Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity

Carlo Briguoria,b,*, Antonio Colombob, Anna Violantea, Pasquale Balestrieria, Fiore Manganellia, Pietro Paolo Eliaa, Bruno Goliaa, Stefano Leporea, Guido Riviezzoa, Pierfranco Scarpatoa, Amelia Focaccioa, Mariateresa Libreraa, Erminio Bonizzonic and Bruno Ricciardellia

a Laboratory of Interventional Cardiology and Department of Cardiology, Clinica Mediterranea, Naples, Italy
b Laboratory of Interventional Cardiology, "Vita e Salute" University School of Medicine, University of Milan, Milan, Italy
c Institute of Medical Statistics and Biometry, University of Milan, Milan, Italy

* Corresponding Author: Carlo Briguori M.D., Ph.D, Interventional Cardiology, Clinica Mediterranea, Via Orazio, 2,I-80121, Naples, Italy. Tel.: +39-081-7259.764; Fax: +39-081-7259-777
E-mail address: carlo.briguori{at}hsr.it

Received 3 July 2003; revised 20 October 2003; accepted 27 November 2003

Abstract

Aims Prophylactic administration of N-acetylcysteine (NAC) (600mg orally twice daily), along with hydration, prevents contrast agent-associated nephrotoxicity (CAN) induced by a low dose of non-ionic, low-osmolality contrast dye. We tested whether a double dose of NAC is more effective to prevent CAN.

Methods and results Two-hundred-twenty-four consecutive patients with chronic renal insufficiency (creatinine level ≥1.5mg/dl and/or creatinine clearance <60ml/min), referred to our institution for coronary and/or peripheral procedures, were randomly assigned to receive 0.45% saline intravenously and NAC at the standard dose (600mg orally twice daily; SD Group; n=110) or at a double dose (1200mg orally twice daily; DD Group; n=114) before and after a non-ionic, low-osmolality contrast dye administration.

Increase of at least 0.5mg/dl of the creatinine concentration 48h after the procedure occurred in 12/109 patients (11%) in the SD Group and 4/114 patients (3.5%) in the DD Group (P=0.038; OR=0.29; 95% CI=0.09–0.94). In the subgroup with low (<140ml, or contrast ratio ≤1) contrast dose, no significant difference in renal function deterioration occurred between the 2 groups. In the subgroup with high (≥140ml, or contrast ratio >1) contrast dose, the event was significantly more frequent in the SD Group.

Conclusions Double dose of NAC seems to be more effective than the standard dose in preventing CAN, especially with high volumes of non-ionic, low-osmolality contrast agent.

Key Words: Contrast media • Kidney • Complications • Prevention

1. Introduction

Radiocontrast media can lead to a reversible form of acute renal failure that begins soon after the contrast dye administration and is generally benign.1However, especially in high-risk patients, transient dialysis may be required: this renal failure requiring dialysis after coronary interventions is associated with poor outcomes, including 40% in-hospital mortality and 19% 2-year survival.2–4

Periprocedural hydration5and the use of a small amount of low osmolality contrast agent6–9are generally recommended in patients at risk of contrast-agent associated nephrotoxicity (CAN). Tepel et al.10firstly reported that oral N-acetylcysteine (NAC) (600mg twice daily) along with hydration is more effective than hydration alone in preventing CAN in patients with chronic renal insufficiency receiving small amount (75ml) of lowosmolality contrast dye. Other studies11–13confirmed or refuted14–16this preliminary observation. When the amount of contrast dye is high (≥140ml), NAC (600mg twice daily for 2 days) along with hydration does not seem to be as effective as with small amount of contrast agent.14A potential mechanism of NAC in preventing contrast-dye nephrotoxicity is the prevention of direct oxidative tissue damage by scavenging reactive oxygen species;10,17,18this antioxidant effect seems to be dose-dependent.19We therefore hypothesized that with a higher amount of contrast dye a higher dose of NAC might be necessary.

2. Methods

2.1. Patient population
This is a prospective, randomized study conducted in our institution from January to September 2002. The local Ethics Committee approved the study protocol. All patients gave written informed consent. Patients scheduled for elective coronary and/or peripheral angiography and/or angioplasty were eligible for the study if they had chronic impairment of renal function (serum creatinine concentration ≥1.5mg/dl and/or creatinine clearance <60ml/min) and stable serum creatinine concentrations. Patients were randomly assigned to receive intravenous saline and the NAC at the standard dosage (SD Group) or at a double dosage (DD Group) before and after administration of the contrast agent. Saline (0.45%) was given intravenously at a rate of 1ml/kg of body weight per hour for 12h before and 12h after administration of the contrast agent.5NAC (Fluimucil, Zambon Group SpA, Milan, Italy) was given orally at a dose of 600mg twice daily in the SD Group,10and at a dose of 1200mg twice daily in the DD Group on the day before and on the day of administration of the contrast agent, for a total of 2 days. None of the patients received theophylline, dopamine, mannitol, or furosemide during the study. Serum creatinine, blood urea nitrogen, sodium and potassium were measured immediately before and 48h after administration of the contrast agent; additional measurements were performed in all cases of significant impairment of renal function. Creatinine clearance (CrCl) was calculated by applying the Cockcroft-Gault formula.20

2.2. Contrast agent
Iobitriolo (Xenetin-350, 350mg iodine/ml, Guerbet, France) a non-ionic, low-osmolality contrast agent was used. Two different cut offs were used to define a high amount of contrast dye administered in each enrolled patient: 1) ≥140ml14and 2) (5xkg body weight) divided by serum creatinine (mg/dl): a weight-and creatinine-adjusted maximum contrast dose (MCD).6This contrast limit was converted to a dichotomous variable by dividing the actual amount of contrast received by the calculated MCD to determine the ‘contrast ratio’. If the ratio was >1 then the MCD was defined as exceeded.6–21

2.3. Study end-point
An acute contrast-agent associated nephrotoxicity in renal function was defined as an increase in the serum creatinine concentration ≥0.5mg/dl of the baseline value 48h or need for dialysis after administration of the contrast media.5Acute renal failure requiring dialysis was defined as a decrease in renal function necessitating acute haemodialysis, ultrafiltration or peritoneal dialysis in the first 5 days post-intervention.

Side effects during NAC administration were recorded in the 2 groups. The reported side effects are:22gastrointestinal (vomiting, nausea), central nervous system (chills, fever, drowsiness, dizziness), and respiratory (bronchospasm, rhinorrea, hemoptysis).

2.4. Statistical analysis
A total sample size of 210 subjects randomised with a 1:1 allocation ratio was calculated to achieve a power (1-ß) of 90% to detect a difference of 15% between the null hypothesis that both group proportions are 20% and the alternative hypothesis that the proportion in the DD group is 5%, using a two-sided Chi-square test with a significance level of 0.05. Continuous variables are given as mean±1 standard deviation. Unpaired Student’s t test was performed to determine differences between mean values for continuous variables when appropriate. Categorical variables were analysed by Chi-square test. Creatinine concentration was not normally distributed; therefore, median and interquartile ranges (IQR) are reported and the nonparametric Wilcoxon and Mann–Whitney tests were used to assess differences. To test our hypothesis (that is, with a higher amount of contrast media a higher dose of NAC might be necessary) we used an ANCOVA model after transforming creatinine levels into natural logarithm (to overcome the problem of the non normal distribution), putting the log-creatinine concentration at 48h as dependent variable, treatment strategy (as defined in SD and DD groups) as fixed factor, and baseline log-creatinine level and the amount of contrast dye as covariates. We also estimated the fixed effects by splitting the effect of amount of contrast media in the 2 groups of treatment. Correlation coefficient between changes in serum creatinine concentration and length of in-hospital stay was estimated using the Pearson’s correlation test. Probability values <0.05 were considered significant. Data were analysed with SPSS 10.0 (Chicago, Illinois) for Windows.

3. Results

3.1. Clinical characteristics
Two-hundred-twenty-four patients were enrolled. One patient in the SD Group experienced acute pulmonary oedema overnight before coronary angiography and was, therefore, excluded from the analysis. The clinical and biochemical characteristics of the 223 patients in the 2 groups are shown in Tables 1 and 2. The total amount of intravenous hydration was comparable: SD Group=1824±384ml vs DD Group=1834±350ml (P=0.94). One patient in the DD Group experienced minor side effect (nausea and vomiting) on the second day of NAC administration.


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Table 1 Clinical characteristics of the patients treated with the standard dose (SD Group) and with the double dose (DD Group) of acetylcysteine

 

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Table 2 Biochemical characteristics of the patients treated with the standard dose (SD Group) and with the double dose (DD Group) of acetylcysteine

 
3.2. Contrast agent-associated nephrotoxicity
The median serum creatinine concentration for all patients was 1.60 (IQR=1.47–1.80)mg/dl. In the SD Group, the creatinine concentration decreased from a median value of 1.56 (IQR=1.47–1.74) to 1.50 (IQR=1.33–1.69)mg/dl 48h after contrast agent administration (P=0.046). In the DD Group, the creatinine concentration decreased from a median value of 1.61 (IQR=1.45–1.86) to 1.46 (IQR=1.31–1.83)mg/dl 48h after contrast agent administration (P<0.001). There was a significant difference in the serum log-creatinine concentration 48h after contrast media administration between the two treatment strategies even when including the baseline serum log-creatinine level and the amount of contrast media as covariate (F=6.52, P=0.001 by ANCOVA model). The estimated fixed effects of ANCOVA-in which we split the effect of the amount of contrast media in the 2 groups of treatment-showed that the relationship between the amount of contrast agent and the creatinine levels at 48h after the procedure was statically significant only in the Group SD (P<0.001) but only borderline in the Group DD (P=0.07).

CAN (that is, increase ≥0.5mg/dl of creatinine concentration) occurred in 12/109 patients in the SD Group (11%) and 4/114 patients in the DD Group (3.5%) (P=0.038; OR=0.29; 95% CI=0.09–0.94; (Fig. 1, Panel A). In no case renal failure requiring temporary dialysis occurred. In the 94 diabetic patients, renal function deterioration occurred in 4/47 (8.5%) in SD Group and in 1/47 (2.1%) in the DD Group (P=0.36). In the 38 patients with left ventricular ejection fraction <40%, renal function deterioration occurred in 4/22 (18.2%) in SD Group and 1/16 (6.3%) in the DD Group (P=0.37). Length of in-hospital stay (from admission to discharge) was longer in the SD Group than DD Group (2.6±0.9 vs 2.2±0.6 days; P=0.018). Furthermore we found a direct correlation between the absolute change of creatinine concentration and the length of hospital stay (r=0.25; P=0.004).



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Fig. 1 Panel A: schematic representation of the distribution of the occurrence of contrast agent-associated nephrotoxicity in patients treated with the standard dose (Standard Dose Group) and with the double dose (Double Dose Group) of acetylcysteine. Panel B: schematic representation of the distribution of the contrast agent-associated nephrotoxicity in patients who received a small (<140ml) or a large (≥140ml) amount of contrast dye and treated with the standard dose (Standard Dose Group) or with the double dose (Double Dose Group) of acetylcysteine.

 
3.3. Amount of contrast dye and nephrotoxicity
The amount of contrast agent was similar in the 2 groups (Table 2). The amount of contrast dye administered was higher in the 16 patients who experienced an acute contrast-associated nephrotoxicity than in the remaining 207 patients (287±130ml vs 171±110ml, P<0.001).

According to the selected cut off, a large amount of contrast dye occurred as follows: (1) ≥140ml: 53/109 (49%) cases in the SD Dose Group, and 56/114 (49%) cases in the DD Group (P=1.0); (2) contrast ratio >1: 26/109 (24%) cases in the SD Group and 28/114 (25%) cases in the DD Group (P=0.88). In patients (n=114) who received a contrast dose <140ml (mean value=101±23ml; range=40–130ml; median=100ml) a significant renal function deterioration occurred in 2/56 (3.6%) in the SD Group and 1/58 (1.7%) in the DD Group (P=0.61) (Fig. 1, Panel B). In patients (n=168) with a contrast ratio ≤1(mean value=132±61ml; range=40–500ml; median=120ml) a significant renal function deterioration occurred in 3/82 (3.7%) in the SD Group and in 1/86 (1.2%) of the DD Group (P=0.36). In patients who received a large amount of contrast dye a significant renal function deterioration occurred significantly less often in the DD Group. In particular, in the subgroup (n=109) with contrast dose ≥140ml (mean value=254±102ml; range=140–550ml; median=245ml) the event occurred in 10/53 (18.9%) cases in the SD Group, and in 3/56 (5.4%) of the DD Group (P=0.039; OR=0.24; 95% CI=0.06–0.94) (Fig. 1, Panel B). In the subgroup (n=55) with the contrast ratio >1 (mean value=308±111ml; range=80–550ml; median=300ml), a significant renal function deterioration occurred in 9/27 (31.3%) in the SD Group and in 3/28 (10.7%) of the DD Group (P=0.055; OR=0.24; 95% CI=0.03–1.15).

4. Discussion

The main result of the present study is that a double dose of NAC seems to be more effective in preventing CAN especially when a large amount of a non-ionic low osmolality contrast dye is utilized. Radiographic contrast media accounts for 10% of all causes of hospital-acquired acute renal failure and represents the third cause of in-hospital renal function deterioration after decreased renal perfusion and post-operative renal insufficiency.23Increase of 0.5mg/dl of creatinine level after contrast media administration represents a clinically important adverse event at least because it can increase the duration of hospitalization.5–13Furthermore, the in-hospital mortality rate in patients developing renal insufficiency is directly related to the magnitude of the increase in serum creatinine concentration.2–4,24

The mechanism by which contrast-induced renal failure occurs is not well understood. The two major theories are renal vasoconstriction,25and direct toxic effects of the contrast agents.26–28Optimal strategy to prevent CAN remains uncertain. At present, recommendations are (1) periprocedural hydration,5(2) use of a low-osmolality contrast,7–9and (3) limiting the amount of contrast agent.6,21Recently, the preliminary data on the effectivess of prophylactic administration of NAC aroused considerable interest.10

4.1. NAC and contrast agent-associated nephrotoxicity
NAC, a potent antioxidant that scavenges a wide variety of oxygen-derived free-radicals, may prevent a CAN both by improving renal haemodynamics and by avoiding direct oxidative tissue damage.17,18,29Tepel et al.10firstly reported that NAC (600mg orally twice daily) plus hydration before and after administration of contrast agent is more effective than hydration alone in preventing CAN in patients with chronic renal insufficiency who were undergoing computed tomography with a constant dose (75ml) of a nonionic, low-osmolality contrast agent. Other studies confirmed11–13or refuted14–16this preliminary observation. In our previous report14we did not find any significant effect of the NAC treatment (according to the dosage suggested by Tepel) on the occurrence of contrast-associated nephrotoxicity in 183 patients with renal insufficiency (who had coronary and/or peripheral angiography and/or angioplasty). In this study the mean contrast dose was 194±127 (range 50–900)ml. We postulated that the higher amount of contrast dye administered may account for the discordance between our study14and the previous ones.10–13The findings of the present study support our hypothesis of the need for higher dose of NAC with larger amount of contrast media.

The antioxidant effect of NAC seems to be dose-dependent.19In vitro, NAC dose-dependently increases the synthesis of cellular glutathione in umbilical endothelial cells depleted of their glutathione by incubation in a sulphur-amino acid-free medium.19Our findings, combined with our previous observation of a protection by the standard dose of NAC limited to patients exposed to low amount of contrast-agent,14supports a dose-dependent protective effect of NAC.

4.2. Role of the amount of contrast dye
The administration of a small amount of contrast dye and the avoidance of repetitive studies closely spaced represent ones of the well-established recommendations to prevent CAN.[6–21,30,31]Low dose has been variably defined as <70ml, <125ml, <140ml, or <5ml/kg (to a maximum of 300ml) divided by the plasma creatinine concentration.4,6,8,14,21The mean dose for coronary angiography is 130ml, and for PCI is 191ml.32In the study by Tepel et al.10a constant low (75ml) dose of contrast was administered. Shyu et al.12and Kay et al.13used a quite low (median value=120–140ml) dose of contrast agent. Our study suggests a significant benefit of the double dose (1200mg orally twice daily) of NAC when a large (≥140ml or contrast ratio >1) amount of contrast dye is necessary.

5. Study limitations

Iodixanol (an iso-osmolality non-ionic contrast media) seems to be less nephrotoxic than the low-osmolality nonionic contrast agents.33Association of iodixanol and NAC should be investigated.

In conclusion, prophylactic administration of double dose of NAC seems to be more effective than the standard dose in preventing CAN, especially when high volumes of a non-ionic, low-osmolality contrast agent are used. Our findings also support once more the necessity for limiting the amount of contrast media when dealing with patients with impaired renal function.

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