Cover Page. The handle holds various files of this Leiden University dissertation

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1 Cover Page The handle holds various files of this Leiden University dissertation Author: Kooiman, Judith Title: Risk and prevention of contrast induced-acute kidney injury Issue Date:

2 Chapter 5 A randomised comparison of one-hour sodium bicarbonate hydration versus standard peri-procedural saline hydration in patients with chronic kidney disease undergoing intravenous contrast enhanced-computerized tomography Judith Kooiman, Yvo WJ Sijpkens, Jean-Paul PM de Vries, Harald FH Brulez, Jaap F Hamming, Aart J van der Molen, Nicolaas JM Aarts, Suzanne C Cannegieter, Hein Putter, Renata Swarts, Wilbert B van den Hout, Ton J Rabelink, Menno V Huisman Nephrol Dial Transplant 2014; 29: Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 Chapter 13

3 64 Chapter 5 Abstract Background Guidelines recommend saline hydration for prophylaxis of contrast induced-acute kidney injury (CI-AKI) in patients with chronic kidney disease (CKD) undergoing intravenous contrast media-enhanced CT (CE-CT). The safety and efficacy of a brief hydration protocol using sodium bicarbonate in this population is unknown. We analysed whether one hour sodium bicarbonate hydration prior to CE-CT is non-inferior to saline hydration prior to and after CE-CT in CKD patients. Methods We performed an open-label multicenter randomized trial. Patients were randomized to 250 ml 1.4% sodium bicarbonate hydration prior to CE-CT or 1000 ml 0.9% saline hydration prior to and, once again after CE-CT. Primary outcome was the relative increase in serum creatinine hours post CE-CT. Secondary outcomes were: incidence of CI-AKI (serum creatinine increase>25%/>44µmol/l[0.5mg/dl]), recovery of renal function, the need for dialysis, and 2-month hospital costs. Results 570 adult CKD patients undergoing CE-CT were randomized between , of whom 548 were included in the intention-to-treat population. Mean relative serum creatinine increase was 1.2% for sodium bicarbonate and 1.5% for saline (mean difference -0.3%; 95% CI -2.7 to 2.1, p-value for non-inferiority < ). CI-AKI occurred in 22 patients (4.1%); 8 (3.0%) randomized to sodium bicarbonate versus 14 (5.1%) to saline (P=0.23). Renal function recovered in 75% and 69% of CI-AKI patients, respectively (P=0.81). No patients developed a need for dialysis. Mean hydration costs per patient were 224 for the sodium bicarbonate and 683 for the saline regime (P<0.001). Other healthcare costs were similar. Conclusions Short hydration with sodium bicarbonate prior to CE-CT was non-inferior to peri-procedural saline hydration with respect to renal safety and may result in healthcare savings.

4 Saliña Trial 65 Introduction Contrast media are commonly used in clinical practice with 45 million patients undergoing computed tomography in the United States (US) per year. Contrast induced-acute kidney injury (CI-AKI) is a well-known complication associated with the use of contrast media 1. Patients with chronic kidney disease (CKD), about 16% of the total CT population, are at a particularly high risk of CI-AKI 2-4 and minimisation of contrast volume, use of low- and iso-osmolar instead of high-osmolar, or non-ionic contrast media, and adequate peri-procedural hydration are strategies that are effective in reducing the risk of CI-AKI The most commonly recommended regime for prevention in patients at high risk of CI-AKI, is peri-procedural intravenous hydration with normal saline 5;9. This treatment requires on average two days of elective hospitalisation, is burdensome to patients and increases healthcare costs 5. Recently, multiple studies have demonstrated the utility of a shorter hydration protocol using 1.4% sodium bicarbonate administered for 1 hour prior to and 6 hours following contrast injection 11-20, with the largest trial including 502 patients 21. It has been hypothesized that even shorter infusions of sodium bicarbonate may be associated with similar prophylactic efficacy while simplifying patient care 22. The volume expansion would prevent patients from being in a hypovolemic state at time of intravenous contrast media-enhanced CT (CE-CT), an important risk factor for CI-AKI 23. In addition, sodium bicarbonate alkalinises urine, theoretically providing an additional protective effect 24;25. We evaluated the comparative efficacy of a novel one-hour hydration regime with 250 ml 1.4% sodium bicarbonate prior to CE-CT as the only preventive measure in patients with pre-existing CKD and compared it with peri-procedural saline hydration. Chapter 5 Methods We performed a randomized, non-inferiority trial in one academic and three nonacademic Dutch hospitals. In- and outpatients electively scheduled for CE-CT regardless of its indication were eligible for inclusion. All patients were at least 18 years, had CKD (egfr <60 ml/min/1.73m2 estimated by the Modification of Diet in Renal Disease formula 26 ), and were eligible to the fluid challenge of saline hydration. Exclusion criteria were pregnancy; previous contrast administration within the last seven days; documented allergy for iodinated contrast media; hemodynamic instability (systolic blood pressure <100mmHg); and previous participation in the trial. All patients provided written informed consent prior to randomization. The trial protocol was approved by the Institutional Review Boards of each participating centre. An independent data and

5 66 Chapter 5 safety monitoring board periodically reviewed study outcomes. The trial complied with good clinical practice guidelines and the Declaration of Helsinki (2004). This trial was registered with the Netherlands Trial Register, NTR Randomization Patients were randomized using a computer-generated allocation sequence to either hydration with 250 ml intravenous 1.4% sodium bicarbonate one hour prior to CE-CT without hydration post CE-CT, or standard peri-procedural intravenous saline hydration. All patients randomized to saline received 2000 ml 0.9% saline, 1000 ml prior to and 1000 ml post CE-CT. Infusion rates were adjusted by the treating physician to a patient s cardiac function, based on symptoms or a history of congestive heart failure, and varied between 83 and 250 ml/hour. Randomization was stratified by hospital of inclusion, and by renal function (egfr 0-19, or 40-59ml/min/1.73m2), and diabetes mellitus, both major risk factors for CI-AKI 9;23. The study had an open-label design. Procedures Patients were hospitalized to undergo CE-CT and to receive their randomized CI-AKI preventing treatment. Patients randomized to sodium bicarbonate were admitted at a daycare department for study purposes. Contrast volumes used were registered and dependent on CE-CT protocol and body mass. CE-CT was performed with low-osmolar contrast media in all hospitals (Iomeprol (Iomeron, Bracco Imaging, Milan, Italy), Iobitridol (Xenetix, Guerbet, Aulnay-sous-Bois, France) or Iodixanol (Visipaque, GE Healthcare, Chalfort St. Giles, United Kingdom). No other CI-AKI preventive treatments were used, such as administration of N-acetylcysteine. Serum and urine samples were collected prior to hydration and once between hours post CE-CT. Urine samples were also obtained at 4-6 hours post CE-CT, after which patients were discharged if they had been randomized to sodium bicarbonate. Patients randomized to saline were discharged after completion of hydration. Serum sampling was repeated two months post CE-CT in patients diagnosed with CI-AKI (i.e. an increase in serum creatinine >25% or >44 µmol/l (0.5 mg/dl) at hours post CE-CT compared with baseline). Samples were analyzed for serum creatinine values centrally in the laboratory of the Leiden University Medical Center using Roche Diagnostics analyzers (Mannheim, Germany) after trial completion. Urinary ph levels were measured at baseline and 4-6 hours post CE-CT, to determine whether sodium bicarbonate hydration had increased urinary ph. The presence of other risk factors of CI-AKI as stated by the European Society of Urogenital Radiology (ESUR) guideline was recorded for each patient (i.e. diabetes mellitus, congestive heart failure New York Heart Association grade 3-4, age over 70 years, contrast volumes 3.7 times baseline egfr value, and use of nephrotoxic medication) 9.

6 Saliña Trial 67 Outcomes Primary outcome was the relative increase in serum creatinine measured between hours post CE-CT compared with baseline. Secondary outcomes were the incidence of CI-AKI (defined as stated above); recovery of renal function in CI-AKI patients (recovery defined as an increase in serum creatinine < 25% or < 44µmol/L (0.5 mg/dl) measured at two months post CE-CT compared with baseline) 27;28 ; the need for dialysis; acute heart failure due to volume expansion; and rehospitalisation or outpatient visits. Patients were assumed to not have developed CI-AKI if CE-CT was cancelled or performed without contrast enhancement and serum creatinine values were therefore not obtained. Serum creatinine values of patients, who did not receive contrast media but in whom these variables were available, were included in the study analysis. Economic evaluation Costs were estimated from a hospital perspective, with a two-month time horizon, at price level Costs included the hydration itself, hospital days and specialist consultations (excluding visits for study purposes). Volumes of healthcare were estimated from hospital information systems. Direct costs per hydration treatment included the costs of the infusions ( 3 for sodium bicarbonate and 2 for saline), mostly short day care for the sodium bicarbonate regime ( 194), and normal day-care or an inpatient hospital day for the saline regime ( 382 and 602, respectively). Other hospitalisations and outpatient visits were valued using standard prices, designed to reflect societal costs and to standardize economic evaluations 29. Cost-effectiveness acceptability curves were used to relate the difference in costs to the difference in the incidence of CI-AKI (according to intention-to-treat with multiple imputation for missing values on the occurrence of CI- AKI and one-sided unequal-variance t-tests). Acceptability curves show the probability that one strategy has a better net benefit (NB = - WTP x incidence - Costs) than the other strategy, depending on the willingness to pay (WTP) to avoid one case of CI-AKI 30. Chapter 5 Statistical analyses The trial was designed for non-inferiority. As a low relative serum creatinine increase in the saline group was expected 31, one-hour sodium bicarbonate hydration prior to CE-CT was considered non-inferior if the mean relative serum creatinine increase in this group was not more than 15% higher compared with the increase in the saline hydration group (in absolute terms). The power calculation was based on this criterion, and the assumption that the actual difference between both groups would be 5% with a standard deviation of 40%. This calculation indicated inclusion of 250 patients per treatment arm to be sufficient (β=0.2, α=0.05). Assuming 15% of patients to be lost to follow-up, we calculated a total sample size of 574 patients.

7 68 Chapter 5 The study was analysed blinded on an intention-to-treat basis. Differences in the mean relative serum creatinine increase, absolute urinary ph levels and healthcare costs between randomisation groups were analysed using an independent samples T-Test with corresponding 95% confidence intervals or p-values. For the primary outcome a one-sided p-value of non-inferiority was calculated under null hypothesis of equivalence. Incidences of CI-AKI, reversibility of CI-AKI, acute heart failure, and the need for dialysis were reported and tested for statistical differences between both groups using relative risks (RR). Subgroup analyses were performed for the primary endpoint and the incidence of CI-AKI in high risk patients (i.e. egfr < 30 ml/min/1.73m2, diabetes mellitus, age > 75 years). No corrections were made for multiple comparisons. Incidences of CI-AKI according to the Acute Kidney Injury Network (AKIN) criteria were compared between both groups in a post-hoc analysis 32. All calculations were performed using SPSS version 20.0 (IBM Corp, Armonk, New York). Results Between January 2010 and June 2012, 570 patients provided written informed consent and were randomized. Twenty-two withdrew consent after randomisation, leaving 548 patients available for the intention-to-treat analysis: 267 patients randomized to sodium bicarbonate hydration prior to CE-CT and 281 to saline prior to and after CE-CT (Figure 1). Protocol violation occurred in ten patients within the intention-to-treat population of whom six were randomized to saline hydration. Four patients randomized to saline had pre-existing severe chronic congestive heart failure and were therefore hydrated with sodium bicarbonate. Another patient in the saline group received a total volume of 1000 instead of 2000 ml by mistake, and in one patient the saline infusion was stopped prematurely (due to acute dyspnoea). Of the four patients in the sodium bicarbonate arm in whom protocol violation occurred, one patient received 500 instead of 250 ml sodium bicarbonate. Another patient received saline hydration. Two other patients received additional 25 and 400 ml of saline, respectively. All other patients received the study mandated randomized treatment. Patient and procedure characteristics at baseline were well balanced between the treatment groups (Table 1). In total, 171 patients within the intention-to-treat population had a baseline egfr < 45 ml/min/1.73m2. Of those with a baseline egfr > 45 ml/ min/1.73m2, 231 (74%) had two or more other risk factor for CI-AKI. Eight out of 548 patients (1.5%) received combination treatment of ACE-inhibitors and angiotensin receptor blockers prior to CE-CT. Infused volumes of sodium bicarbonate and saline per kilogram bodyweight are presented in Appendix 1.

8 Saliña Trial patients randomised with informed consent 281 hydration prior to CT with sodium bicarbonate 289 hydration with saline prior to and after CT 14 Withdrawn informed consent 8 Withdrawn informed consent 267 included in the intention-to-treat analysis 281 included in the intention-to-treat analysis 15 with missing primary endpoint - 2 treated according to protocol - 5 CT without i.v. contrast - 8 CT cancelled and no hydration 20 with missing primary endpoint - 7 treated according to protocol - 7 CT cancelled and no hydration - 4 CT without i.v. contrast - 2 treated with sodium bicarbonate 252 available for analysis on primary endpoint treated according to protocol - 3 CT without i.v. contrast - 1 saline pre- and post-hydration - 1 saline stopped prematurally (acute dyspnoea) - 1 egfr > 60 ml/min and no hydration - 1 CT cancelled and no hydration 261 available for analysis on primary endpoint treated according to protocol - 8 CT without i.v. contrast - 2 sodium bicarbonate hydration - 2 egfr > 60 ml/min and no hydration - 2 CT cancelled and no hydration Chapter 5 Figure 1. Trial profile CT = computed tomography, egfr = estimated glomerular filtration rate, i.v. = intravenous Patient outcome The primary outcome was assessed in 93.6% (513/548) of patients. In 24 of the 35 patients in whom the primary outcome was not assessed, CE-CT was cancelled or performed without intravenous contrast enhancement. Mean relative serum creatinine increase hours post CE-CT compared with baseline was 1.2% (SD 13.3%) in the sodium bicarbonate versus 1.5% (SD 14.2%) in the saline group, for a mean difference of -0.3% (95%CI -2.7 to 2.1%, p-value for non-inferiority <0.0001). Follow-up on the endpoint of CI-AKI was complete in 98.2% (538/548). The incidence of CI-AKI did not differ significantly between groups, i.e. 3.0% (8/264) in the sodium bicarbonate and 5.1% (14/274) in the saline group (RR 0.59, 95%CI ). Risks of CI-AKI were similar for patients in whom diuretics were withheld prior to CE-CT (4/83, 4.9%) and those in whom diuretic therapy was continued (8/173, 4.6%). Incidences of CI-AKI defined by the AKIN criteria are presented in Table 2. The results on the primary endpoint and the risk of CI-AKI comparing sodium bicarbonate with saline hydration were consistent under the predefined subgroups (Figure 2ab). No significant interactions between subgroups and treatment were found. Follow-up on recovery of renal function was complete in 95% (21/22) of CI-AKI patients. Renal function had recovered two months after CE-CT in 75% (6/8) of CI-AKI patients randomized to sodium bicarbonate versus 69% (9/13) randomized to saline (RR 1.08, 95% CI ). egfrs two months post CE-CT of CI-AKI

9 70 Chapter 5 Table 1. Patient characteristics at baseline. Sodium bicarbonate (N=267) Saline (N=281) Mean age, years 71.6 (9.8) 72.5 (9.5) Sex, male 160 (59.9) 171 (60.9) Outpatients 252 (94.4) 253 (90.0) Mean egfr 49.9 (13.4) 50.9 (13.9) egfr > 45 ml/min/1.73m2 186 (69.7) 191 (68.0) egfr ml/min/1.73m2 59 (22.1) 71 (25.3) egfr ml/min/1.73m2 19 (7.1) 18 (6.4) egfr < 15 ml/min/1.73m2 3 (1.1) 1 (0.4) Mean systolic blood pressure (23.0) (21.9) Mean diastolic blood pressure 78.7 (13.7) 77.2 (12.5) Diabetes mellitus 71 (26.6) 76 (27.0) Peripheral arterial disease 82 (30.7) 95 (33.8) Coronary artery disease 83 (31.1) 100 (35.6) Congestive heart failure 42 (15.7) 48 (17.1) Primary renal or urological disease 124 (46.4) 117 (41.6) Microalbuminuria* 34 (12.7) 41 (14.6) Macroalbuminuria* 42 (15.7) 51 (18.1) Anemia** 69 (25.8) 69 (24.6) Medication 206 (77.2) 221 (78.6) NSAIDS*** 8 (3.0) 19 (6.8) Diuretics 124 (46.4) 132 (47.0) ACE-inhibitors 107 (40.1) 108 (38.4) Angiotensin II receptor blockers 48 (18.0) 59 (21.2) Chemotherapy 7 (2.6) 5 (1.8) Preprocedural stop of medication 53 (19.9) 60 (21.4) Type of CT-scan CT abdomen 96 (36.0) 81 (28.8) CT thorax 26 (9.7) 31 (11.0) CT angiography 88 (33.0) 110 (39.1) Other 57 (21.3) 59 (21.0) Mean contrast volume in ml (21.0) (21.6) Mean iodine dose in grams 36.6 (8.3) 35.5 (10.5) Median time in hours between CT and creatinine measurements (IQR) 70 (56-86) 70 (51-94) Data are mean (SD), n (%) egfr = estimated glomerular filtration rate. CKD = chronic kidney disease. * Microalbuminuria was defined as albumin-creatinine ratio mg/g, macroalbuminuria as albumincreatinine ratio > 300 mg/g. ** defined as Hb < 7.4 mmol/l if female and Hb < 8.1 mmol/l if male. *** Nonsteroid anti-inflammatory drugs

10 Saliña Trial 71 patients in whom renal function had not recovered were 32 and 51 ml/min/1.73m2 in patients randomized to sodium bicarbonate and 22, 24, 27, and 47 ml/min/1.73m2 in those randomized to saline. None of the CI-AKI patients developed a need for dialysis. Acute heart failure due to volume expansion (based on the treating physician s clinical judgement) occurred in none of the patients in the sodium bicarbonate group versus 6/281 patients in the saline group (p=0.03). Consequently, saline hydration was prematurely stopped in 1/281 patients. Four other patients received intravenous furosemide. One of them was admitted to the Intensive Care Unit for two days and underwent emergency percutaneous transluminal coronary angioplasty. Another patient had to be rehospitalized. Saline volumes per kilogram bodyweight were similar for patients who did and didn t develop acute heart failure, with mean volumes of 29.7 (SD 3.3) and 26.6 ml (SD 5.4), respectively, (95% CI -1.3 to 7.4, p = 0.16). Three out of six patients developing acute heart failure were on diuretic treatment prior to CE-CT, yet none of them used NSAIDs. Four of these six patients had a history of congestive heart failure. Mean urinary ph was 6.1 (SD 0.9) at baseline and 6.6 (SD 1.0) at 4-6 hours post CE-CT in the sodium bicarbonate group. For saline these values were 5.8 (SD 0.8) and 6.1 (SD 6.1), respectively, (p <0.001 for difference in mean ph at 4-6 hours post CE-CT between both groups). Chapter 5 Economic evaluation Of the outpatients treated with sodium bicarbonate, 96% underwent CE-CT in mostly short day care, and 4% were admitted for a median duration of 2.0 days ( percentile ) because of other imaging or interventional procedures. Of the outpatients treated with saline, 58% were treated in day care setting, whereas the other 42% of patients were hospitalised for a median duration of two days ( percentile days) using a lower saline infusion rate of 1000 ml in twelve hours prior to and post CE-CT. The difference in hydration-related costs was 459 per patient in favour of the sodium bicarbonate group (95%CI 383 to 535, Table 3), due to more extensive day care and more frequent inpatient hospitalisation for the saline regime. Other categories of hospital costs during the two months of follow-up were comparable (p 0.16). Whether a hydration strategy is cost-effective, depends on how much one is willing to pay (WTP) to avoid one case of CI-AKI. Figure 3 shows the probability that one-hour hydration prior to CE-CT with sodium bicarbonate is cost-effective compared with saline hydration prior to and after CE-CT. Taking all hospital costs into account, hydration with sodium bicarbonate is at least 92% likely to be cost-effective, regardless the WTP. For example, if one is willing to pay 10,000 to prevent one case of CI-AKI, then it is 96% certain that hydration with sodium bicarbonate is cost-effective. Restricting to only the hydration-related costs (i.e. including the required hospitalisation, but assuming non-inferiority on other costs), makes hydration with sodium bicarbonate almost 100% certain to be cost-effective for WTP up to 10,000 per case of CI-AKI.

11 72 Chapter 5 Baseline creatinine clearance < 30 ml/min (n=38) >= 30 ml/min (n=475) Diabetes mellitus Yes (n=140) No (n=373) Age <= 75 years (n=302) > 75 years (n=211) Overall estimate Favors sodium bicarbonate Effect size estimate Favors saline Figure 2a. Subgroup analyses on the primary outcome of a relative increase in serum creatinine hours post intravenous contrast media-enhanced CT. Effect size is calculated as the difference in the mean relative increase in serum creatinine between both randomisation groups. The dashed line indicates the point estimate of the entire study population and the straight line indicates no effect. Baseline creatinine clearance < 30 ml/min (n=40) >= 30 ml/min (n=498) Diabetes mellitus Yes (n=149) No (n=389) Age <= 75 years (n=319) > 75 years (n=219) Overall estimate Favors sodium bicarbonate Relative risk Favors saline Figure 2b. Subgroup analyses on the secondary outcome of risk of contrast-induced acute kidney injury, calculated as relative risk. The dashed line indicates the point estimate of the entire study population and the straight line indicates no effect.

12 Saliña Trial 73 Table 2. Incidence of CI-AKI according to the AKI criteria AKIN Stage Sodium bicarbonate (95%C) Saline (95%C) Relative risk (95% CI) I: (Increase > 26.5 µmol/l or 150% to 200% from baseline) II : (Increase % from baseline) III : (Increase > 300% from baseline, or 354 µmol/l, or on RRT) 11/263, 4.2% ( ) 17/ % ( ) 0.7 ( ) 0/263 ( ) 0/273 ( ) 1.0 ( ) 0/263 ( ) 0/273 ( ) 1.0 ( ) AKIN = Acute Kidney Injury Network Table 3. Estimated hospital costs per patient between randomisation and two months follow-up Direct costs of hydration Sodium Bicarbonate Sodium Chloride N = 267 N = 281 Volume* Costs in Volume* Costs in hydration treatment 96.3% 96.1% P-value for difference in costs total hydration costs <0.001 infusions <0.001 extra hospitalization day care <0.001 extra hospitalization non-day care Hospitalisation due to hydration complications hospitalization non-icu hospitalization ICU Other hospitalization non-icu ICU day care Outpatient visits emergency department nephrology non-nephrology Total costs Chapter 5 * Volumes represent percentage of patients or mean number of procedures, hospital days or visits i.e. acute heart failure due to volume overload Discussion Our study demonstrates that a novel one-hour hydration regime prior to CE-CT with 250 ml sodium bicarbonate is non-inferior to standard peri-procedural saline hydration. Secondly, the short sodium bicarbonate treatment resulted in a substantial decrease

13 74 Chapter 5 Figure 3. Whether a hydration strategy is cost-effective, depends on how much one is willing to pay (WTP) (in euro) to avoid one case of CI-AKI. This figure shows the probability that one-hour hydration prior to CE-CT with sodium bicarbonate is cost-effective compared with saline hydration prior to and after CE-CT. in hydration costs by 459 per patient, without impact on clinical outcome. As a result, one-hour hydration with sodium bicarbonate prior to CE-CT is at least 90% likely to be more cost-effective. This is the first randomized trial that has compared head-to-head a one-hour hydration scheme of 250 ml sodium bicarbonate prior to CE-CT with peri-procedural saline hydration to prevent CI-AKI. Prior studies have evaluated different hydrating regimes with the goal of simplifying the hydration strategy. One earlier study among patients undergoing either CE-CT or intra-arterial contrast administrations demonstrated saline hydration to be more effective for CI-AKI prevention than sodium bicarbonate infusion before contrast administration in combination with both oral sodium bicarbonate and water administration 33. As the sample size of this study was small, and the patient population heterogeneous, it is difficult to compare these results to the current study. Additionally, there is a large body of data demonstrating the efficacy of a seven hour infusion of sodium bicarbonate compared with normal saline with most studies and meta-analyses concluding either non-inferiority or a slight benefit of sodium bicarbonate among patients undergoing invasive cardiac and peripheral vascular procedures 11-20;34. However, there has been a paucity of data on the ideal prophylactic strategy for patients undergoing CT-CE, a very common procedure worldwide. We evaluated a relatively simple protocol that is likely to be more practical and has the feasibility of easy adoption and improving patient satisfaction. Moreover, the risk of hospital acquired infections might

14 Saliña Trial 75 decrease by the use of the short sodium bicarbonate regime that can be implemented in an out-patient setting. This is especially of importance for CKD patients, who are at increased risk of developing infections 35. Further, in our study, there was a slight excess of complications associated with saline hydration. Four patients randomized to saline did not receive it because of pre-existing severe chronic congestive heart failure and six of the patients receiving saline hydration developed symptoms of acute heart failure due to volume expansion. In two patients this required even temporary (ICU) readmission. Finally, in the absence of clinical important differences between the two strategies, cost implications must be considered In our study, the clinical efficacy of a short infusion with sodium bicarbonate in preventing CI-AKI was comparable with the saline hydration scheme, whereas the costs were only a third. Therefore, from a value based care perspective, the use of sodium bicarbonate hydration prior to CE-CT should be preferred over saline hydration. Our study extends prior work in the field. It had a robust trial design, with few drop-outs or missing data. A short hydration has been assessed, which is easy to apply in clinical practice and has strong potential for drastically decreasing healthcare costs for preventive hydration, and at the same time reducing the inconvenience for the patient. The results of our study were homogenous throughout the population, and can therefore be extrapolated to clinical practice of CKD patients undergoing CE-CT. In addition, we used standardized hydration volumes instead of volumes adjusted to bodyweight to ease the clinical use of the infusions. At the same time, these standardized volumes corresponded well with the volumes that would have been achieved using a bodyweight adjusted approach (data not shown). Some aspects of our trial warrant comment. First, CI-AKI is frequently defined by an increase in serum creatinine > 25% or > 44 µmol/l (0.5 mg/dl) 5;39-41, but this definition is often debated 9. One of the most prominent disadvantages is that this definition leads to CI-AKI being a rare event, which as a consequence requires a very large study sample size in a non-inferiority study. We therefore chose the relative increase in serum creatinine as our primary endpoint (and CI-AKI as a secondary endpoint). This endpoint has been used in several previous studies on CI-AKI prevention It resulted in a feasible sample size, and importantly, it allowed us to analyze expected small differences in contrast media induced-nephrotoxicity between treatment arms, for which an increase in serum creatinine is an earlier and more sensitive marker. Second, our cost-analysis is specific for the Dutch healthcare system. Nevertheless, we expect the reduction in hospital days for preventive hydration to be generalizable to other settings. Although the exact numbers may differ from country to country, the health economic impact of our results can be substantial worldwide. Third, we included patients with a baseline egfr < 60 ml/min/1.73m2 while the updates of both the ESUR guideline and European Chapter 5

15 76 Chapter 5 Renal Best Practice advise to use preventive hydration only in patients with an egfr < 45 ml/min/1.73m2 when undergoing CE-CT 5;9. However, a sensitivity analysis of our study confirmed non-inferiority of sodium bicarbonate to saline in patients with an egfr < 45 ml/min/1.73m2 (data not shown). Fourth, based on our study design, we were unable to determine whether smaller volumes of saline (comparable with the sodium bicarbonate regime but not resulting in alkalisation of urine as seen in the sodium bicarbonate group), would also be non-inferior to peri-procedural saline hydration. Fifth, although the vast majority of international guidelines recommend preventive hydration in CKD patients undergoing intravascular contrast administration (CE-CT or intra-arterial contrast injections) 5;9, the American College of Radiology manual on contrast media does not endorse its routine use prior to CE-CT 49. We therefore can t exclude that the results of our study may have less clinical impact on hospitals adhering to that guideline. In summary, in this trial we show that a simple preprocedural regime with sodium bicarbonate is non-inferior to standard peri-procedural saline infusion in CKD patients undergoing CE-CT and results in considerable healthcare savings. Further research is needed to study whether one-hour sodium bicarbonate hydration is also non-inferior to peri-procedural saline hydration in patients undergoing invasive (cardiac) procedures requiring intra-arterial administration of iodinated contrast media. Acknowledgement The authors thank Dr. Hitinder S. Gurm, MD, for his input and critical appraisal of this manuscript.

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19 80 Chapter 5 Appendix Sodium bicarbonate Saline Volume in ml/kg bodyweight Volume in ml/kg bodyweight Appendix Figure 1. Infused total volumes of sodium bicarbonate and saline standardized to bodyweight.