This article is accompanied by the following Invited Commentary:
Navarro LH, Chew MS. Postoperative acute kidney injury. A never-ending challenge. Eur J Anaesthesiol 2018; 35:639–640.
Increasing attention has been given to enhanced recovery after surgery (ERAS) protocols for various major surgical procedures aiming to reduce the negative impact of surgery on organ function, postoperative complication rates and length of hospital stay (LOS).1,2 One of the cornerstones of ERAS protocols is the optimisation of fluid management with avoidance of salt and water overload.2 Peri-operative hydration protocols aiming for zero fluid balance significantly reduced overall major and gastro-intestinal complications in patients undergoing major abdominopelvic surgery.3,4 In addition, restrictive hydration has been associated with reduced mortality and complication rates after major abdominal surgery in multiple meta-analyses.5–7
However, concerns remain that restrictive hydration and the supportive use of vasopressors can cause hypovolaemia, which in turn can lead to renal dysfunction.8 On the one hand, peri-operative urinary output is still widely considered as a surrogate of renal function, and additional fluid boluses are generally administered to reverse oliguria despite a lack of evidence for their use.7,9,10 On the other hand, administration of noradrenaline has been linked to impaired microcirculation that could result in organ dysfunction and affect renal function.11,12
Postoperative acute kidney injury (AKI) has been associated with increased LOS, morbidity and mortality in multiple major cardiac and noncardiac procedures.13–18 Little is known about the impact of intra-operative administration of colloids and crystalloids and the use of vasopressors like noradrenaline on postoperative AKI in major urological abdominopelvic surgery.19 A secondary analysis of a randomised clinical trial suggests that renal function was not affected when restrictive hydration was combined with the pre-emptive administration of noradrenaline.4,19
The goals of this study were to determine whether intra-operative administration of vasopressors and the degree of hydration affect postoperative renal function and to identify risk factors for AKI in a consecutive series of patients undergoing cystectomy and urinary diversion.
Patients and methods
The current retrospective observational study reports a consecutive case series from a single tertiary centre and is in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology statement. Ethical approval for this study was provided by the Ethical Committee of the Canton Bern, Switzerland (KEKBE 2016-00660) on 2 June 2016 and the need for informed consent was waived. The study was not registered.
All patient data were evaluated from a prospectively maintained cystectomy database that fully complies with the legal requirements of the federal act on research involving human beings. Patients and procedures from 1 June 2007 to 31 December 2016 were manually identified from the database and the required data was recorded retrospectively from the paper charts and anaesthetic protocols.
Surgical technique and peri-operative management
At our institution, open cystectomy and urinary diversion (ileal orthotopic bladder substitution, ileal conduit, catheterisable ileal reservoir, ureterocutaneostomy or ureterosigmoidostomy) have been performed following the same standardised surgical techniques for the last 10 years, as previously described, and all patients were followed prospectively.20,21 Briefly, after cystectomy, using a standard intraperitoneal approach, a distal ileal segment was isolated and urinary diversion was performed with the ureters implanted into the proximal end of the ileal segment. The ureters were spatulated, implanted in an end to side fashion and splinted using mono-J ureteric stents.
During the observation period, fluids administered were lactated or maleated Ringer's solution and 6% hydroxyethyl starch 130/0.4 (in 0.9% saline or balanced Voluven, Fresenius Kabi). A systematic restrictive fluid administration protocol was followed with fluid maintenance around 1 to 3 ml kgBW−1 h−1 of crystalloids. If necessary, a continuous infusion of noradrenaline was started at around 1 to 2 μg kg−1 h−1. Noradrenaline was then titrated intra-operatively to achieve a mean arterial blood pressure (BP) between 60 mmHg (in patients with hypertension >65 mmHg) and 100 mmHg. Blood loss was primarily replaced with crystalloids, but in some cases with colloids either at the discretion of the anaesthetist in charge, or in the event of persistent hypovolaemia due to severe blood loss (increased plasma lactate value, metabolic acidosis with base excess <−5). Packed red blood cells were transfused if haemoglobin (Hb) values decreased to less than 80 g l−1 (<100 g l−1 in patients with coronary artery disease) peri-operatively. The peri-operative administration of fresh frozen plasma was driven by observed bleeding in the surgical field and after discussion between the anaesthesiologist and urologist in charge and secondly by the number of packed red blood cells administered. Assessment of urinary output (diuresis) was not feasible during surgery due to external diversion of the ureters for prolonged periods.
Postoperative hydration consisted primarily of 1000 ml of lactated Ringer's solution and 500 ml of glucose 5% per day until resumption of normal food intake.22 In the event of hypotension, an additional bolus of 250 to 500 ml of lactated Ringer's solution was administered. Immediately after surgery, patients were offered clear fluids. A peroral liquid diet as well as active mobilisation was started on postoperative day (POD) 1.23
Data collection and outcomes
Data collected included age, sex, BMI, ASA physical status score, presence of diabetes mellitus, pre-operative Hb value and presence of chronic kidney disease. Antihypertensive medication (angiotensin-converting enzyme inhibitors, calcium channel blockers, beta-blockers) was also recorded. Surgical factors recorded included duration of surgery, oncological vs. functional surgery, type of urinary diversion, intra-operative blood loss and the need for blood transfusion. Anaesthetic factors recorded included the type and the total amount of fluid administered (total amount of crystalloids and colloids in ml) and differentiated in ml per kg bodyweight per hour (ml kgBW−1 h−1) for crystalloids and in ml per kg bodyweight (ml kgBW−1) for colloids. Intra-operative fluid balance, the difference between the amount of fluid administered (IN: crystalloid, colloid and blood transfusion in ml) and fluid loss (OUT: blood loss in ml), was calculated accordingly. Likewise, the continuous administration of noradrenaline (μg kg−1 h−1) was recorded. LOS, the 90-day postoperative complication (Clavien-Dindo classification) and readmission rates were also recorded.
Plasma creatinine value was determined pre-operatively and on POD 1, 2, 3, 7 and 12 at 6 a.m. according to our institutional protocol. AKI was defined according to the classification of the Acute Kidney Injury Network (AKIN) based on changes in plasma creatinine levels over 72 postoperative hours. A clinically relevant decrease in renal function was defined as a 50% increase in plasma creatinine compared with the baseline before surgery.24 We decided to use the AKIN classification due to its superior sensitivity compared with the Risk Injury Failure Loss End-stage criteria and limited the time frame to 72 postoperative hours to ensure that AKI was related to pre-operative factors and intra-operative interventions.25 In addition, for urinary diversion, ureteral stents were always left in place for more than 6 PODs, thus reducing the risk of bias due to postrenal obstruction. Urine output data were not used for diagnosis of AKI because of inconsistent recording. Estimated glomerular filtration rate (eGFR) was calculated based on the chronic kidney disease (CKD) epidemiology collaboration equation.26–28
The primary endpoint was the incidence of AKI within 72 postoperative hours. We also compared postoperative renal function in patients who received noradrenaline during surgery and those who did not. The impact of intra-operative fluid balance, type and amount of fluid (crystalloids and colloids) on AKI was also analysed. Finally, we aimed to identify independent risk factors for AKI.
Baseline, intra-operative and postoperative variables were compared between patients who developed AKI and those who did not. Data were expressed as median with interquartile range for continuous variables and frequencies for categorical ones. We performed exploratory landmark analyses for categorical data using the Fisher's exact or the χ2 test, and for continuous data the Mann–Whitney U test.
Multiple logistic regression analyses using a stepwise backward selection procedure (alpha to enter = 0.05 and alpha to remove = 0.05) including interactions were applied to identify independent risk factors for AKI and reported as Wald χ2P value and adjusted odds ratio (OR) with 95% confidence intervals (CI). Factors that were selected a priori based on their potential association with postoperative AKI were ASA scores, sex, antihypertensive medication, diabetes mellitus, BMI, age (decade), pre-operative plasma creatinine values, intra-operative volumes of crystalloids and colloids administered, pre-operative Hb values, blood loss, blood transfusion, duration of surgery and the use of noradrenaline. Due to the limited number of events and to avoid overfitting the regression, a parsimonious model was chosen with respect to known pre-operative and intra-operative risk factors for AKI. Thus, pre-operative risk factors not associated with AKI in the final regression model with a P value less than 0.05 were not included (diabetes mellitus, blood transfusion, BMI, ASA score). Interaction terms used were ‘duration of surgery’ × ‘blood loss’, ‘blood loss’ × ‘blood transfusion’, ‘crystalloids’ × ‘use of noradrenaline’, ‘colloids’ × ‘use of noradrenaline’ and ‘ASA score’ × ‘age’. The fit and predictive power of the model was assessed using the Hosmer–Lemeshow goodness-of-fit test and receiver operating characteristic-area under the curve (ROC-AUC). A two-sided P less than 0.05 was considered significant. The statistical software used was Statistical Analysis System software (version 9.3; SAS Institute, Cary, North Carolina, USA).
We identified 775 consecutive patients who underwent open cystectomy and urinary diversion for oncological or functional reasons in the Department of Urology University Hospital Bern between 1 June 2007 and 31 December 2016. Patients with insufficient follow-up (n=4), pre-operative haemodialysis (n=1) and death within 72 h after surgery (n=1) were excluded, leaving 769 (data missing: 0.8%) for the analysis.
Postoperative AKI was present in 86/769 patients (11.2%). AKIN stage 1 was present in 75/86 patients (87.2%), stage 2 in 6/86 patients (6.9%) and stage 3 in 5/86 patients (5.8%). None of the patients needed renal replacement therapy during the first 72 h.
Personal and peri-operative data
AKI patients had a higher BMI (27 [24 to 31] vs. 25 [23 to 28] kg m−2; P = 0.006), a more frequent use of antihypertensive medication (55 vs. 44%, P = 0.034), and higher pre-operative Hb values (134 [122 to 146] vs. 128 [114 to 140]g l−1; P = 0.001) (Table 1). According to the CKD classification, pre-operative renal function did not differ significantly between AKI patients and non-AKI patients.
Duration of surgery was longer in AKI patients (404 [365 to 448] vs. 390 [340 to 429] min; P = 0.013). AKI patients received slightly less crystalloids per kg bodyweight per hour (3.5 [2.5 to 4.8] vs. 4.2 [3.1 to 5.7] ml kgBW−1 h−1; P = 0.001) but not if the total amount of crystalloids administered was considered (1900 [1200 to 2800] vs. 2000 [1400 to 2600] ml; P = 0.850) (Table 2). The amount of colloids administered did not differ significantly between AKI and non-AKI patients. Overall, 8.6% of the patients received colloids with a median total amount of 500 [500 to 750] ml and a median value of 6.5 [5.1 to 9.8] ml kgBW−1. Colloids were administered in 10.5% of the AKI patients and this incidence did not differ significantly from the non-AKI patients (8.2%); P = 0.535.
Noradrenaline was administered at an overall median infusion rate of 2.1 [1.2 to −3.4] μg kgBW−1 h−1 intra-operatively and did not differ between AKI patients (2.2 [1.1 to 3.1] μg kgBW−1 h−1 and non-AKI patients (2.1 [1.2 to 3.4] μg kgBW−1 h−1); P = 0.630.
Factors influencing renal function
Independent factors identified with multiple logistic regression analyses associated with AKI were antihypertensive medication (P = 0.005), higher pre-operative Hb values (P = 0.010), older age (per decade, P = 0.002), longer duration of surgery (P = 0.001) and lower amount of administered crystalloids per hour (P = 0.002), but not the administration of noradrenaline (P = 0.802) nor the amount of administered colloids (P = 0.461) (Table 3). The model accorded well with the Hosmer–Lemeshow test (P = 0.537) and ROC-AUC was 0.716 (95% CI, 0.667 to 0.767).
The predicted probability for developing AKI was plotted with a mean administered amount of colloids of 0.7 ml kg−1, mean duration of surgery of 386 min, a mean pre-operative plasma creatinine value of 95 μmol l−1 and a mean pre-operative Hb value of 127 g l−1, and it increased rapidly depending on the amount of crystalloids administered in patients treated with antihypertensive medication and stratified according to the noradrenaline administered (categorised in 0, >0 to ≤1 μg kg−1 h−1, >1 to ≤3 μg kg−1 h−1, >3 μg kg−1 h−1). Overall, the probability of developing AKI doubled in patients treated with antihypertensives and increased rapidly if the total administration of crystalloids was less than 4 ml kg−1 h−1 (blue = antihypertensive medication and red lines = no antihypertensive medication in Fig. 1).
Acute kidney injury and postoperative outcome
On POD 7 and 12, plasma creatinine values and eGFR were similar between AKI and non-AKI patients (Table 4). One AKI patient had an eGFR of 26.2 ml min−1 1.73 m−2 on POD 12, not necessitating haemodialysis during LOS.
Postoperative AKI was associated with longer LOS (18 [15 to 22] vs. 16 [15 to −19] days; P = 0.035). The 90-day postoperative major complication rate according to the Clavien–Dindo classification (≥3a) was higher in AKI patients (41.9%, 36/86 patients) than in non-AKI patients (27.5% 188/683 patients); P = 0.002. The 90-day mortality did not differ significantly between AKI patients and non-AKI patients (Table 4).
Overall, AKI occurred within 72 h in 11.2% patients undergoing cystectomy and urinary diversion. No patient required haemodialysis. Factors independently associated with AKI were antihypertensive medication, longer duration of surgery, older age (per decade) and the amount of administered crystalloids. Continuous intra-operative administration of noradrenaline did not affect the incidence of AKI, which was associated with longer LOS and increased 90-day morbidity. Our short-term overall mortality compares with the studies included in the meta-analysis of O’Connor et al.29; however, they reported a 12.6% increased risk of death associated with AKI which was not corroborated in our series.
AKI is common after major abdominal surgery and has been associated with poor postoperative outcome. In a recent meta-analysis, a 13% pooled incidence of AKI and a 12-fold AKI-related relative risk of death in the postoperative period after major abdominal surgery was reported.18,29 However, the incidence and impact of AKI have rarely been reported in patients undergoing cystectomy and urinary diversion. This is surprising given that major abdominopelvic surgery of this nature involves the urinary tract, it is associated with surgery of long duration and significant blood loss and involves polymorbid old patients, of whom only around 28% present with normal pre-operative renal function, as in our series. Our incidence of 11.2% is slightly lower than reported by O’Connor et al. in their meta-analysis and significantly lower than the 33% reported in another recent publication. However, renal function was followed over a longer interval of 7 days and after removal of the ureteric stents,29,30 which has an impact on plasma creatinine values, as after stent removal urine has contact with the mucosa of the ileum used for the urinary diversion, and creatinine can be reabsorbed from the urine. Also, postrenal ureteric obstruction causing hydronephrosis can occur.31,32 Assessing renal function within 3 days after surgery with the ureteric stents in place as in our series bypasses these issues. This excludes confounding factors and allows for a more accurate assessment of the relationship between pre-operative and intra-operative variables and early postoperative AKI.
Interest in restrictive hydration has increased, as ERAS protocols recommend avoidance of water and salt overload during the peri-operative period.2 A postoperative positive fluid balance has been associated with increased morbidity after colorectal surgery and cystectomy.4,33 However, restrictive hydration is still thought to induce or aggravate renal dysfunction in major surgery and the association between the use of noradrenaline in patients with volume-resuscitated vasodilatory shock and AKI remains a matter of controversy. In this series, the continuous low-dose administration of noradrenaline did not affect the incidence of AKI. In response to short-term noradrenaline infusion, renal blood flow is increased and renal vascular resistance is decreased. These effects can be attributed to an increase in systemic BP and cardiac output, which decreases renal sympathetic tone through a baroreceptor response, leading to vasodilatation. Thus the restoration of arterial BP with noradrenaline may be nephroprotective.34,35
There was no association between the administration of colloids and AKI; however, the total amount (median 500 ml) and the amount per kg bodyweight (median 6.5 ml kgBW−1) was very low in patients who received colloids. This suggests that the administration of a low-dose of colloids (6% hydroxyethyl starch 130/0.4) does not contribute to AKI. The low number of patients who received colloids (8.6%) and the indication (replacement of severe blood loss) could limit the interpretation of this finding.
Restrictive intra-operative hydration was associated with an increased probability of developing AKI and was more pronounced in patients treated with antihypertensive medication. This highlights the fact that administration of fluid tailored to the individual has as much or more importance than the use of vasopressors per se, in protecting renal function. It is not only fluid volume overload leading to positive balance that contributes to AKI in patients at risk by inducing renal compartment syndrome, renal venous congestion and impaired tissue oxygenation,36,37 but also overly restrictive intra-operative hydration.
A factor worthy of discussion is the role of antihypertensives. Peri-operative BP is one of the risk factors for AKI that is amenable to manipulation.38 Patients prescribed medication for hypertension may have been subject to poor BP control before surgery and are more likely to suffer from a labile BP after surgery; both may contribute to AKI. In the peri-operative phase, the strict control of hypertension generally recommended may be detrimental to some patients at high risk of AKI.39 Moreover, individualised peri-operative management of BP (including the use of vasopressors) to within 10% of the reference values has been shown to improve postoperative outcomes including renal function.40
Another observation from our series was that the duration of surgery strongly affects the probability of developing AKI. In the context of old comorbid patients, optimisation of the surgical technique with a reduced duration of surgery is recommended. Higher pre-operative Hb values were associated with more postoperative AKI. This contradicts the results of Walsh et al.41 and a large cohort of noncardiac surgery patients in whom a low pre-operative Hb (<120 g l−1) strongly correlated with postoperative AKI. Although statistically significant, median Hb values between AKI (134 g l−1) and non-AKI patients (128 g l−1) did not differ greatly and were above the threshold chosen by Walsh et al., which questions the clinical significance. In addition, we could postulate that patients with lower pre-operative Hb were more likely to be preconditioned to organ damage from inflammation and oxidative stress response.42
The current study has several limitations. There is a potential bias from unmeasured risk factors in this retrospective case series with prospectively assessed data and some missing values, albeit less than 1%. Despite the use of multiple regression analysis and risk adjustment, the potential for residual confounding factors cannot be completely eliminated. Another issue is that it is still unclear as to what extent creatinine is reabsorbed by the ileum used for the urinary diversion, especially in the early postoperative period, and if this re-absorption is clinically relevant. It was also impossible to diagnose AKI based on urinary output for the following reasons: intra-operative diuresis cannot be assessed due to externalisation of the ureters during surgery, and postoperative urine output can be biased due to polyuria (e.g. after resolving pre-existing postrenal obstruction). However, oliguria per se does not always occur because of decreased renal perfusion pressure or glomerular perfusion and therefore cannot be prevented by fluid administration. Peri-operative neurohumoral regulation induced by surgical stress is probably unresponsive to fluids, and their administration to increase urine output may lead to fluid overload.7,10
No haemodynamic data were presented, and we cannot rule out that transient hypotension could have occurred. This limitation is relevant, as hypotension has been associated with postoperative renal dysfunction.43 However, the titration of noradrenaline to maintain mean arterial BP above 60 mmHg should have bypassed this issue.
Finally, our data are generated from a high case load centre specialised in this kind of surgery and whether our results can be can be generalised remains speculative.
Intra-operative administration of noradrenaline did not affect the incidence of AKI in patients undergoing cystectomy and urinary diversion. An overly restrictive intra-operative administration of crystalloids was associated with an increased risk of developing AKI, particularly in older patients, those treated with antihypertensive medication and with prolonged surgery. The low-dose administration of colloids did not increase the risk of AKI. These observations should be taken into account when considering fluid management in the peri-operative setting as these patients probably require more fluid to protect renal function.
Acknowledgements relating to this article
Assistance with the study: the authors thank Prof J. Huesler, PhD (Institute of Mathematical Statistics and Actuarial Science, University of Bern, Bern, Switzerland) for support in the statistical analyses.
Financial support and sponsorship: this study was supported by internal institutional research funds of the Department of Anaesthesiology and Pain Medicine and of the Department of Urology, University Hospital Bern, Bern, Switzerland and the Bernese Cancer League Switzerland. The internal institutional research funds of the Department of Anaesthesiology and Pain Medicine and of the Department of Urology, University Hospital Bern, Bern, Switzerland and the Bernese Cancer League, Berne Switzerland had no role in design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the article; and decision to submit the article for publication.
Conflicts of interest: none.
Presentation: preliminary data for this study were presented as a poster at Euroanaesthesia, 03 to 05 June 2017, Geneva, Switzerland.
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