N-acetylcysteine

N-acetylcysteine (NAC) is an acetylated derivate of the amino acid, cysteine. It can be administered via oral, intravenous (IV) or respiratory routes. NAC is used commonly as a mucolytic agent in various respiratory conditions such as emphysema, bronchitis and cystic fibrosis. Inhalation of NAC leads to splitting of disulphide bonds between the glycopeptides in viscous mucus, and loosening of obstructive plugs.

IV NAC is also an effective antidote for paracetamol overdose. The reactive metabolite of paracetamol, N-acetylbenzoquinoneimine, depletes the liver’s antioxidant stores of glutathione and damages hepatic cells directly, causing acute liver failure.

NAC provides cysteine as a substrate for the synthesis of more glutathione and prevents liver damage when given within eight hours. Glutathione and acetylcysteine bind to, and detoxify, the reactive metabolite. Glutathione stores are also replenished, preventing further oxidative cell injury.

Contrast-Induced Nephropathy

Contrast-induced nephropathy (CIN) is a common and serious complication after the administration of iodinated contrast media used in radiological diagnostic and interventional procedures. CIN is generally described as an increase in serum creatinine of at least 0.5mg/dL (44.2 µmol/L), or more than 25% above the baseline value after exposure to a contrast medium. The increase in serum creatinine level usually begins shortly after the completion of the procedure, peaks at three to five days, and returns to baseline within one to three weeks.

The risk factors associated with the development of CIN are the following:

  • Pre-existing renal insufficiency,
  • Diabetic nephropathy,
  • Age > 70 years,
  • Volume depletion,
  • Anaemia,
  • Heart failure,
  • Hypotension,
  • Concomitant use of nephrotoxic drugs such as NSAIDs, diuretics, aminoglycosides, amphotericin B, ACE inhibitors, angiotensin II receptor antagonists, some immunosuppressants (e.g. cyclosporin), and various chemotherapy agents (e.g. cisplatin),
  • High dose of a contrast medium (>125mL), or a repeat dose within 72 hours, and
  • Type of contrast medium; high-osmolar contrast media are more nephrotoxic than low- or iso-osmolar agents in patients with pre-existing renal impairment.

Creatinine clearance calculated using both the Cockcroft-Gault and the Modification of Diet in Renal Disease (MDRD) formulae are better for estimating the glomerular filtration rate (GFR), than using only serum creatinine levels.

The MDRD formula is currently used by pathology laboratories in Australia and New Zealand, and an estimated GFR (eGFR) figure is routinely provided whenever a serum creatinine level is reported. It is suggested that patients with an eGFR of <30mL/min are at highest risk.

Prevention of CIN

The nephroprotective mechanism of NAC is postulated to be due firstly to its antioxidant properties, thereby decreasing oxidative tissue damage generated by the contrast media, and secondly its vasodilatory effect, leading to an improvement in renal blood flow and a reduced risk of developing CIN.

NAC was first shown to be effective in reducing the incidence of CIN in patients with chronic renal dysfunction by Tepel in 2000. Since then, multiple trials have been conducted but the results were conflicting and inconsistent.

Meta-analyses have found a high level of heterogeneity across these studies therefore definitive conclusions could not be made.

In 2011, the Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT) was published. It found that NAC does not reduce the risk of CIN in at-risk patients undergoing coronary and peripheral vascular angiography.

It is important to note that although the ACT is a large multicentre randomised controlled trial, like many trials there were limitations. The patients were at lower risk (the procedures were being done for diagnostic rather than interventional purposes) and a lower volume of contrast dye was used (100mL) etc.

As there is some evidence of its efficacy in preventing CIN, NAC is still used in clinical practice. It is inexpensive, safe and is well tolerated by patients. Except in emergency situations, oral administration is preferred because most of the available evidence has been demonstrated with this route, and because IV NAC is associated with a minor risk of anaphylactoid reactions.

It is suggested that the original Tepel dosage should be used i.e. 600mg twice daily on the day before and the day of contrast exposure.

In clinical trials, 600mg or 1200mg has been well tolerated. Gastrointestinal discomfort and dizziness have been reported. Patients should also be warned about the “rotten-egg” smell of NAC.

This can be minimised by proper dilution. When using the commercial 20% vial of NAC, each dose of 600mg/3mL or 1200mg/6mL can be diluted in at least 10mL or 20mL, respectively, of a cola drink or other soft drink (or water only if NAC is given via nasogastric tube). The preparation is not stable beyond one hour, hence it should be mixed just before use.

The only well-established strategy for the prevention of CIN is the periprocedural administration of IV fluids to avoid volume depletion. Sodium chloride has been studied the most and isotonic saline (0.9%) is preferred over hypotonic (0.45%) solutions.

It has also been postulated that alkalinising renal tubular fluid may be beneficial, as free radical formation is promoted in an acidic environment but inhibited at a higher pH.

As free radicals increase the risk of developing CIN, alkalinisation with isotonic sodium bicarbonate may reduce the risk of renal cell injury. Note that patients with heart failure or on dialysis, however, should not receive fluid loading.

Interestingly, theophylline has been studied for this indication. After exposure to the contrast agent, the renal concentration of adenosine increases, causing vasoconstriction thereby impairing renal blood flow.

Theophylline is an antagonist for adenosine receptors and is thought to prevent the development of CIN by improving renal blood flow. Trial results on theophylline have been conflicting. However, it is said that it offers additive protection to saline hydration and oral NAC.

The usage of theophylline clinically to prevent CIN may be problematic, as it may interact with the patients’ medications such as macrolide antibiotics, fluoroquinolones, rifampicin, phenytoin, carbamazepine, barbiturates, and cimetidine.

Note that other drugs such as mannitol, frusemide, simvastatin, iloprost, dopamine, fenoldopam, calcium channel blockers, and ascorbic acid have also been evaluated. They have not been found beneficial in preventing CIN and are therefore not recommended.

If possible, nephrotoxic drugs should be discontinued up to 48 hours before the procedure. Metformin should also be withheld to avoid the risk of lactic acidosis, should acute renal failure occur. Avoid using high osmolar contrast media in patients with renal impairment. Renal function should be monitored 48 hours after contrast administration.

Conclusion

The impairment of renal function following exposure to a contrast medium is usually transient, however may be permanent in some cases. The treatment for established CIN is limited to supportive measures and dialysis.

Therefore, screening for high-risk patients and having appropriate preventive strategies are important. The benefits of performing contrast media-enhanced procedures in these patients need to be weighed against the risks of developing CIN.

The decision to perform these procedures however, should not be influenced by the availability of NAC due to its inconsistent efficacy in preventing CIN.

References:

  1. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomised acetylcysteine for contrast-induced nephropathy trial (ACT). Circulation 2011;124(11): p. 1250-9.
  2. Baskurt M, Okcun B, Abaci O, Dogan GM, Kilickesmez K, Ozkan AA, et al. N-acetylcysteine versus N-acetylcysteine + theophylline for the prevention of contrast nephropathy. Eur J Clin Invest 2009;39(9): p. 793-9.
  3. Bilasy M, Oraby M, Ismail H, Maklady F. Effectiveness of theophylline in preventing contrast-induced nephropathy after coronary angiographic procedures. J Interven Cardiol 2012;25(4): p. 404-10.
  4. Fishbane S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin J Am Soc Nephrol 2008;3: p. 281-7.
  5. Kagan A, Sheikh-Hamad D. Contrast-induced kidney injury: focus on modifiable risk factors and prophylactic strategies. Clin Cardiol 2010;33(2): p. 62-6.
  6. Massicotte A. Contrast medium-induced nephropathy: strategies for prevention. Pharmacotherapy 2008;28(9): p. 1140-50.
  7. Rossi S, editor. Australian Medicines Handbook 2013. Adelaide: Australian Medicines Handbook Pty Ltd; 2013.
  8. Standards of Practice and Accreditation Committee. RANZCR Guidelines for Iodinated Contrast Administration. Sydney: The Royal Australian and New Zealand College of Radiologists; 2009.
  9. 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: p. 180-4.
  10. The Medicines and Healthcare products Regulatory Agency. Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine. Drug Safety Update 2012; 6(2): A1.

Subscribe Knowledge Centre Updates

Enter your details to receive Knowledge Centre updates