248-NAC to Prevent Contrast Nephropathy in Cardiac Angiog

8/13/2019 248-NAC to Prevent Contrast Nephropathy in Cardiac Angiog

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Kidney International, Vol. 62 (2002), pp. 22022207

A randomized controlled trial of N-acetylcysteine to preventcontrast nephropathy in cardiac angiography

J OHN D. D URHAM , CHRISTOPHER CAPUTO , JOHN DOKKO , THOMAS ZAHARAKIS ,M OHSEN PAHLAVAN , JAN KELTZ , PAULA DUTKA , KEVIN MARZO , JOHN K. MAESAKA , andSTEVEN FISHBANE

Division of Nephrology, Department of Pharmacy, and Division of Cardiology, Winthrop-University Hospital, Mineola,New York, USA

A randomized controlled trial of N-acetylcysteine to prevent contrast nephropathy, including increased age, decreasedcontrast nephropathy in cardiac angiography. renal function, diabetic nephropathy, hypertension and

Background. Contrast nephropathy (CN) is a common cause congestive heart failure [4]. It is important to note thatof renal dysfunction after cardiac angiography. Recently, N-ace-these risk factors are highly prevalent among patientstylcysteine (NAC) has been found to reduce the risk of CNrequiring interventional cardiac procedures. [5, 6].after CT imaging with contrast enhancement. The purpose of

the current study was to evaluate the efcacy of NAC for the The precise physiological insult underlying contrastprevention of CN in the setting of cardiac angiography. nephropathy is unclear and may well involve the inter-

Methods. Eligible patients were those undergoing cardiac play of several pathogenic factors. These may include vaso-angiography with serum creatinine 1.7 mg/dL. Patients wereconstrictive forces [7] resulting in medullary ischemia [8],randomized to one of two groups: Group 1, IV hydration anddecreased production of local prostaglandin-mediatedNAC, 1200 mg one hour before angiography, and a second dose

3 hours after; Group 2, IV hydration and placebo. CN was vasodilatation [7], a direct effect on renal tubular cellsdened as an increase of 0.5 mg/dL in serum creatinine. [9], and damage caused by oxygen radicals [10, 11]. Sev-

Results. Seventy-nine patients completed the study. There eral drug interventions based on one or more of thesewere no signicant differences between the groups in baselinemechanisms have been tested in trials for prophylaxischaracteristics, duration of angiography, mean volume of dyeagainst the development of renal dysfunction. Amonginfused or mean IV hydration. Contrast nephropathy developed

in 24.0%of subjects,26.3% NAC, and22.0%placebo( P NS). these are aminophylline [12], calcium-channel blockersAmong subjects with diabetes mellitus, there was no signicant [13], theophylline [14], atrial naturetic peptide [15], man-difference in the rate of CN between the groups (42.1% NAC, nitol [16], prostaglandins [17] and endothelin antagonists27.8% placebo; P 0.09). The independent predictors of CN

[18]. Unfortunately, studies have generated few resound-risk were diabetes mellitus and preexisting chronic renal insuf-ciency. ingly positive results. Therefore, these treatments are

Conclusions. NAC was not effective for the prevention of not widely utilized. At present, only intravenous hydra-CN after cardiac angiography. tion and avoidance of nephrotoxic drugs are recognized

as methods to decrease the incidence of contrast ne-phropathy [16].

Contrast nephropathy is generally dened as acute re- Based on the possible role of oxidative damage innal failure occurring within 48 hours of exposure to intra- the kidney following contrast administration, Tepel et alvenous radiographic contrast that is not attributable to postulated that the antioxidant N-acetylcysteine (NAC)other causes [1]. Although generally mild, it can occa- prevents renal dysfunction. They found that the inci-sionally result in the need for dialysis treatment, extended dence of contrast nephropathy following computed to-hospital stays and increased morbidity and mortality [2, 3]. mography (CT) in patients with chronic renal insuf-There are well known risk factors for the development of ciency was greatly reduced with NAC [19]. A signicant

proportion of contrast nephropathy cases in the hospitalsetting occurs after cardiac angiography. We performedKey words: computed tomography, nephrotoxicity, acute renal failure,

radiographic contrast media, interventional cardiac procedures. a prospective, placebo controlled, randomized trial todetermine if oral NAC could decrease the incidence of Received for publication April 8, 2002contrast nephropathy in patients with chronic renal in-and in revised form June 25, 2002

Accepted for publication July 15, 2002 sufciency receiving contrast media during cardiac angi-ography procedures. 2002 by the International Society of Nephrology

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Durham et al: N-acetylcysteine to prevent contrast nephropathy 2203

Table 1. Patient characteristicsMETHODSPlacebo NACStudy subjectsN 4 N 38 P value

Eligible patients were among those referred for car-Age years 69.8 9.7 71.4 12.2 NS

diac angiography at Winthrop-University Hospital, in- Male/female 28/13 24/14 NSEthnicity C / AA /H /O 36/2/3/0 32/4/1/1 NScluding both diagnostic and therapeutic procedures, whoDiabetes % 46.3 50 NShad baseline serum creatinine 1.7mg/dL. Patients wereHypertension % 64.4 57 NSenrolled between December 2000 and November 2001. CHF % 23.2 26.8 NSDiuretic use % 46.8 50 NSSubjects were excluded if they were less than 18 yearsMean systolic BP mm Hg 141.9 19.5 138.5 15.4 NSold, the renal disease was determined by a nephrologist Mean diastolic BP mm Hg 75.5 10.7 73.3 11.9 NS

to have a reversible component, patient unwilling or un- Mean weight pounds 175.2 31.7 171.8 31.6 NSMean baseline BUN mg /dL 42.8 18.8 41.0 14.9 NSable to provide informed consent, adequate time priorMean baseline S Cr mg /dL 2.3 0.5 2.2 0.4 NSto angiography was not available to perform the study

Abbreviations are: NAC, N-acetylcysteine; C/AA/H/O, Caucasian/Africanprocedures, patient had any evidence of active athero-American/Hispanic/Other;CHF, chronic heart failure;BP, bloodpressure;BUN,

embolic disease, including but not limited to blue toes, blood urea nitrogen; S Cr, serum creatinine.livedo reticularis or eosinophilia, known prior insensi-tivity to acetylcysteine, severe asthma, breast feedingwomen, severe peptic ulcer disease, or respiratory de-

tify those with a prior history of diabetes mellitus (DM),pression. Patients were excluded also if serum creatininehypertension, chronic heart failure (CHF) and identica-measurements varied by more than 15% in the threetion of medications being taken. Other pertinent datadays prior to angiography. Women of child bearing po-collected were patients weight, probable cause of thetential not using an approved method of contraceptionpatients underlying renal insufciency, indication forwere not enrolled. The study protocol and informed con-cardiac catheterization, blood pressure, record of any dyesent were approved by the hospitals Institutional Re-exposure over the preceding four weeks, and laboratoryview Board.data (comprehensive metabolic prole, liver functiontests, complete blood count, urinalysis, and serum creati-Study designnine for the week prior to catheterization). FollowingRandomization was performed using a computer gen- cardiac catheterization, pertinent data recorded includederated randomization list by the research pharmacy. Eli- any side effect(s) due to study drug, blood urea nitrogengible patients were randomized on a 1:1 basis to one of (BUN), and serum creatinine immediately after cathe-the two following arms: ( 1) Group 1, N-Acetylcysteineterization, at 48 hours and 144 hours following catheter-(NAC) plus conventional therapy; ( 2) Group 2, placebo ization, total volume of contrast administered, total IVplus conventional therapy. hydration administered, and a record of the type of cath-

Conventional therapy consisted of hydration with 1.0 eterization procedure performed.mL/kg/h of 0.45% saline for up to 12 hours prior to con-trast administration andcontinuing forup to12 hours after Statistical analysiscontrast administration. The actual rate and duration of Contrast nephropathy was dened as an increase inIV hydration was at the discretion of the nephrologist or serum creatinine of 0.5 mg/dL at 48 hours after angiogra-cardiologist, who were permitted to modify the regimen phy. Differences between the groups involving continu-depending on the clinical status of the patient. Only low ous variables were analyzed using the Student unpairedosmolality nonionic contrast media was used Omnipa- t tests. For discrete variables analysis was performedque (iohexol; Amersham Health Inc., Princeton, NY, using Fishers Exact Test. Multivariate testing was con-USA). The dose of NAC used for this study was 1200 mg ducted by logistic regression. All results are presented asorally, administered one hour prior to and three hours mean standard deviation. Statistical signicance wasfollowing cardiac catheterization (total 2400 mg). considered to be P values of less than 0.05.

Study drug was prepared as a mixture of 6 mL NAC20% solution with 6 mL of orange juice. The juice was

RESULTSadded to mask the sulfurous odor of NAC, as previ-ously described [20]. A series of taste tests were con- Eighty-one subjects were enrolled, and 79 were includedducted to ensure blinding. Placebo was simply 12 mL of in the nal analysis. Two patients were lost to follow-uporange juice. because of immediate hospital discharge after cardiac

angiography and failure to have subsequent study bloodData collection work performed. Patient characteristics are presented in

Demographic information was gathered at baseline, in- Table 1. There were no signicant differences betweenthe groups at baseline in any measured parameter. Thecluding age, gender, ethnicity, a review of systems to iden-


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Durham et al: N-acetylcysteine to prevent contrast nephropathy2204

Table 2. Cardiac angiography data

Placebo NAC P value

Mean duration minutes 48.1 30.9 44.8 19.1 NSMean dye volume mL 84.7 42.1 77.4 35.9 NSMean hydration volume mL 1061 442 1255 713 NS

Fig. 2. Change from pre-angiography to 48 hours post-angiographylevels of serum creatinine in individual patients in the placebo andNAC groups.

Table 3. Risk factors for contrast acute renal failure

RR P value

Diabetes 3.8 0.007Age per 10 years 0.9 NSHypertension 0.8 NSCHF 1.1 NS

Fig. 1. Acute renal failure developed in a similar number of patients in Baseline S Cr 2.1 mg/dL 2.5 0.03the N-acetylcysteine (NAC) andplacebo groups. In patients withdiabetes Volume dye per 10 mL 1.0 NSmellitus, there was statistically signicant difference, but a notable trend Volume hydration per 100 mL 1.0 NSto greater risk for acute renal failure (ARF) in the NAC group. Systolic blood pressure 140 mm Hg

immediately pre-procedure 1.7 0.04Diastolic blood pressure 90 mm Hg 1.1 NS

cause of renal insufciency was attributed to diabetic ne-phropathy in 42% of patients, hypertensive nephrosclero-

risk of renal failure in patients treated with NAC (pla-sis in 29%, chronic glomerulonephritis 7%, polycysticcebo 5 of 18, 27.8%; NAC 8 of 19, 42.1%; P 0.09).kidney disease in 2%, and undetermined in 20%. TheNineteen subjects had an initial serum creatinine greaterindication for coronary angiography was an acute coro- than 2.5 mg/dL. Acute renal failure developed in 5 of nary syndrome in 15 of 79 patients (19.0%), chronic 12 (41.7%) of these subjects in the placebo group and 3stable angina or an abnormal stress test 15 of 79 (19.0%), of 7 (42.8%) in the NAC group ( P NS). A measure-congestive heart failure 6 of 79 (7.6%), combined factors ment of serum creatinine was made immediately post-

21 of 79 (26.6%), preoperative evaluation 5 of 79 (6.3%), angiography to determine if NAC had any direct effectother 5 of 79 (6.3%), and not clear 12 of 79 (15.2%). on the assay. In the placebo group the mean serum creati-There were no signicant differences between thegroups nine was 2.1 mg/dL pre-procedure and 2.2 mg/dL imme-on the indication for study. diately afterwards ( P NS). In the NAC group the

The mean duration of cardiac angiography was 46.3 pre-procedure serum creatinine was 2.1 mg/dL and was24.2 minutes. There were no signicant differences be- unchanged afterwards ( P NS between the groups).tween the groups in mean duration, mean volume of There were no adverse events noted after treatment withinfused dye or mean total intravenous hydration admin- NAC administration.istered (Table 2). Acute renal failure, dened as an in- By univariate analysis, predictors of the developmentcrease in serum creatinine of 0.5 mg/dL, occurred in 19 of acute renal failure post-angiography were the pres-of 79 patients (24.0%). An increase of serum creatinine ence of diabetes mellitus, an elevated baseline serum

1.0 mg/dL was found in 5 of 79 patients (6.3%), and creatinine and elevated immediate pre-procedure sys-an increase of greater than 2.0 mg/dL in 2 of 79 (2.4%). tolic blood pressure (Table 3). Importantly, neither vol-Both of these latter patients required temporaryhemodi- ume of administered contrast dye nor total volume of alysis support. intravenous hydration were important risk predictors. In

There was no signicant difference between the rate addition, although elevated systolic blood pressure wasof renal failure in the placebo (9 of 41; 22.0%) compared a predictor of risk, a history of hypertension by itself to the NAC (10 of 38; 26.3%; P NS) study groups was not. Both diabetes mellitus and elevated serum cre-(Figs. 1 and 2). Among patients with diabetes mellitus, atinine at baseline remained independent predictors of

acute renal failure risk by multivariate analysis.there was a non-signicant trend toward an increased


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DISCUSSION while our study protocol administered the drug at 1200mg one hour prior to the procedure and then three hoursThe objective of this study was to determine whetherafterwards. It would seem unlikely that this differencethe nding of Tepel et als study, that is, NAC preventsin administration schedule would explain the absence of contrast nephropathy in patients undergoing CT imagingNAC efcacy in our study. Orally administered NAC[19], could beextended to include patients undergoing per-leads to peak serum levels in approximately one hour,cutaneous coronary angiography. These patients as welland the elimination half-life is 2.1 hours [21]. It is un-as those undergoing other interventional radiographic likely, therefore, that administration on the day prior toprocedures are becoming the major source of contrastexposure would be effective. Our administration sched-mediated nephropathy in hospitalized patients [5, 6], andule was more rational from the standpoint of pharmaco-the discovery of a simple and effective means by whichkinetics. However, since it cannot be excluded that ato prevent this complication would be widely adopted.metabolite of NAC might have antioxidant or other fa-Unfortunately, our present study fails to demonstratevorable properties, it is possible that earlier administra-that oral NAC prevents acute renal failure followingtion could have been helpful in Tepel et als study.cardiac angiography.

It is possible that the difference in study results oc-As discussed later in this article, both the pathogenesiscurred by chance. Our study may have failed to detectof contrast-induced renal dysfunction and the mecha-a difference in study groups that was truly present (Typenisms of potential NAC protection are poorly under-II statistical error) or Tepel et al may have found astood. Therefore, they do not provide a strong founda-difference in study groups that did not represent a truetion upon which to explain thedifference in theoutcomes drug effect (TypeI error). The magnitude of effect foundof these two studies. However, discussion of the proce-by Tepelwasdramatic, a reductionof contrast nephropa-dural, demographic, pharmacokinetic, and probable dif-thy from 22% in the placebo group to 2% in the NACferences between the two studies may prove to be useful group (greater than 90% risk reduction). Such a largein formulating further studies on the possible protective treatmenteffectwould make it quite unlikely that chanceeffects of NAC. alone would explain the difference in efcacy found inThe denition of renal failure was the same in both the studies. Another possible explanation for the lack

studies: an increase in serum creatinine of 0.5 mg/dL at of effect for NAC might relate to subtle differences be-48 hours post-contrast exposure. There were differences tween groups in saline diuresis or in diuretic use. Sincebetween the studies, however, that might help explain we do not have data on actual urine output post-salinethe discrepant results. First, we studied contrast use not infusion, it is possible that certain predisposed patientsin the setting of CT imaging, but instead in cardiac angi- did not have a satisfactory diuresis. The likelihood of ography. As a result, our patient population was slightly this is diminished by the fact that on average patientsolder (by 4 years) and had a greater proportion of received more than theprescribed salineinfusionvolumemen (66.7 vs. 56.6%) and diabetics (48.1 vs. 32.5%). The and that there were no signicant difference in infusionbaseline serum creatinine was similar in the two studies volume between the placebo and NAC groups. In addi-(2.3 vs. 2.4 mg/dL). Intravenous hydration, which may tion, while there were no signicant differences betweenreduce the risk of contrast nephropathy, was used in diuretic use in the two groups, we cannot exclude theboth studies. In the study by Tepel et al it appears that possibility that use of diuretics in certain predisposedapproximately 1500 mL of volume was given [19], while individuals might have affected the results.in our study the amount was somewhat less at 1180 mL. The pathogenesis of contrast-induced renal dysfunc-Both studies used nonionic, low osmolality contrast dye, tion is incompletely understood [22]. There is some evi-but patients in our study received a slightly higher mean dence that either renal vasoconstriction and/or tubulardose (81.6 vs. 75 mL). In addition, as opposed to the toxic damage may play a role. Contrast infusion causesintravenous injection of dye in CT imaging, in cardiac a brief and transient increase in renal plasma ow andangiography injection is directly interarterial. On bal- glomerular ltration rate, followed almost immediatelyance, it would appear that subjects in our study probably by a sustained decrease in both of these parametershad a somewhat higher net risk for developing contrast [23, 24]. In parallel there is a sustained increase in renalnephropathy. However, acute renal dysfunction devel- vascular resistance. These hemodynamic changes areoped in a similar proportion of placebo group subjects caused by release of vasoactive mediators in the kidney.in both studies (22 vs. 21%), suggesting a counterbalanc- The best evidence to date is for the role of endothelining of risk effects. in driving these processes [2527]. However, a clinical

Another difference between our study and that of trial of an endothelin receptor antagonist failed to dem-Tepel et al was in the protocol for NAC administration onstrate a protective effect [18]. Moreover, a correlation[19]. Tepel et al gave the drug at 600 mg orally twice between renal vasoconstriction and the development of

renal failure has not been found in humans [7].daily, the day before and the day of contrast infusion,


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Durham et al: N-acetylcysteine to prevent contrast nephropathy2206

6. Thomsen HS : Contrast-medium-induced nephrotoxicity: Are allRenal tubular toxic damage also may be induced byanswers in for acetylcysteine? Eur Radiol 11:23512353, 2001

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8. Prasad PV, Priatna A, Spokes K, Epstein FH : Changes in intra-dation and tubular oxidative damage presumably could renaloxygenation as evaluated by BOLD MRI in a rat kidney model

for radiocontrast nephropathy. J Mag Res Imaging 13:744747, 2000lead to transient renal dysfunction. However, it should9. Porter G : Contrast associated nephropathy: Presentation, patho-be noted that research evidence supporting the role of physiology and management. Miner Electrolyte Metab 20:232243,

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induced declines in renal function: A role for oxygen free radicals.If NAC were to have a protective effect in contrast Am J Physiol 258(1 Pt 2):F115F120, 1990nephropathy, it would likely be because of itsantioxidant 11. YoshiokaT, Fogo A, Beckman JK : Reduced activity of antioxidant

enzymes underlies contrast media-induced renal injury in volumeeffects, since it probably has no vasodilatory properties.depletion. Kidney Int 41:10081015, 1992

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function of its thiol group, interactions with free radicals 13. Neumayer HH, Junge E, Kufner A, Wenning A: Prevention of radiocontrast media-induced nephrotoxicity by the calcium chan-result in the conversion to NAC disuldes [31]. In vitro,nel blocker nitrendipine: A prospective randomized clinical trial.

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nary oxygen damage and adult respiratory distress syn- new agent for the prevention of renal dysfunction in high risk pa-tients caused by radiocontrast media? PGE1 Study Group. Neph-drome [33]. The study of Tepel etal is the only previouslyrol Dial Transplant 15:4349, 2000reported randomized clinical trial of NAC in renal dis- 18. Wang A, Holcslaw T, Bashore TM, et al : Exacerbation of radio-

ease in humans [19]. A protective effect of NAC in ani- contrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 57:16751680, 2000mals has been demonstrated in both gentamicin and

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20. Clifton JC III: Ill have my N-acetylcysteine with an orange twist.is inexpensive, readily available and safe, should con-Pediatr Emerg Care 17:82, 2001

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248-NAC to Prevent Contrast Nephropathy in Cardiac Angiog