limitations. None the less, as a single arm study, it highlights the potential for future comparisons between liberal vs restricted blood transfusion in patients undergoing radical cystectomy. Randomized controlled trials in hip²⁷ and cardiac surgery²⁸ have not shown any superiority of liberal blood transfusion over restricted blood transfusion. It remains important that causation between blood transfusion and complications cannot be determined, but our results suggest a clear association between blood transfusion requirement and perioperative complications that are independent of preoperative anemia. It must also be considered that transfusion requirement may be a surrogate for quality of surgery that itself could be the cause of postoperative complications. Indeed, surgical complications have been shown to be responsible for the majority of major complications following iRARC.²⁹

Conclusion

This study confirms that preoperative anemia is not associated with increased perioperative complications in patients treated with iRARC. However, requirement for blood transfusion and specifically postoperative blood transfusion is strongly associated with 90-day all and major complications.

Footnotes

Acknowledgments

The authors are grateful to the UCLH Biomedical Research Centre and The Urology Foundation for funding their work.

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

References

Musallam

, Tamim

, Richards

, et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: A retrospective cohort study. Lancet, 2011; 378:1396–1407.

Whitlock

, Kim

, Auerbach

. Harms associated with single unit perioperative transfusion: Retrospective population based analysis. BMJ, 2015; 350:h3037.

Glance

, Dick

, Mukamel

, et al. Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery. Anesthesiology, 2011; 114:283–292.

Gierth

, Mayr

, Aziz

, et al. Preoperative anemia is associated with adverse outcome in patients with urothelial carcinoma of the bladder following radical cystectomy. J Cancer Res Clin Oncol, 2015; 141:1819–1826.

Parekh

, Messer

, Fitzgerald

, Ercole

, Svatek

. Perioperative outcomes and oncologic efficacy from a pilot prospective randomized clinical trial of open versus robotic assisted radical cystectomy. J Urol, 2013; 189:474–479.

Khan

, Gan

, Ahmed

, et al. A single-centre early phase randomised controlled three-arm trial of open, robotic, and laparoscopic radical cystectomy (CORAL). Eur Urol, 2016; 69:613–621.

Nix

, Smith

, Kurpad

, Nielsen

, Wallen

, Pruthi

. Prospective randomized controlled trial of robotic versus open radical cystectomy for bladder cancer: Perioperative and pathologic results. Eur Urol, 2010; 57:196–201.

Bochner

, Dalbagni

, Sjoberg

, et al. Comparing open radical cystectomy and robot-assisted laparoscopic radical cystectomy: A randomized clinical trial. Eur Urol, 2015; 67:1042–1050.

Tan

, Khetrapal

, Tan

, Rodney

, Chau

, Kelly

. Robotic assisted radical cystectomy with extracorporeal urinary diversion does not show a benefit over open radical cystectomy: A systematic review and meta-analysis of randomised controlled trials. PLoS One, 2016; 11:e0166221.

10.

Novara

, Catto

, Wilson

, et al. Systematic review and cumulative analysis of perioperative outcomes and complications after robot-assisted radical cystectomy. Eur Urol, 2015; 67:376–401.

11.

Tan

, Sridhar

, Goldstraw

, et al. Robot-assisted intracorporeal pyramid neobladder. BJU Int, 2015; 116:771–779.

12.

Shabsigh

, Korets

, Vora

, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol, 2009; 55:164–176.

13.

World Health Organisation.. Nutritional Anaemias. Report of a WHO Scientific Group. Geneva, Switzerland: WHO; 1968.

14.

Tan

, Lamb

, Kelly

. Evolution of the neobladder: A critical review of open and intracorporeal neobladder reconstruction techniques. Scand J Urol, 2016; 50:95–103.

15.

Tan

, Sridhar

, Ellis

, et al., eds. Analysis of open and intracorporeal robotic assisted radical cystectomy shows no significant difference in recurrence patterns and oncological outcomes. Urol Oncol, 2016; 34:257.e1–e9.

16.

Pujade-Lauraine

, Gascón

. The burden of anaemia in patients with cancer. Oncology, 2004; 67(Suppl. 1):1–4.

17.

Sui

, Onyeji

, Matulay

, et al. Perioperative blood transfusion in radical cystectomy: Analysis of the National Surgical Quality Improvement Program database. Int J Urol, 2016; 23:745–750.

18.

Landers

, Hill

, Wong

, Fox

. Blood transfusion-induced immunomodulation. Anesth Analg, 1996; 82:187–204.

19.

Moschini

, Bianchi

, Gandaglia

, et al. The impact of perioperative blood transfusion on survival of bladder cancer patients submitted to radical cystectomy: Role of anemia status. Eur Urol Focus, 2016; 2:86–91.

20.

Blumberg

, Heal

. Perioperative blood transfusion and solid tumor recurrence—A review. Cancer Invest, 1987; 5:615–625.

21.

Hill

, Frawley

, Griffith

, Forestner

, Minei

. Allogeneic blood transfusion increases the risk of postoperative bacterial infection: A meta-analysis. J Trauma, 2003; 54:908–914.

22.

Triulzi

, Vanek

, Ryan

, Blumberg

. A clinical and immunologic study of blood transfusion and postoperative bacterial infection in spinal surgery. Transfusion, 1992; 32:517–524.

23.

Vincent

, Baron

, Reinhart

, et al. Anemia and blood transfusion in critically ill patients. JAMA, 2002; 288:1499–1507.

24.

Spahn

. Anemia and patient blood management in hip and knee surgery: A systematic review of the literature. Anesthesiology, 2010; 113:482–495.

25.

Prentis

, Trenell

, Vasdev

, et al. Impaired cardiopulmonary reserve in an elderly population is related to postoperative morbidity and length of hospital stay after radical cystectomy. BJU Int, 2013; 112:E13–E19.

26.

Lamb

, Tan

, Eneje

, et al. Benefits of robotic cystectomy with intracorporeal diversion for patients with low cardiorespiratory fitness: A prospective cohort study. Urol Oncol, 2016; 34:e17–e23.

27.

Carson

, Terrin

, Noveck

, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med, 2011; 365:2453–2462.

28.

Murphy

, Pike

, Rogers

, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl J Med, 2015; 372:997–1008.

29.

Tan

, Lamb

, Tan

M-Y

, et al. In-depth critical analysis of complications following robot-assisted radical cystectomy with intracorporeal urinary diversion. Eur Urol Focus, 2016 [Epub ahead of print].

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