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Angiography with Sodium Bicarbonate and Acetylcysteine

To the Editor

In the Prevention of Serious Adverse Events Following Angiography (PRESERVE) trial reported by Weisbord et al. (Feb. 15 issue),1 eligible patients who received intravenous 1.26% sodium bicarbonate (150 mmol per liter) had a mean (±SD) urine pH value of 6.7±0.8 after angiography. However, benefit was observed by Tamai et al.2 at a higher concentration of sodium bicarbonate (833 mmol per liter) with urinary alkalinization at a pH of 8.5±0.94.

Tepel et al.3 reported a protective effect of acetylcysteine with dosing that was different than that in the PRESERVE trial. An oral dose of 600 mg of acetylcysteine twice daily was initiated on the day before the administration of the contrast agent, with concomitant intravenous saline hydration. It was also given on the day of administration of the contrast agent, for a total of 2 days. The mean serum creatinine level at baseline was also higher than that in the PRESERVE trial (2.4±1.3 mg per deciliter [216±116 μmol per liter] vs. 1.5 mg per deciliter; interquartile range, 1.3 to 1.8 [133 μmol per liter; interquartile range, 115 to 159]). The unique pharmacokinetic properties of acetylcysteine, including 30% renal clearance, extensive first-pass metabolism, and poor bioavailability,4,5 suggest that a heightened antioxidative effect of acetylcysteine may play a role.

The effect of an increased sodium bicarbonate level and a different dose and timing of acetylcysteine, especially when combined with saline hydration, is unknown. Therefore, we cannot safely rule out protective effects of these two agents. With no other alternatives, more aggressive dosing is needed to prevent contrast-associated kidney injury.

Rakhee Makhija, M.D.
Regional Medical Center, San Jose, CA

Smita Divyaveer, M.D., D.M.
R. G. Kar Medical College and Hospital, Kolkata, India

No potential conflict of interest relevant to this letter was reported.

  1. 1. Weisbord SD, Gallagher M, Jneid H, et al. Outcomes after angiography with sodium bicarbonate and acetylcysteine. N Engl J Med 2018;378:603614.

  2. 2. Tamai N, Ito S, Nakasuka K, et al. Sodium bicarbonate for the prevention of contrast-induced nephropathy: the efficacy of high concentration solution. J Invasive Cardiol 2012;24:439442.

  3. 3. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent–induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180184.

  4. 4. Olsson B, Johansson M, Gabrielsson J, Bolme P. Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine. Eur J Clin Pharmacol 1988;34:7782.

  5. 5. Fishbane S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin J Am Soc Nephrol 2008;3:281287.

To the Editor

In the PRESERVE trial, sodium bicarbonate and acetylcysteine were not clinically effective in preventing acute kidney injury or associated adverse outcomes after the administration of contrast material during angiography. Although urinary alkalinization was not defined as a therapeutic goal in the trial, the mean urine pH value after angiography was higher in the sodium bicarbonate group than in the sodium chloride group (6.7±0.8 vs. 6.0±0.8).

Issues related to the prevention of contrast-associated kidney injury are not limited to the administration of a specific agent. For example, a protective effect of urinary alkalinization against contrast-associated kidney injury has been suggested. In a meta-analysis published in 2009, increased urine pH was clearly associated with a beneficial effect of sodium bicarbonate, and a hypothesis that sodium bicarbonate should be dosed to achieve urinary alkalinization was postulated.1 Single studies investigating sodium citrate and potassium citrate2 and acetazolamide3 have suggested that the requisite urine pH value for prevention of contrast nephropathy is higher than 6.2,3 The PRESERVE trial may provide the opportunity to investigate this hypothesis and to identify the point of possible protective urinary alkalinization against contrast-associated kidney injury.

Viktor Čulić, M.D., Ph.D.
University of Split School of Medicine, Split, Croatia

No potential conflict of interest relevant to this letter was reported.

  1. 1. Meier P, Ko DT, Tamura A, Tamhane U, Gurm HS. Sodium bicarbonate-based hydration prevents contrast-induced nephropathy: a meta-analysis. BMC Med 2009;7:2323.

  2. 2. Markota D, Markota I, Starčević B, Tomić M, Prskalo Z, Brizić I. Prevention of contrast-induced nephropathy with Na/K citrate. Eur Heart J 2013;34:23622367.

  3. 3. Assadi F. Acetazolamide for prevention of contrast-induced nephropathy: a new use for an old drug. Pediatr Cardiol 2006;27:238242.

Response

The authors reply: Makhija and Divyaveer suggest that the lack of benefit of bicarbonate and acetylcysteine in the PRESERVE trial was related to the dosing regimens used. Although they cite the protocol used by Tepel et al.1 regarding the use of acetylcysteine for prevention of contrast-associated acute kidney injury, in the majority of subsequent studies,2 1200 mg was administered twice daily beginning on the day of the procedure, as was done in our trial. Given the pharmacokinetic properties of oral acetylcysteine, administering smaller doses the day before exposure to contrast material is unlikely to augment any benefit.3 Conversely, we provided the first dose just before the administration of contrast material and extended the administration of acetylcysteine over the following 4 days for a total of 10 doses, rather than the shorter duration used in prior studies.

Similarly, multiple studies suggested a benefit of isotonic sodium bicarbonate as compared with isotonic saline; hence the selection of the regimen used in our trial to assess comparative effectiveness.4 Although hypertonic sodium bicarbonate is likely to provide greater urinary alkalinization than isotonic sodium bicarbonate, its use is not without potential risk, and it should not be used without careful evaluation in an appropriately powered clinical trial.

Čulić questions the relation between achieved urinary alkalinization and protection from contrast-associated acute kidney injury. We agree that data from our trial present an opportunity to examine this possibility.

Steven D. Weisbord, M.D.
Veterans Affairs (VA) Pittsburgh Healthcare System, Pittsburgh, PA

Martin Gallagher, M.D., Ph.D.
George Institute for Global Health, Sydney, NSW, Australia

Paul M. Palevsky, M.D.
VA Pittsburgh Healthcare System, Pittsburgh, PA

Since publication of their article, the authors report no further potential conflict of interest.

  1. 1. Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent–induced reductions in renal function by acetylcysteine. N Engl J Med 2000;343:180184.

  2. 2. Xu R, Tao A, Bai Y, Deng Y, Chen G. Effectiveness of N-acetylcysteine for the prevention of contrast-induced nephropathy: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2016;5(9):e003968e003968.

  3. 3. Fishbane S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin J Am Soc Nephrol 2008;3:281287.

  4. 4. Brar SS, Hiremath S, Dangas G, Mehran R, Brar SK, Leon MB. Sodium bicarbonate for the prevention of contrast induced-acute kidney injury: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2009;4:15841592.

Source: Massachusetts Medical Society: New England Journal of Medicine: Table of Contents