Prevention of contrast-induced nephropathy: the rational use of sodium bicarbonate
The incidence of contrast-induced nephropathy (CIN) is increasing due to the growing number of patients undergoing radiocontrast studies. More than a million radiocontrast procedures are performed in the United States annually and, of the patients who undergo these procedures, approximately 150,000 of them experience CIN each year. At least 1% of these patients require dialysis and prolonged hospital stay at a cost of approximately $32 million annually. For patients who do not require dialysis, the average prolongation of hospital stay due to CIN is by 2 days, which represents an additional medical care cost of $148 million annually (McCullough & Soman, 2005).
The mortality rate for CIN is significant: Gleeson and Bulugahapitiya (2004) studied more than 16,000 patients undergoing contrast-enhanced examinations and found the mortality rate to be 34% for patients who developed CIN (CIN was defined by the investigators as an increase in serum creatinine levels 25% or higher above baseline or an absolute increase of at least 0.5 mg/dL within 48 hours after administration of radiographic contrast media and persisting for 2-5 days).
The purpose of this article is to provide a brief overview of strategies for preventing CIN and then focus on the rational use of sodium bicarbonate in this setting.
The current hypothesis of the pathogenesis of CIN involves the combination of (a) intrarenal vasoconstriction and ischemia, (b) reperfusion injury, and (c) direct cellular toxicity. Because dehydrated patients are at highest risk of developing CIN due to a higher concentration of toxic substances in the renal tubule, volume expansion is the mainstay of CIN prophylaxis. Volume expansion via saline hydration is currently the standard of care for CIN prophylaxis (Marenzi & Bartorelli, 2004). In an effort to find other options, alternate strategies have been tried, most of them without success.
Aminophylline, theophylline, endothelin receptor antagonists, and ascorbic acid have shown no or equivocal benefit as CIN prophylaxis (McCullough & Soman, 2005). Likewise, furosemide, calcium channel blockers, atrial natriuretic peptide, and fenoldopam have been disappointing (Sanaei-Ardekani, Movahed, Movafagh, & Ghahramani, 2005). Three studies found modest benefit from using mannitol infusion, but all three studies were uncontrolled (Anto, Chou, Porush, & Shapiro, 1981; Old, Durate, Lahrner, Henry, & Sinnott, 1981; Weisberg, P.B. Kurnik, & B.R. Kurnik, 1994). Diuretics plus low-dose dopamine demonstrated only a modest reduction in the rates of CIN (Stevens et al., 1999).
Low osmolar, non-ionic contrast media, iohexol, was compared with the iso-osmolar, non-ionic media, iodixanol, and investigators found that the iso-osmolar agent significantly minimizes the risk of CIN (Aspelin et al., 2003). The risk of CIN is greatest when a hyperosmolar contrast is used, e.g., diatrizoate (Marenzi & Bartorelli, 2004).
Prehydration with intravenous half-normal saline was compared with prehydration with normal saline in a large, randomized trial, and the results favored normal saline for CIN prophylaxis. Regardless of which is used, however, the more important factor is that the patient be adequately hydrated prior to injection of contrast media (Mueller et al., 2002).
Hemofiltration has been tested for accelerating removal of contrast agent. One study did not show any benefit as compared with saline hydration alone (Frank et al., 2003), possibly because hemodialysis may induce hypovolemia, which can worsen renal ischemic injury. However, another study combining prophylactic hemodialysis with N-acetylcysteine suggested that this combination may have a renoprotective role in high-risk patients (Marenzi, Marana, et al., 2003), but any strategy using hemodialysis is an expensive one.
Oral and IV N-acetylcysteine (NAC) administration has been studied for prevention of CIN. NAC has several mechanisms of action. Radiocontrast agents increase the production of renal free radicals, which cause direct injury to the renal tubules, and NAC is a free radical scavenger. Also, NAC increases production of nitric oxide, which counters the vasoconstricting effects of contrast agents. In addition, NAC increases glutathione concentration, which has cytoprotective effects. However, it takes time for glutathione levels to increase, which may explain NAC’s lack of efficacy when it is initiated on the procedure day (most NAC protocols require that it be initiated the day before the procedure) (Bagshaw & Ghali, 2004).
Some studies show conflicting results with NAC (Briguori et al., 2002; Tepel et al., 2000) and one meta-analysis concluded that beneficial effect of NAC is doubtful (Bagshaw & Ghali, 2004), while another meta-analysis showed NAC is beneficial (Meine & Washam, 2004). These conflicting results may be blamed on differences in the study designs in dosing regimen of NAC, in the volume of contrast media that was used, and in the degree of pre-existing renal insufficiency of randomized patients.
Recently, in reviewing the overall data, Shalansky et al. (2005) concluded there is actually little evidence that NAC improves clinical outcomes in terms of reducing length of hospital stay, need for dialysis, or mortality. In spite of this, NAC is generally recommended for CIN prophylaxis. The reason for this is that multiple, well-conducted, randomized studies have shown superiority of NAC over saline hydration alone and this, together with the fact that NAC is well tolerated, inexpensive, readily availability, and easy to administer, makes NAC a rational and convenient option for routine CIN prophylaxis (Baker et al., 2003; Birck et al., 2003; Kay et al., 2003; Shyu, Cheng, & Kuan, 2002).
What about sodium bicarbonate? The rationale behind using sodium bicarbonate in this setting is that it alkalinizes the renal tubules, thus protecting them from free radicals (an acidic environment promotes free radical formation). It has been shown in animal models that sodium bicarbonate is more protective than sodium chloride in preventing ischemic renal injuries (Sanaei-Ardekani, Movahed, Movafagh, & Ghahramani, 2005). At the time of this writing, only one study has evaluated the renoprotective effect of sodium bicarbonate in humans and an analysis of that study follows.
Analysis of the Merten Sodium Bicarbonate Trial
In a prospective, single-center, randomized, partially blinded trial, Merten et al. (2004) compared isotonic sodium bicarbonate solution with normal saline for prevention of CIN. One hundred-nineteen (119) patients with serum creatinine exceeding 1.1 mg/dL were randomized to receive isotonic sodium bicarbonate (n = 60) or isotonic saline (n = 59) at a rate of 3 mL/kg/hour for 1 hour before and 1 mL/kg/hour for 6 hours after contrast administration. CIN was defined as an increase in serum creatinine of at least 25%. Eight patients (13.6%) in the saline group developed CIN as opposed to only 1 patient (1.7%) in the sodium bicarbonate group (P = 0.02).
This study was not completely blinded. Patients were not told to which group they were randomized but the investigators had access to the results of randomization. However, according to the authors, the only direct contact investigators had with patients consisted of obtaining informed consent before randomization. Most importantly, the primary end point, serum creatinine level, was determined by laboratory personnel who had no knowledge of patient study groups.
The primary end point of this study was an increase of 25% or more in serum creatinine within 2 days of contrast. Statistical analysis of this end point, however, did not answer the question of whether sodium bicarbonate affects clinical outcomes such as length of hospital stay, need for dialysis, and mortality. To definitively answer this question, a larger study, one with sufficient power to detect the effect on clinical outcomes, is required.
Finally, while the results of this study are promising, one should be cautious about drawing definite conclusions from a small sample size and a single center’s results. Until large-scale, multicenter studies confirm the findings of the Merten trial, experts do not advocate the routine use of sodium bicarbonate infusion for CIN prophylaxis (Asif, Garces, Preston, & Roth, 2005; Merten et al., 2004). However, some experts do advocate sodium bicarbonate hydration in cases where there is insufficient time to achieve adequate hydration with normal saline and NAC administration has not yet started (Van den Berk, Tonino, de Fijter, Smit, & Schultz, 2005).
Advantages and Disadvantages of Sodium Bicarbonate
The advantages of sodium bicarbonate infusion for the prevention of CIN are:
* It is more efficacious than normal saline (Merten et al., 2004).
* Practicality–Sodium bicarbonate requires pretreatment only 1 hour before contrast injection, whereas actylcysteine protocols generally require that N-acetylcysteine be initiated the day before the procedure and that at least 12 hours of prehydration with normal saline precede contrast injection.
* It is inexpensive.
* Readily available.
* Few side effects, generally.
* Sodium bicarbonate inhibits free radical formation by alkalinizing renal tubules, something normal saline does not do.
The disadvantages of sodium bicarbonate are:
* It is contraindicated in patients with alkalosis (pH greater than 7.45), hypernatremia, hypocalcemia, severe pulmonary edema, and unknown abdominal pain (because it may cause gastric distension).
* As with saline hydration, sodium bicarbonate hydration should be used with caution in patients with hypertension, congestive heart failure, or oliguric renal failure, due to the risk of sodium retention and volume overload.
Implications for Nephrology Nurses
The use of sodium bicarbonate is not without risks. To protect the patient, nurses need to be aware of the contraindications, precautions, and pertinent monitoring parameters of sodium bicarbonate, as well as the proper way to administer it when using it to prevent CIN. As an aid to meeting these clinical goals, nurses may refer to the quick-reference checklist shown in Table 1.
Of all the options available for CIN prophylaxis, prehydration with normal saline is currently the gold standard but this may change if future studies confirm superiority of sodium bicarbonate hydration over normal saline hydration. Using nonionic, iso-osmolar contrast media (e.g., iodixanol), limiting the contrast volume to less than 100 mL, and spacing out contrast procedures at least 10 days apart lowers the risk of CIN.
In addition to limiting the patient’s exposure to contrast media and avoiding nephrotoxic medication, oral N-acetylcysteine initiated the day before the procedure has become routine practice as part of CIN prophylaxis. So far, there are no head-to-head studies comparing N-acetylcysteine with sodium bicarbonate for preventing CIN, but current data suggests that the best pharmacological approach is to use Nacetylcysteine and sodium bicarbonate either in combination or as alternatives (Schultz, Baas, Van der Sluijs, Stamkot, & Smit, 2006). Since these agents work through different mechanisms they may work synergistically, but more research is needed to establish the optimal use of these agents.
Anto, H.R., Chou, S.Y., Porush, J.G., & Shapiro, W.B. (1981). Infusion intravenous pyelography and renal function: Effect of hypertonic mannitol in patients with chronic renal insufficiency, archives of Internal Medicine, 141, 1652-6.
Asif, A., Garces, G., Preston, R.A., & Roth, R. (2005). Current trials of interventions to prevent radiocontrast-induced nephropathy. American Journal of Therapeutics, 12, 127-132.
Aspelin, P., Aubry, P., Fransson, S.G., Strasser, R., Willenbrock, R., & Berg, KJ. (2003). Nephrotoxic effects in high-risk patients undergoing angiography. New England Journal of Medicine, 348, 491-9.
Bagshaw, S.M., & Ghali, W.A. (2004). Acetylcysteine for prevention of contrast-induced nephropathy after intravascular angiography: A systematic review and meta-analysis. British Medical Journal, 2(1), 38.
Baker, C.S.R., Wragg, A., Kumar, S., De Palma, R., Baker, L.R.I., & Knight, CJ. (2003). A rapid protocol for the prevention of contrast-induced renal dysfunction: the RAPPID study. Journal of the American College of Cardiology, 41, 2114-2118.
Birck, R., Krzossok, S., Markowetz, E, Schnulle, R, van der Woude, F.J., & Braun, C. (2003). Acetylcysteine for prevention of contrast nephropathy: Meta-analysis. Lancet, 362, 598-603.
Briguori, C., Manganelli, F., Scarpato, R, Elia, P.P., Villari, B., Colombo, A., & Ricciardelli, B. (2002). Acetylcysteine and contrast agent-associated nephrotoxicity. Journal of the American College of Cardiology, 40, 298-303.
Frank, H., Werner, D., Lorusso, V., Klinghammer, L., Daniel, W.G., Kunzendorf, U., et al. (2003). Simultaneous hemodialysis during coronary angiography fails to prevent radiocontrast-induced nephropathy in chronic renal failure. Clinical Nephrology, 60, 176-182.
Gleeson, T.G., & Bulugahapitiya, S. (2004). Contrast-induced nephropathy. American Journal of Roentgenology, 183, 1673-1689.
Kay, J., Chow, W.H., Chan, T.M., Lo, S.K., Kwok, O.H., Yip, A., et al. (2003). Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: A randomized controlled trial. Journal of the American Medical Association, 289, 553-558.
Marenzi, G., & Bartorelli, A.L. (2004). Recent advances in the prevention of radiocontrast-induced nephropathy. Current Opinion in Critical Care, 10, 505-509.
Marenzi, G., Marana, I., Gianfranco, L., Assanelli, E., Grazi, j., Campodonico, J., et al. (2003). The prevention of radiocontrast-agent-induced nephropathy by hemofiltration. New England Journal of Medicine, 349, 1333-40.
McCullough, P.A. & Soman, S.S. (2005). Contrast-induced nephropathy. Critical Care Clinics, 261-280.
Meine, T.J., & Washam, J.B. (2004). N-Acetylcysteine to prevent contrast nephropathy. American Heart Journal, 147(3), 440-1.
Merten, G.J., Burgess, W.P., Gray, L.V., Holleman, J.H., Roush, T.S., Kowalchuk, G.J., et al. (2004). Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. Journal of the American Medical Association, 291, 2328-34.
Mueller, C., Buerkle, G., Buettner, H.J., Petersen, J., Perruchoud, A.P., Eriksson, Urs, et al. (2002). Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Archives of Internal Medicine, 162, 329-336.
Old, C.W., Durate, C.M., Lahrner, L.M., Henry, A.R., & Sinnott, R.C. (1981). A prospective evaluation of mannitol in the prevention of radiocontrast acute renal failure [abstract]. Clinical Research, 29, 470A.
Sanaei-Ardekani, M., Movahed, M.R., Movafagh, S., & Ghahramani, N. (2005). Contrast-induced nephropathy: A review. Cardiovascular Revascularization Medicine, 6(2), 82-88.
Schultz, M.J., Baas, M.C., Van der Sluijs, H.P., Stamkot, G.A., & Smit, W. (2006). N-acetylcysteine and other preventive measures for contrast-induced nephropathy in the intensive care unit. Current Medicinal Chemistry, 13(21), 2565-70.
Shalansky, S.J., Vu, T., Pate, G.E., Levin, A., Humphries, K.H., & Webb, J.G. (2005). N-acetylcysteine for prevention of radiographic contrast material-induced nephropathy: Is the intravenous route best? Pharmacotherapy, 25(8), 1095-103.
Shyu, K.G., Cheng, J.J., & Kuan, P. (2002). Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. Journal of the American College of Cardiology, 40, 1383-1388.
Stevens, M.A., McCullough, P.A., Tobin, K.J., Speck, J.P., Westveer, D.C., Guido-Allen, D.A., et al. (1999). A prospective randomized trial of prevention measures in patients at high risk for contrast nephropathy. Journal of the American College of Cardiology, 33(2), 403-11.
Tepel, M., Van der Giet, M., Schwarzfeld, C., Lanfer, U., Liermann, D., & Zidek, W. (2000). Prevention of radiographic-contrast-agent induced reductions in renal function by acetylcysteine. New England Journal of Medicine, 343, 180-184.
Van den Berk, G., Tonino, S., de Fijter, C., Smit, W., & Schultz, M.J. (2005). Bench-to-bedside review: preventive measures for contrast-induced nephropathy in critically ill patients. Critical Care, 9, 361-370.
Weisberg, L.S., Kurnik, P.B., & Kurnik, B.R. (1994). Risk of radiocontrast nephropathy in patients with and without diabetes mellitus. Kidney International, 45, 259-65.
Reymond Barreto, PharmD, BCPS, is Staff Pharmacist, Orange Regional Medical Center, Middletown, NY. For more information on this Article, contact the author at email@example.com.
Sodium Bicarbonate Quick Reference Checklist
Contraindications of Sodium Bicarbonate Yes  No 1. Alkalosis (pH greater than 7.45). Yes  No 2. Hypernatremia (serum sodium greater than
145 mmol/L). Yes  No 3. Severe pulmonary edema. Yes  No 4. Hypocalcemia (corrected calcium less
than 8 mg/dL). Yes  No 5. Unknown abdominal pain.
If patient has any of the above conditions, sodium
bicarbonate should be avoided.
Precautions Informed consent
Has informed consent been obtained and risk of CIN discussed with
the patient? In high risk patients, CIN may occur even if sodium
bicarbonate is used; therefore, informed consent should be obtained.
High risk patients include patients with hypertension, congestive
heart failure, diabetes (especially diabetic nephropathy), volume
depletion, creatinine clearance less than 60 mL/minute, and patients
receiving nephrotoxic drugs such as nonsteroidal anti-inflammatory
drugs (NSAIDs). Compatibility issues
Sodium bicarbonate has extensive incompatibility issues, therefore
consult pharmacy before using the same IV line to administer other
I.V. medications. Creatinine clearance
Is the patient’s creatinine clearance less than 15 mL/minute? If
so, a nephrology consult should be obtained and intravenous sodium
bicarbonate hydration approved by the nephrologist. Nephrology
consult should include possible planning for dialysis after the
procedure. Nephrotoxic agents held?
Is the patient taking any nephrotoxic drugs? Nephrotoxic agents
should be held the day before and the day of the procedure unless
holding the agent is worse for the patient. Examples of nephrotoxic
agents: acyclovir, amphotericin B, aminoglycosides, cyclosporine,
diuretics (especially loop diuretics), foscarnet,
and NSAIDs. Metformin should be held prior to and for 48 hours
after the injection of contrast media and reinstated when renal
function normalizes to reduce the risk of lactic acidosis.
Monitoring Parameters Serum chemistries
Obtain a basic metabolic panel of serum chemistries on the morning
of the procedure and on postprocedure days 1 and 2, and until any
increase of serum creatinine resolves. Monitor blood pH and serum
potassium because the alkaline load from sodium bicarbonate may
decrease serum potassium levels (so long as this decrease is minute,
this should not create any disturbance in cardiac rhythm). Volume status
Before initiating sodium bicarbonate, check blood pressure and
weight to evaluate patient’s volume status, as well as signs and
symptoms of pulmonary congestion or respiratory distress. Due to
the sodium content of sodium bicarbonate, physicians must use
discretion in patients with volume overload, CHF, hypertension,
and oliguric renal failure. The presence or worsening of pulmonary
congestion and elevation of blood pressure are potential signs of
Preparation and Administration of Sodium Bicarbonate for
Prevention of Contrast-Induced nephropathy Preparation
Prepare the sodium bicarbonate solution by adding 3 ampules (150
mEq) of sodium bicarbonate to 1 liter of 5% dextrose in H2O,
yielding a 130-mEq/Liter concentration of sodium bicarbonate and
4.35% dextrose. Administration of bolus
Administer the intravenous bolus of
sodium bicarbonate exactly 1 hour before contrast injection. The
bolus dose is 3.5 mL/kg of a 130 mEq/Liter concentration of sodium
bicarbonate over one hour, but do not exceed 110 Kg when
calculating the bolus dose (i.e., for patients weighing more than
110 Kg, use 110 Kg as the dosing weight).
Note: If significant blood pressure increase occurs with the bolus
of sodium bicarbonate, discontinue the bicarbonate and diurese the
patient. After the blood pressure stabilizes, an alternative
hydration protocol should be chosen (e.g., half normal saline)
prior to radiocontrast imaging procedure, at the physician’s
discretion. Administration of continuous drip
After the radiocontrast procedure, administer the sodium bicarbonate
drip at a rate of 1.18 mL/Kg/hour for 6 hours using the same fluid
as before (130 mEq/Liter concentration of sodium bicarbonate), but
do not exceed 110 Kg when calculating the drip rate (i.e., if patient
weighs more than 110 Kg, using 110 Kg as the dosing weight).
Follow-Up Monitoring Urine pH
Obtain urinary pH measurement after the initial bolus
of sodium bicarbonate when the patient next spontaneously voids (to
confirm urinary alkalinization). Urine flow
Make sure urine flow rate is greater than 150 mL/hour
after procedure to ensure adequate hydration (McCullough & Soman,
2005). Volume status
Continue monitoring blood pressure for at
least 12 hours after contrast administration. Discharging the patient
For outpatients, especially those with a creatinine
clearance of less than 60 mL/min, an overnight stay or discharge to
home with 48-hour follow-up and serum creatinine measurement is
advised. For those who have not had an increase in serum creatinine
of more than 0.5 mg/dL in the first 24 to 48 hours after the
procedure, and have had an uneventful course, discharge to home may
be considered. Scheduling another contrast procedure
Do not schedule another contrast procedure for at least 10 days.
Contrast procedures should be spaced out at least 10 days from each
other to minimize risk of contrast-induced nephropathy (McCullough
& Soman, 2005).
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