Original Papers. Intensive Care Unit, Royal Perth Hospital, Perth, Western Australia, Australia

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1 Anaesth Intensive Care 2008; 36: Original Papers Use of isotonic sodium bicarbonate to prevent radiocontrast nephropathy in patients with mild pre-existing renal impairment: a meta-analysis K. M. Ho*, D. J. Morgan Intensive Care Unit, Royal Perth Hospital, Perth, Western Australia, Australia Summary Acute renal dysfunction after radiocontrast in patients with pre-existing renal impairment is not uncommon and is associated with significant morbidity and mortality. Isotonic sodium bicarbonate solution was first reported to reduce radiocontrast nephropathy in This first study was, however, limited by its small sample size and as such, the use of isotonic sodium bicarbonate to prevent radiocontrast nephropathy is still not widely used by many anaesthetists and intensivists. We meta-analysed relevant randomised controlled studies sourced from the Cochrane Controlled Trial Register (2007 issue 4), EMBASE and MEDLINE databases (1966 to April 15, 2008) without any language restriction. The use of isotonic sodium bicarbonate was associated with a significant reduction in risk of an incremental rise in serum creatinine concentration 25% above baseline (relative risk 0.22, 95% confidence interval [CI]: 0.11 to 0.44, P <0.0001; I 2 =0%) and had a protective effect on the absolute change in serum creatinine concentration (weighted-mean-difference -9.4 µmol/l, 95% CI: to -1.7, P=0.02; I 2 =0%) and creatinine clearance (weighted-mean-difference 3.7 ml/min, 95% CI: 0.55 to 6.80, P=0.02; I 2 =57.1%) after radiocontrast. The incidence of acute renal failure requiring dialysis was low (1.4%) and was not significantly different after the use of isotonic sodium bicarbonate (relative risk 0.59, 95% CI: 0.15 to 2.42, P=0.47; I 2 =0%). With the limited data available, isotonic sodium bicarbonate appears to be safe and very effective in reducing radiocontrast nephropathy in patients with mild pre-existing renal impairment. A large randomised controlled study is needed to confirm whether isotonic bicarbonate can improve patient centred clinical outcomes. Key Words: contrast, renal dysfunction, renal protection Radiocontrast nephropathy is the third leading cause of hospital-acquired renal failure, especially in patients with pre-existing renal impairment 1,2. Although radiocontrast nephropathy requiring dialysis is not common (0.7%) among those who receive radiocontrast, it is associated with significant morbidity and attributable mortality (>26%) 1. The mechanism of radiocontrast nephropathy is complex and may include direct toxic effect on cell proliferation and mitochondrial function, and * M.B., B.S., M.P.H., F.R.C.P., F.A.N.Z.C.A., F.J.F.I.C.M., Intensive Care Unit Consultant. M.B., B.S., F.A.C.E.M., F.J.F.I.C.M., Intensive Care Unit Consultant. Address for reprints: Dr K. M. Ho, Intensive Care Unit, Royal Perth Hospital, Perth, WA Accepted for publication on June 13, formation of free radicals in an acidic environment in the renal medulla resulting in vasoconstriction and ischaemia 2-4. Different pharmacological agents and procedures have been suggested to prevent radiocontrast nephropathy, including N-acetylcysteine, ascorbic acid, theophylline, fenoldopam, calcium antagonists and periprocedural haemofiltration with variable results 3. N-acetylcysteine is an antioxidant that can scavenge reactive oxygen species and regenerate glutathione stores and has been shown to attenuate radiocontrast nephropathy when administered before the onset of renal insult 5,6. However, N-acetylcysteine should ideally be commenced the night before the radiocontrast administration and hence this limits its utility mostly to elective radiocontrast-related procedures 7. Haemofiltration also appears to be effective in preventing radiocontrast nephropathy and can be commenced

2 a n d c o n t ra s t n e p h r o pat h y 647 during and after a procedure. It is, however, invasive and may not be cost effective in patients who are scheduled for simpler procedures 8. Intravenous sodium bicarbonate can alkalise the urine and may potentially reduce the formation of free radicals from radiocontrast in the renal medulla 9. Intravenous isotonic sodium bicarbonate was first reported to be effective in reducing radiocontrast nephropathy four years ago 9. In this study, isotonic sodium bicarbonate was started one hour before the radiocontrast-related procedure and was continued for six hours after the procedure. Because the isotonic sodium bicarbonate is started only one hour before the procedure, it is theoretically applicable to many patients including those who undergo emergency radiocontrast-related procedures. The original study which evaluated the effectiveness of isotonic sodium bicarbonate was, however, limited by its relatively small sample size and the low incidence of radiocontrast nephropathy. As such, many anaesthetists and intensivists have not adopted its use in preventing radiocontrast nephropathy. In this meta-analysis we assessed effectiveness of isotonic sodium bicarbonate in preventing radiocontrast nephropathy. MATERIALS AND METHODS Search strategy The literature search was performed on the Cochrane Controlled Trials Register (2007 issue 4), EMBASE (January 1990 to April 15, 2008) and MEDLINE databases (1966 to April 15, 2008). During the electronic database search, the following exploded MeSH terms were used: bicarbonate, alkalinization or alkaline with renal failure, renal dysfunction, dialysis, nephropathy or renal replacement therapy with contrast or radiocontrast. The initial search results were then limited to clinical trials, letters, editorial, reviews or randomised controlled trials only. The reference lists of related editorial, reviews and original articles identified were searched for relevant trials. Finally, the websites of International Network of Agencies of Health Technology Assessment and International Society of Technology Assessment in Health Care were searched to ensure all suitable trials were included. There were no language restrictions in this meta-analysis. Selection criteria and validity assessment Randomised controlled clinical trials, comparing sodium bicarbonate with either a placebo (e.g. no drug or 5% dextrose) or normal saline control, in patients who underwent a radiocontrast-related procedure were included. Studies comparing sodium bicarbonate with a placebo or normal saline and with equal co-interventions (e.g. N-acetylcysteine) in both arms were also included. There were no restrictions on timing of the intervention or population studied in this meta-analysis. However, studies evaluating the effects of sodium bicarbonate in sepsis or shock without the use of radiocontrast or studies that used unequal co-interventions (e.g. comparing N-acetylcysteine with sodium bicarbonate against a placebo or normal saline) were excluded. Two independent reviewers examined the full text of all identified trials to confirm that they fulfilled the inclusion criteria. They examined and recorded the trial characteristics and outcomes independently, using a pre-designed data abstraction form. This abstraction form was used to record information regarding the quality of the trial such as allocation concealment, randomisation method, blinding of treatment, intention-to-treat analysis, inclusion and exclusion criteria. The grading of allocation concealment was based on the Cochrane approach, that is, adequate or uncertain or inadequate. There were no disagreements between the two independent reviewers in the data extracted. Data were checked and entered into the Review Manager (version for Windows. Oxford, England: The Cochrane Collaboration, 2003) database for further analyses. Statistical analysis The proportion of patients with an incremental rise in serum creatinine concentration of greater than 25% above the baseline (or >0.50 mg/dl [44 µmol/l]) was chosen as the main outcomes of interest in this study. An incremental rise in serum creatinine concentrations of greater than 25% above the baseline was often used as a surrogate end-point in many studies on radiocontrast nephropathy because it is relatively common (10 to 15%) and also between 5% and 10% of those patients with an incremental rise in serum creatinine greater than 25% from baseline may eventually require dialysis 1,9. The other outcomes assessed included acute renal failure requiring dialysis, mortality, urinary ph after the administration of the isotonic sodium bicarbonate and absolute change in serum creatinine concentration and creatinine clearance (measured or estimated) from the baseline. The categorical outcomes were reported as relative risk (RR) with 95% confidence interval (CI), using a fixed effect model. The continuous outcomes were reported

3 648 K. M. Ho, D. J. Mo r ga n as a weighted-mean-difference (WMD) with 95% CI, also using a fixed effect model. If the mean and standard deviation of the continuous outcomes were not reported in the studies, we assigned the median as the mean and estimated standard deviation (SD) from the range (i.e. SD=range 0.95/4). The presence of heterogeneity between trials was assessed by the χ 2 statistics and the extent of inconsistency was assessed using I 2 statistics 10. An I 2 over 40% was regarded as having significant heterogeneity. All tests were two-tailed and a P value less than 0.05 was regarded as significant in this meta-analysis. If there were more than 10 studies identified, funnel plot would be used to assess publication bias 11. RESULTS Study description Four randomised controlled studies from four countries with a total of 573 adult patients with undergoing radiocontrast-related procedures were considered (Figure 1) 9, Three studies were excluded because they were not randomised controlled studies and one study was excluded because a combination of sodium bicarbonate and N-acetylcysteine was used to compare with normal saline control 18. The proportion of patients lost to follow-up was less than 10% in all studies but only two studies had adequate allocation concealment. None of the studies was blinded. Overall, there was a moderate risk of bias in the design of the pooled studies. Three studies involved patients with a baseline serum creatinine concentration above between 97 and 106 µml/l and one study looked at patients with a baseline serum creatinine concentration above 176 µmol/l 13. Two studies (338 patients) evaluated the effects of isotonic bicarbonate in patients undergoing a variety of radiocontrast-related procedures including vascular procedures and computed tomography 9,14, and the other two studies (235 patients) looked at only patients undergoing diagnostic or therapeutic cardiac catheterisation 12,13. Studies comparing isotonic sodium bicarbonate with a placebo or normal saline in preventing radiocontrast nephropathy in MEDLINE, EMBASE and Cochrane Controlled Trials Register Databases (n=400) Studies excluded in this meta-analysis - (n=396) - Studies not relevant or review articles (n=392) - Observational studies (n=3) Study used unequal co-intervention (n=1) 18 Studies suitable for detailed data extraction (n=4) Studies reported the post treatment urinary ph (n=3) Studies reported the proportion of patients with an incremental rise in serum creatinine concentration 25% above baseline (n=4) Studies reported the proportion of patients required dialysis (n=4) Studies reported the proportion of patients with mortality (n=1) Studies reported the changes in creatinine clearance and serum creatinine from baseline (n=3) Figure 1: Flow chart showing trial inclusion and exclusion in this meta-analysis.

4 a n d c o n t ra s t n e p h r o pat h y 649 Study, year, country Participants, inclusion and exclusion of origin Reference criteria Merten et al, 2004, 119 adult patients, with a serum USA 9 creatinine concentration >97.2 µmol/l but <707 µmol/l. Other exclusions included renal dialysis, multiple myeloma, pulmonary oedema, uncontrolled hypertension (systolic blood pressure >160 or diastolic blood pressure >100 mmhg), emergency catheterisation, exposure to radiocontrast within 2 weeks, allergy to the contrast and pregnancy. Masuda et al, 2007, 59 adult patients, with creatinine Japan 12 concentration >97 µmol/l. Exclusions included pre-existing dialysis, exposure to radiocontrast within 2 days before study, allergy to the contrast, pregnancy or planned administration of mannitol. Ozcan et al, 2005, 176 adult patients with creatinine Turkey 13 concentration >106 µmol/l but <352 µmol/l. Other exclusions included uncontrolled hypertension (systolic blood pressure > 160 and diastolic blood pressure >110 mmhg), emergency catheterisation, exposure to radiocontrast within 2 days of the study and volume overload. between 100 and 400 µmol/l [1.1 and 4.5 mg/ dl], undergoing elective open heart on-pump surgery. Patients with renal transplantation and chronic dialysis were excluded. Briguori et al, 2007, 219 adult patients, with pre-existing Italy 14 creatinine concentration >176 µml/l but <704 µmol/l. Other exclusions included pre-existing dialysis, multiple myeloma, pulmonary oedema, acute myocardial infarction, exposure to radiocontrast within 2 days of study and pregnancy. =sodium bicarbonate. Ta b l e 1 Characteristics of the included trials Interventions Outcomes Allocation concealment, blinding, intention to treat analysis group (n=60): IV 3 ml/kg/h of isotonic 1 hour before the procedure and then 1 ml/kg/h during and the procedure until 6 hours after the procedure. Control group (n=59): Same volume as in group. The solution was made of 154 mmol of sodium chloride in 5% dextrose. An incremental rise in serum creatinine concentration >25% above baseline, number of patients required dialysis, change in serum creatinine concentration, potassium concentration, urinary ph and creatinine clearance from the baseline. Allocation concealment adequate, unblinded, analysis not by intention to treat, loss to follow-up 7.3%. group (n=30): IV 3 ml/kg/h of isotonic 1 hour before the procedure and then 1 ml/kg/h during and the procedure until 6 hours after the procedure. Control group (n=29): Same volume as in group. The exact composition of the solution was not described. Mortality, an incremental rise in serum creatinine concentration >25% above baseline, number of patients required dialysis, change in serum creatinine concentration, urinary ph and creatinine clearance from the baseline. Allocation concealment adequate, unblinded, analysis not by intention to treat, loss to follow-up 3.3%. group (n=88): IV 1 ml/kg/h of isotonic 6 hours before the procedure and then 1 ml/kg/h during and the procedure until 6 hours after the procedure. Control group (n=88): Same volume as in group. The solution was made of 154 mmol/l of sodium chloride solution. BOTH groups also received oral N-acetylcysteine 600 mg twice a day started before the day before the procedure. Number of patients required dialysis, change in serum creatinine concentration and creatinine clearance from the baseline. Allocation concealment unclear, unblinded, analysis appeared to be by intention-to-treat. group (n=108): IV 3 ml/kg/h of isotonic 1 hour before the procedure and then 1 ml/kg/h during and the procedure until 6 hours after the procedure. Control group (n=111): Same volume as in group. The solution was made of 154 mmol/l of sodium chloride solution. BOTH groups also received oral N-acetylcysteine 1200 mg twice a day started before the day before the procedure. An incremental rise in serum creatinine concentration >25% above baseline, number of patients required dialysis, and change in serum potassium concentration and urinary ph from the baseline. Allocation concealment unclear, unblinded, analysis not by intention-to-treat, loss to followup 6.4%.

5 650 K. M. Ho, D. J. Mo r ga n Study Control WMD (fixed) Weight WMD (fixed) N M ean (SD) N M ean (SD) 95% CI % 95% CI Merten [9] (0.80) (0.60) [0.69, 1.11] Briguori [14] (0.90) (0.80) [0.77, 1.23] Masuda [12] (1.20) (0.90) [0.86, 1.94] Total (95% CI) [0.83, 1.13] Test for heterogeneity: Chi²=2.92, df=2 (P =0.23), I²=31.5% Test for overall effect: Z=13.04 (P < ) Favours NaCl Favours Figure 2: The effect of isotonic sodium bicarbonate on urinary ph. Study Control RR (fixed) Weight RR (fixed) n/n n/n 95% CI % 95% CI Merten [9] 1/60 8/ [0.02, 0.95] Briguori [14] 2/108 11/ [0.04, 0.82] Masuda [12] 2/30 10/ [0.05, 0.81] Ozcan [13] 4/88 12/ [0.11, 0.99] Total (95% CI) [0.11, 0.44] Total events: 9 (NaCO 3 ), 41 (Control) Test for heterogeneity: Chi²=0.95, df=3 (P =0.81), I²=0% Test for overall effect: Z=4.27 (P <0.0001) Favours Favours NaCl Figure 3: The effect of isotonic sodium bicarbonate on risk of an incremental rise in serum concentrations 25% above the baseline. Study Control WMD (fixed) Weight WMD (fixed) N M ean (SD) N Mean (SD) 95% CI % 95% CI Merten [9] (21.70) (17.00) [1.60, 15.60] Masuda [12] (20.90) (22.70) [-0.54, 21.74] Ozcan [13] (15.30) (8.69) [-2.12, 5.24] Total (95% CI) [0.55, 6.80] Test for heterogeneity: Chi²=4.66, df=2 (P =0.10), I²=57.1% Test for overall effect: Z=2.30 (P =0.02) Favours NaCl Favours Study Control WMD (fixed) Weight WMD (fixed) N M ean (SD) N M ean (SD) 95% CI % 95% CI Merten [9] (36.08) (24.64) [-20.76, 1.40] Masuda [12] (29.92) (36.08) [-35.42, -1.54] Ozcan [13] (51.92) (44.00) [-16.86, 11.58] Total (95% CI) [-17.20, -1.66] Test for heterogeneity: Chi²=1.97, df=2 (P =0.37), I²=0% Test for overall effect: Z=2.38 (P =0.02) Favours Favours NaCl Figure 5: The effect of sodium bicarbonate on changes in serum creatinine concentrations (µmol/l) from the baseline.

6 a n d c o n t ra s t n e p h r o pat h y 651 Study Control RR (fixed) Weight RR (fixed) n/n n/n 95% CI % 95% CI Merten [9] 0/60 0/59 Not estimable Briguori [14] 1/108 1/ [0.07, 16.22] Masuda [12] 1/30 3/ [0.04, 2.92] Ozcan [13] 1/88 1/ [0.06, 15.74] Total (95% CI) [0.15, 2.42] Total events: 3 (NaCO 3 ), 5 (Control) Test for heterogeneity: Chi²=0.58, df=2 (P =0.75), I²=0% Test for overall effect: Z=0.72 (P =0.47) Favours Favours NaCl Figure 6: The effect of isotonic sodium bicarbonate on risk of acute renal failure requiring dialysis. Two of the four included studies also used oral N-acetylcysteine (600 mg or 1200 mg) twice daily, started the day before the procedure, in both normal saline and isotonic sodium bicarbonate group 13,14. Two studies had adequate allocation concealment but blinding was not used in any of the studies 9,12. Three studies used the same isotonic sodium bicarbonate protocol (154 mmol of sodium bicarbonate in 154 ml added to 846 ml of 5% dextrose, 3 ml/kg/h for one hour before the procedure then 1 ml/kg/h during procedure and six hours after the procedure) 9,12,14 and the other study used similar isotonic sodium bicarbonate solution but started six hours before at 1 ml/kg/h and continued until six hours after the procedure 13. The detail characteristics of the included studies are described in Table 1. Effects of isotonic sodium bicarbonate on renal outcomes The use of isotonic sodium bicarbonate was associated with a significant increase in urinary ph (WMD 0.98, 95% CI: 0.83 to 1.13, P < , I 2 =31.5%) and a reduction in risk of an incremental rise in serum creatinine concentration 25% above baseline (RR 0.22, 95% CI: 0.11 to 0.44, P <0.0001; I 2 =0%) (Figures 2 and 3). It also had a protective effect on the absolute change in serum creatinine concentration (WMD -9.4 µmol/l, 95% CI: to -1.7, P=0.02; I 2 =0%) and creatinine clearance (WMD 3.7 ml/min, 95% CI: 0.55 to 6.80, P=0.02; I 2 =57.1%) from the baseline after the use of radiocontrast (Figures 4 and 5). The incidence of acute renal failure requiring dialysis was low (1.4%) and was not significantly different after the use of isotonic sodium bicarbonate (RR 0.59, 95% CI: 0.15 to 2.42, P=0.47; I 2 =0%). % CI: 0.58 to 1.92) (Figure 6). There was significant heterogeneity only in the change in creatinine clearance from the baseline between the pooled studies. Significant treatment-related adverse effect was observed in only one patient during the bolus infusion of isotonic sodium bicarbonate in the four pooled studies 9. Two studies reported on the changes in serum potassium concentration after the treatment of isotonic sodium bicarbonate solution and did not find a significant difference 9,14. Mortality was reported in one study and there was no significant difference between patients who received isotonic sodium bicarbonate or normal saline (RR 0.18, 95% CI: 0.01 to 3.92, P=0.28) but the total length of hospital stay was not reported in any of the pooled studies 12. Funnel plot was not performed because of the small number of studies included in this meta-analysis. DISCUSSION This meta-analysis shows that isotonic sodium bicarbonate is effective in increasing urinary ph and reducing a rise in serum creatinine concentrations after radiocontrast in patients with mild pre-existing renal impairment. There is, however, a lack of patientcentred outcome data because of the small number of patients included in this meta-analysis. Our results showed that isotonic sodium bicarbonate is effective in reducing a rise in serum creatinine after radiocontrast. This conclusion was different from the results of a recent retrospective observational study in which sodium bicarbonate was not associated with an improved renal outcome. Observational studies can, however, be affected by undetected bias and confounding. The moderate quality and consistency of results of the pooled randomised controlled studies suggest that sodium bicarbonate is more likely to be effective than normal saline in reducing radiocontrast nephropathy. Sodium bicarbonate is inexpensive and would be potentially very cost-effective if it could prevent acute renal dysfunction or failure after radiocontrast. Also,

7 652 K. M. Ho, D. J. Mo r ga n because sodium bicarbonate can be administered in a diluted form as an isotonic solution, central vascular access is not necessary, making it a very attractive alternative option when compared to other drugs or procedures such as haemofiltration. Furthermore, isotonic sodium bicarbonate can be administered 60 minutes before the administration of radiocontrast, and as such, its role in emergency radiocontrast-related procedures is likely to be more important than N-acetylcysteine. Finally, two of the pooled studies evaluated the combination of isotonic sodium bicarbonate with N-acetylcysteine, and from their results it appears that isotonic sodium bicarbonate can offer additional protective benefits in reducing radiocontrast nephropathy. It also appears that the magnitude of protection offered by isotonic sodium bicarbonate solution in preventing an incremental rise in serum creatinine concentrations 25% above baseline is similar to high dose N-acetylcysteine (1200 mg twice a day for two days) (RR 0.22 vs. 0.24) 6. The mechanism by which sodium bicarbonate can prevent radiocontrast nephropathy remains uncertain. It has been postulated that free radical formation is promoted by an acidic environment and inhibited by a higher ph in the urine 9. Our results confirmed that infusing a relatively small dose of isotonic sodium bicarbonate solution over seven to 12 hours can increase the urinary ph from around 5.5 to between 6 and 7. While N-acetylcysteine works as a free radical scavenger, isotonic sodium bicarbonate works by reducing the formation of free radicals by inducing an alkaline environment in the renal tubules in preventing radiocontrast nephropathy and, as such, it is highly possible that they can have additional protective effect on radiocontrast nephropathy. This small dose of isotonic sodium bicarbonate appears to be fairly safe, the only adverse event reported being a transient increase in blood pressure during the bolus infusion (3 ml/kg/h) 9. Although hypokalaemia was not found to be a significant problem in two pooled studies, it is still possible for isotonic sodium bicarbonate to induce hypokalaemia and cardiac arrhythmias in some susceptible patients. This meta-analysis has significant limitations. First, as with any overview, meta-analysis is prone to bias. In order to avoid selection bias, we have searched studies from three databases without language restrictions. Second, there was significant heterogeneity in the continuous outcomes in the pooled studies. This is likely due to different patient characteristics in different cohorts and also most studies estimated the creatinine clearance by Cockcroft-Gault equation which may not be reliable in critically ill hospitalised patients 19 and, as such, the pooled mean estimate of these continuous outcomes should be interpreted with caution and is not generalisable. Third, although isotonic sodium bicarbonate has a protective effect on the risk of an incremental rise in serum creatinine concentration greater than 25% above the baseline, other important patient-centred outcomes such as risk of mortality and dialysis were not significantly altered by the use of isotonic sodium bicarbonate. In this regard, we cannot exclude a type II error because of the small sample size of this meta-analysis (n=573). Because the incidence of acute renal failure requiring dialysis from radiocontrast nephropathy is low (1.4% overall), a sample size of 2400 patients will be needed to achieve a power of 80% to confirm a 70% relative risk reduction in acute renal failure requiring dialysis (from 1.7% to 0.5%) after the use of isotonic sodium bicarbonate. Finally, length of hospital stay is important in cost-effective analysis of any new treatments, but none of the studies reported this important clinical outcome. A large randomised controlled study is therefore needed to confirm the effects of isotonic sodium bicarbonate on important patient-centred outcomes and its cost effectiveness in patients with pre-existing renal impairment who undergo radiocontrast-related procedures. References 1. Gruberg L, Mehran R, Dangas G, Mintz GS, Waksman R, Kent KM et al. Acute renal failure requiring dialysis after percutaneous coronary interventions. 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