• 
• 

Three Part Question

In [adults with established renal impairment receiving IV contrast] is [IV N-acetylcysteine given immediately pre (+/-post) contrast better than standard IV hydration] at [preventing contrast induced nephropathy]

Clinical Scenario

A 77 year old diabetic male attends the emergency department with sudden onset "tearing" interscapular pain and a widened medistinum on CXR. You suspect aortic dissection and request a contrast enhanced CT Angiogram. The radiologist reluctantly agrees, but notes his diabetic history and metformin use as high risk factors for contrast induced nephropathy (CIN). You have no available U&E results, but previous values record an eGFR of 45ml/min. A cardiology colleague mentions off hand that N-acetylcysteine is used regularly to prevent CIN post elective angiography in patients with renal impairment. You wonder whether there is any evidence for its use immediately pre contrast in the acute setting.

Search Strategy

Medline 1950-date and EMBASE 1974-date using dialog datastar.
[(renal OR kidney) NEAR Failure OR Nephropathy Or exp kidney failure] AND (IV contrast OR exp contrast media OR intravenous$ NEAR contrast) AND (N-acetylcysteine OR acetylcysteine OR exp acetylcysteine OR NAC OR Parvolex) LIMIT to RCT OR Meta analysis

Search Outcome

196 of which five papers directly answered the three part question. Multiple papers were excluded on the basis that prophylactic NAC was given orally, given >6 hours pre contrast or patients had normal renal function.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Webb et al. Sep, 2004 Vancouver, Canada	487 patients with renal dysfunction (as defined by cockroft Gault <50ml/min) undergoing cardiac catheterisation with a mean of 136ml low osmolarity contrast, randomised to 500mg IV NAC immediately pre-procedure or placebo.	Prospective, double blinded RCT	CIN defined as a reduction in CrCl from basline of >5ml/min.	Study terminated at interim analysis due to equal incidence of CIN in IV NAC and placebo patients (approx 20%). No benefit seen with IV NAC.	Use of low dose IV NAC Bolus not weight adjusted, with no continual infusion post contrast as used in previous trials. Exclusion of any clinically unstable patients.
Marenzi et al. June 2006 Milan, Italy	354 patients undergoing primary angioplasty of whom approximately 30% had renal dysfunction (defined as serum level >133micromol/litre). Randomised to 116 patients receiving standard dose IV NAC (600mg) pre-procedure with BD 600mg oral NAC for 48hours, 119 receiving a double dose at the same time intervals and 119 patients to placebo.	PRCT	CIN as defined by 25% increase in serum creatinine from baseline at 72 hours post angiography.	Dose dependant reduction in the rate of CIN: 33% in the control group, 15% in the standard dose NAC group, 8% in the high dose NAC group.	Acute MI patients undergoing primary angioplasty only included group. Broad spectrum of renal function at baseline in patients. Rise in serum creatinine only used as marker for CIN. Moderate incidence of ionotrope use, intraaortic balloon pump, mechanical ventilation as seperate reasons for acute renal impairment.
			Combined endpoint of death, ARF or mechanical ventilation	Combined endpoint rate of 18% in the control group, 7% in the standard dose group, 5% in the high dose group
Baker et al. March 2003 London, England	80 patients undergoing cardiac catheterisation with stable renal dysfunction as defined by a CrCl <50ml/min (estimated using Cockroft-Gault equation) randomised to IV NAC (150mg/kg pre-procedure followed by 50mg/kg over four hours post procedure) or placebo with standard hydration.	PRCT	CIN defined as increase in serum Cr by 25% from baseline on day 2 or 4 post procedure	21% rate of CIN in control group (8/39 patients), with only 5% rate in IV NAC group (2/41 patients). Also 14.6% IV NAC group reported anaphylactoid reactions.	Study terminated early. Unmatched control group - 12 hour pre-procedure fluids in control group, compared to fluids with NAC immediately pre-procedure. 50% diabetes rate in CIN patients not stratified between control and trial group. Small sample size. No measurements at >48 hours; ?missed incidence of late CIN
Kotylar et al. October, 2005 Adelaide, Australia	60 day case patients with renal impairment defined as serum creatinine >130micromol/L, undergoing elective coronary, carotid or peripheral angiography and/or PTCA and stenting. Patients were randomised to 300mg IV NAC 1-2hour pre and 2 hours post-contrast, double dose, or IV hydration only	Prospective double blinded RCT	CIN defined by increase in serum creatinine concentration >0.044mmol/L or >25% above baseline at 48 post contrast	No occurence of CIN in any group	Limited numbers. Low risk patient group. CIN based on isolated measurement of serum creatinine at 48 hours. Lower number of diabetics in control group. ?Missed CIN at 72-96 hours
			Increase in serum creatinine >0.044mmol/L at 30 days	13% occurence in all patients, 11% (2/19) in control group, 10% (2/21) in 600mg IV NAC group, 20% (4/20) in 300mg IV NAC group (P=0.06)
			Clinical adverse events including anaphylaxis, CCF or need for haemodialysis	No major adverse clinical outcome in any patient included in data analysis
Rashid et al. September 2004 London, England	94 patients with peripheral vascular disease undergoing elective angiography or angioplasty, of which 38 (group one)had initial renal impairment defined by serum creatinine >120micromol/litre in men and >97micromol/L in women. Group two had normal renal function at baseline. All patients in both groups were then randomised to recieve 1g IV NAC pre and post contrast or placebo. All patients received a standard IV hydration regime.	Prospective, double blinded RCT	Incidence of RCIN defined as a rise in serum creatinine of 25% at 48hours post contrast	No sinificant difference in incidence of RCIN in patients with renal impairment, whether receiving IV NAC (3/17 17.6%) or Placebo (3/21 14.3% ) at P=1.000	Use of a low risk population negating results? Low incidence of diabetes, low contrast volume but all patients >70. Lower dose of IV NAC given compared to favourable trials. Possible low serum levels as IV NAC given 4-6hours pre contrast and prior studies showing benefit gave IV NAC immediately pre contrast.
			Change in serum Cr and CrCl at 1,2,7 days	No significant difference between the IV NAC and placebo groups. Of note, the renal impairment group had a significant decline in renal function at day two with CrCL falling by 14%+/-41% compared to an increase in the normal renal function group of 18%+/-51% (p=0.0142)
			Significant morbidity or mortality	No ignificant difference in morbidity/mortality between the groups

Comment(s)

With the increasing use of contrast enhanced CT scanning in emergency patients and the escalating life expectancy of the general public, it remains imperative to 'do no harm' when investigating acutely unwell patients with co-morbidities. Multiple strategies have been utilised in the battle to prevent acute contrast induced nephropathy. Low dose non ionic contrast agents, intravenous sodium bicarbonate, diuretic therapy and oral/intravenous N-acetylcysteine have all been examined to varying degrees. Although the jury currently seems in consensus regarding the use of oral prophylactic NAC 24 hours pre/post procedure to prevent CIN in elective patients undergoing contrast studies, the evidence is lacking in its emergency use. The available literature is limited when addressing the specific question posed, despite the plethora of papers on the subject of prophylactic oral NAC pre-angiography. Although two of the trials above suggest benefit with immediate high dose IV NAC in preventing CIN, both are hampered by high risk patient groups, poor substratification and use of elevated serum creatinine as an isolated acute marker of renal impairment, rather than GFR. In fact, NAC is actually thought to directly affect the serum creatinine prior to any alteration in renal function and while this is being used as a primary outcome measure data remains unreliable. Also small sample sizes, mulitple co-morbidities in acutely unwell patitent groups and varying incidence of unstratified confounding factors limit the use of the data. The most rigourous RCT in the above group in fact shows no benefit from pre procedure IV NAC, although this trial notes the use of a much lower dose and no continual treatment, thought to be highly important in the prevention of CIN. It's general conclusions are supported however, by other smaller studies included above, which use high doses and trial IV NAC both pre and post intravenous contrast.

Clinical Bottom Line

The current evidence does not support the routine use of IV NAC to prevent contrast nephropathy in patients with renal impairment. Administration also comes with a reasonable risk of anaphylactoid reaction (14.6% in one trial). Simple measures such as IV hydration with isotonic saline and use of non ionic contrast should be utilised. A large double blind PRCT looking at the effect on GFR of high dose IV NAC with normal saline therapy pre and post contrast, in patients with renal impairment, is needed to establish benefit.

References

1. Webb et al. A Randomised Controlled Trial of Intravenous N-acetylcysteine for the Prevention of Contrast Induced Nephropathy after Cardiac Catheterization: Lack of Effect Am Heart J Sep 2004; 148(3):422-429
2. Marenzi et al. N-acetylcysteine and Contrast-Induced Nephropathy in Primary Angioplasty The New England Journal of Medicine June, 2006;Vol 354:2773-2782
3. Baker et al. A Rapid Protocol for the Prevention of Contrast-Induced Renal Dysfunction: the RAPPID Study J Am Coll Cardiol March 2003; 41:2114-2118
4. Kotylar et al. Prehydration Alone is Sufficient to Prevent Contrast-induced Nephropathy after Day-only Angiography Procedures—A Randomised Controlled Trial Heart-Lung-Circ Dec 2005; vol. 14 no. 4; p245-51
5. Rashid et al Prevention of Contrast-Induced Nephropathy in Vascular Patients Undergoing Angiography: A Randomized Controlled Trial of Intravenous N-acetylcysteine Journal of Vascular Surgery December 2004; p1136-1141