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DOI: 10.1148/radiol.2393041456
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(Radiology 2006;239:793-804.)
© RSNA, 2006

Genitourinary Imaging

Prophylaxis of Contrast Material–induced Nephropathy in Patients in Intensive Care: Acetylcysteine, Theophylline, or Both? A Randomized Study1

Wolfgang Huber, MD, Florian Eckel, MD, Michael Hennig, PhD, Hilkea Rosenbrock, PhD, Annette Wacker, MD, Dieter Saur, MD, Angelika Sennefelder, MD, Romain Hennico, MD, Cordula Schenk, MD, Alexander Meining, MD, Renate Schmelz, MD, Ralph Fritsch, MD, Wolfgang Weiss, MD, Peter Hamar, MD, Uwe Heemann, MD and Roland M. Schmid, MD

1 From the II. Medizinische Klinik (W.H., F.E., D.S., A.S., R.H., C.S., A.M., R.S., R.F., U.H., R.M.S.); Institut für Medizinische Statistik und Epidemiologie (M.H.), Institut für Klinische Chemie (H.R.), Universitaetsklinik Tuebingen, Kinderkardiologie (A.W.), and Department of Radiology (W.W.), Klinikum Rechts der Isar, Technische Universität München, Intensivstation 2/11, Ismaningerstr 22, D-81675 Munich, Germany; and Institut für Pathophysiologie; Semmelweiss Universität, Budapest, Hungary (P.H.) Received August 24, 2004; revision requested October 11; revision received May 20, 2005; accepted June 21; final version accepted September 6. Address correspondence to W.H. (e-mail: Wolfgg.Huber{at}t-online.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively compare the protective effect of acetylcysteine, theophylline, and both agents combined in patients who are admitted to the intensive care unit with at least one risk factor for contrast material–induced nephropathy and who receive at least 100 mL of iodinated contrast medium.

Materials and Methods: Institutional ethics review board approval and informed consent were obtained. A total of 91 patients (mean age, 58.5 years ± 14.8 [standard deviation]; 31 women, 60 men; 150 examinations) were admitted to the intensive care unit with at least one risk factor for contrast-induced nephropathy and received either (a) 200 mg theophylline 30 minutes before contrast medium administration (group T), (b) 600 mg acetylcysteine twice daily on the day of and (if possible) the day before the examination (group A), or (c) both agents combined (group AT). The primary endpoint for this study was the incidence of contrast-induced nephropathy ({chi}2 test).

Results: Groups T, A, and AT were comparable with regard to baseline creatinine levels and the amount of contrast medium administered. The incidence of contrast-induced nephropathy in groups T, A, and AT was 2%, 12%, and 4%, respectively, and was significantly lower in group T than in group A (P = .047). There was no significant difference in the incidence of contrast-induced nephropathy between groups A and AT (P = .148) or between groups T and AT (P = .53). For group A, serum creatinine did not change after 12, 24, or 48 hours compared with baseline. Creatinine levels in group T decreased 12 hours (1.19 mg/dL ± 0.58; P = .008) and 48 hours (1.16 mg/dL ± 0.55; P = .034) after contrast material injection compared with baseline (1.25 mg/dL ± 0.61). In group AT, creatinine significantly decreased 24 hours (1.21 mg/dL ± 0.74; P = .003) and 48 hours (1.17 mg/dL ± 0.69; P < .001) after contrast material injection compared with baseline (1.28 mg/dL ± 0.74). Group A had significantly higher maximal increases in creatinine than groups T and AT (P = .014).

Conclusion: For prophylaxis of contrast-induced nephropathy in patients who are admitted to the intensive care unit and who receive 100 mL or more of contrast medium, theophylline is superior to acetylcysteine.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Despite the use of low-osmolarity contrast media and prophylactic hydration, the impairment of renal function after contrast medium administration continues to be a clinical problem. With a prevalence of 12%, contrast material–induced (hereafter, contrast-induced nephropathy) nephropathy is the third most frequent cause of acute renal failure (1). The frequency of contrast-induced nephropathy strongly depends on a number of risk factors, including already impaired renal function, high amounts of contrast medium, and diabetes (Fig 1). Although the incidence is low in the absence of risk factors, in the worst case contrast-induced nephropathy occurs in more than 50% of patients (2–4,7–12). Contrast-induced nephropathy, which is defined according to Barrett and Parfrey (10) as an increase in serum creatinine levels of at least 0.5 mg/dL within 48 hours after the administration of contrast medium, results in longer hospitalization (11) and increased mortality (2,12). The in-hospital mortality of patients with contrast-induced nephropathy who require dialysis can be as high as 35.7% (2).


Figure 1
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  		Figure 1: Risk factors for contrast-induced nephropathy. Where available, references are listed in parentheses.

 
Most of these risk factors are frequently found in patients who have been admitted to the intensive care unit. Therefore, substantial effort has been invested in preventing contrast-induced nephropathy. Despite the protective effects of hydration that are described in several studies (13–15), other researchers have reported incidences of between 20% and 50% in patients who were thoroughly hydrated (8,9). Furthermore, it is often not possible to delay contrast medium radiography until adequate hydration has been achieved in emergency situations. Additionally, the resulting volume load of approximately 2 L/d is not without risk, especially for patients in the intensive care unit who have poor left ventricular function, adult respiratory distress syndrome, or decompensated cirrhosis.

The results of several studies (5,6,16–18) and those of a recent meta-analysis (19) have demonstrated a considerable reduction in the incidence of contrast-induced nephropathy by using medical prophylaxis with theophylline 30 minutes before contrast medium administration in patients with impaired renal function or other risk factors. Acetylcysteine administered 24 hours (9,20,21) or immediately (22,23) before contrast medium injection was preventive in patients with impaired renal function in five studies but was not preventive in at least 16 trials (24–32).

To our knowledge, there have been no clinical studies to date that compare these two prophylactic agents. Therefore, the purpose of our study was to prospectively compare the protective effect of acetylcysteine, theophylline, and both agents combined in patients who are admitted to the intensive care unit with at least one risk factor for contrast-induced nephropathy and who receive at least 100 mL of iodinated contrast medium.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Our institutional ethics review board approved this study, and informed consent was obtained from all patients or their relatives.

A power analysis was performed according to previous data on theophylline prophylaxis (5,6), with contrast-induced nephropathy incidences of 20% in the group without theophylline prophylaxis and 4% in the groups with theophylline prophylaxis. Assuming an additional prophylactic effect of acetylcysteine, the incidence of contrast-induced nephropathy in the combined group was estimated as 1%. On the basis of the assumed incidences of contrast-induced nephropathy (1%, 4%, and 20%), a sample size of 47 cases per group was calculated for detecting a difference between these three rates with a power of 90% (nQuery, version 4.0; Statistical Solutions, Saugus, Mass).

Study Design
Between August 20, 2000, and May 27, 2002, 91 patients (31 women, 60 men) who were admitted to the intensive care unit with at least one risk factor listed in Figure 1, who had stable serum creatinine levels, and who were undergoing 150 consecutive radiographic imaging examinations with a minimum of 100 mL of parenteral contrast medium were randomly selected to receive either theophylline (group T), acetylcysteine (group A), or both agents combined (group AT).

Theophylline (200 mg) was administered intravenously as a short infusion 30 minutes before contrast medium injection. Acetylcysteine was given intravenously at a dose of 600 mg twice daily on the day before and the day of contrast medium administration. In case of emergency examination on the day of randomization, 600 mg of acetylcysteine was administered exclusively 30 minutes before and 12 hours after contrast medium injection. Patients in group AT received 200 mg of theophylline 30 minutes before contrast medium injection and 600 mg of acetylcysteine, as described for patients in group A (ie, two to four doses of 600 mg acetylcysteine).

Patients who were already undergoing pretreatment with theophylline or acetylcysteine were exclusively randomized into groups that included the preexisting prophylactic agent. Patients undergoing pretreatment with both agents were excluded. Figure 2 schematically shows the randomization procedure.


Figure 2
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  		Figure 2: Chart demonstrates randomization procedure. Patients who were already undergoing pretreatment with theophylline or acetylcysteine were randomized into groups that included the preexisting prophylactic agent. Patients undergoing pretreatment with both agents were excluded.

 
In a setting that included patients with acute renal failure, only those with stable renal function were eligible. The stability of renal function was verified by comparing the baseline creatinine value obtained immediately before contrast medium administration with at least one screening value obtained during the preceding 2 days. Patients with a difference of more than 0.4 mg/dL were excluded.

A total of 30 of 91 patients underwent repeat (up to four) radiographic examinations. To avoid the influence of previous examinations and randomization, patients who had undergone previous examinations were eligible for repeat examinations only after a minimum of 4 days had elapsed since their last examination and, in case of the absence of contrast-induced nephropathy, after the preceding contrast material–enhanced procedure. The criteria for the second randomization were the same as for the first randomization. Therefore, the same patient could be randomized according to different regimens for repeat examinations. The mean patient age ± standard deviation was 58.5 years ± 14.8 (range, 21–89 years). A total of 31 women underwent 54 examinations, and 60 men underwent 96 examinations.

Of the 151 radiographic procedures, 129 (85.4%) were performed with computed tomography, 11 (7.3%) with coronary angiography, four (2.6%) with a transjugular intrahepatic portosystemic shunt procedure, one (0.7%) with pulmonary angiography, three (2.0%) with celiac and mesenteric angiography, and three (2.0%) with cerebral arteriography. One patient underwent two consecutive radiographic examinations within 30 minutes. Therefore, the total amount of contrast medium that was administered during both examinations (CT and pulmonary angiography) was added, and this case was evaluated as a single examination for a total of 150 examinations.

All patients received at least 100 mL (100–400 mL) of the low-osmolarity contrast medium iomeprol (Imeron 350, Byk-Gulden, Germany [coronary angiography procedures, n = 11] or Imeron 300, Byk-Gulden [all other examinations, n = 139]).

The most frequent underlying diseases and/or indications for radiography were sepsis (24 [16%] of 150 cases), pancreatitis (27 [18%] of 150 cases), complications of liver cirrhosis (15 [10%] of 150 cases), other gastrointestinal disorders (24 [16]% of 150 cases), and cardiac (18 [12%] of 150 cases), pulmonary (21 [14%] of 150 cases), and central nervous system (21 [14%] of 150 cases) impairment. Exclusion criteria were pregnancy or contraindications to theophylline (untreated high-grade arrhythmia or history of seizures) or acetylcysteine (previous allergy).

Hydration was performed according to clinical data, laboratory results (fractional excretion of sodium), radiographic evidence (chest radiography), and hemodynamic findings (central venous pressure and hemodynamic monitoring by using a pulmonary arterial catheter or PiCCO [Pulse Conture Cardiac Output; Pulsion Medical Systems, Munich, Germany]) if available. The choice of hydration solution was made with respect to underlying disease and to the results of serum electrolyte analysis in patients admitted to the intensive care unit.

Serum creatinine and blood urea nitrogen levels were determined once 12–48 hours before ("screening"), immediately before ("baseline"), and 12, 24, and 48 hours after contrast medium administration.

Urinary excretion of N-acetyl-ß-glucosaminidase, creatinine, total protein, albumin, and {alpha}-1-microglobulin were determined 0, 12, 24, and 48 hours after the administration of contrast medium. To exclude the dilution effects of osmotic diuresis induced by the contrast medium, proteinuria markers were calculated in relation to urinary creatinine concentration.

Urine volume and fluid balance were determined at 12-hour intervals before and up to 48 hours after the administration of contrast medium. Follow-up was performed in patients with contrast-induced nephropathy and included daily determination of serum creatinine levels until discharge or death.

Endpoints
The incidence of contrast-induced nephropathy was the primary endpoint. Secondary endpoints included the time course of renal retention parameters for serum creatinine and blood urea nitrogen levels (compared with baseline values), a regression analysis with regard to the maximum increase in serum creatinine levels (see below), a comparison of the prevalence of risk factors between patients with and those without contrast-induced nephropathy, the follow-up of patients with contrast-induced nephropathy until discharge or death, and the documentation of side effects attributable to theophylline or acetylcysteine.

The monitoring of patients and the decisions regarding hydration were performed by authors who were working in the intensive care unit (W.H., F.E., A.W., D.S., A.S., R.H., C.S., A.M., R.S., R.F.). The data acquisition and evaluation were performed by four authors (W.H., F.E., M.H., H.R.).

Statistical Analysis
Dichotomous parameters were compared by using the {chi}2 test. The Wilcoxon test for unpaired samples was used to compare continuous parameters between the treatment groups, and the Wilcoxon test for paired samples was used to compare follow-up results with respective baseline values within each treatment group.

Risk factors pertaining to contrast-induced nephropathy (Fig 1) were documented prospectively. An explorative analysis was performed by using a multiple regression analysis (backward selection) with Y = maximum increase in serum creatinine level, as compared with baseline values, within 48 hours, as well as variables for group (A, T, or AT), age, weight, diabetes (yes or no), hypertension (yes or no), serum creatinine and blood urea nitrogen levels at baseline, Cigarroa quotient at baseline (contrast medium [in milliliters] x serum creatinine level [in milligrams per deciliter] per kilogram body weight), amount of contrast medium administered, nephrotoxic medication (yes or no), pathologic urinary screening, and pathologic renal ultrasongraphy (US). All statistical analyses were performed by using a commercially available software program (SAS, version 6.12; SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Risk Factors and Baseline Characteristics
Patients receiving theophylline, acetylcysteine, or both agents combined were comparable with regard to risk factors for contrast-induced nephropathy, including baseline creatinine levels (1.25 mg/dL ± 0.61 for group T vs 1.25 mg/dL ± 0.74 for group A vs 1.28 mg/dL ± 0.74 for group AT), screening creatinine levels (1.24 mg/dL ± 0.61 for group T vs 1.33 mg/dL ± 0.81 for group A vs 1.38 mg/dL ± 0.89 for group AT), amount of contrast medium administered (163.4 mL ± 58.1 for group T vs 150.6 mL ± 33.4 for group A vs 157.0 mL ± 45.0 for group AT), Cigarroa quotient (2.76 ± 1.54 for group T vs 2.62 ± 1.52 for group A vs 2.86 ± 1.87 for group AT), and prevalence of diabetes (29% for group T vs 32% for group A vs 20% for group AT) (Table 1). Differences were not significant for any of these factors. The only significant difference between the three groups was a higher baseline value for blood urea nitrogen levels in group AT (34.3 mg/dL ± 20.0; P = .035) compared with group T (25.2 mg/dL ± 14.8) and group A (28.3 mg/dL ± 21.3). The mean baseline and screening creatinine levels were not significantly different between any of the three groups.


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  		Table 1. Demographic Data and Main Risk Factors

 
Primary Endpoint: Incidence of Contrast-induced Nephropathy
The overall incidence of contrast-induced nephropathy, which was assessed according to the definition by Barrett and Parfrey (10), was low and occurred after only nine (6%) of 150 examinations. As shown in Figure 3, the incidence of contrast-induced nephropathy according to Barrett and Parfrey's definition was significantly lower (P = .047) among patients who received only theophylline (one of 51 cases) compared with those who received only acetylcysteine (six of 50 cases). No statistically significant difference in the incidence of contrast-induced nephropathy was found between groups A and AT (P = .148) or between groups T and AT (P = .53).


Figure 3
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  		Figure 3: Bar graph demonstrates that the incidence of contrast-induced nephropathy was significantly lower among patients who received theophylline alone (one of 51 cases) than among those who received acetylcysteine alone (six of 50 cases) (P = .047). All other comparisons were not significant.

 
A subgroup analysis of patients with serum creatinine levels of more than 1.5 mg/dL gives further evidence that theophylline is superior to acetylcysteine for prophylaxis of contrast-induced nephropathy in these patients: The incidence of contrast-induced nephropathy in patients with creatinine levels of more than 1.5 mg/dL was significantly higher in group A (five [45%] of 11 cases) than in group T (zero [0%] of 12 cases; P = .008) or group AT (one [7%] of 14 cases; P = .026). The incidence of contrast-induced nephropathy was not significantly different between groups T and AT (P = .345).

Secondary Endpoints
Time course of renal retention parameters.—Figure 4 shows the time course for two renal retention parameters—that is, serum creatinine and blood urea nitrogen levels—within the three groups. Neither mean serum creatinine level nor mean blood urea nitrogen level increased in any group 12, 24, or 48 hours after the administration of contrast medium.


Figure 4
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  		Figure 4a: Time course of (a) serum creatinine and (b) blood urea nitrogen levels presented as the difference from baseline with 95% confidence intervals. Serum creatinine and blood urea nitrogen levels did not increased in any group after 12, 24, or 48 hours. In group A, serum creatinine did not change after 12, 24, or 48 hours compared with baseline. In group T, serum creatinine levels significantly decreased after 12 and 48 hours compared with baseline. In group AT, serum creatinine levels significantly decreased after 24 and 48 hours. Blood urea nitrogen levels were stable in groups T and A and decreased in group AT after 12 (P = .009) and 24 (P = .014) hours. Values for serum creatinine can be converted to micromoles per liter by multiplying by 88.4.

 

Figure 4
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  		Figure 4b: Time course of (a) serum creatinine and (b) blood urea nitrogen levels presented as the difference from baseline with 95% confidence intervals. Serum creatinine and blood urea nitrogen levels did not increased in any group after 12, 24, or 48 hours. In group A, serum creatinine did not change after 12, 24, or 48 hours compared with baseline. In group T, serum creatinine levels significantly decreased after 12 and 48 hours compared with baseline. In group AT, serum creatinine levels significantly decreased after 24 and 48 hours. Blood urea nitrogen levels were stable in groups T and A and decreased in group AT after 12 (P = .009) and 24 (P = .014) hours. Values for serum creatinine can be converted to micromoles per liter by multiplying by 88.4.

 
Overall, the time course for retention parameters was slightly more favorable among patients who received theophylline alone or in combination with acetylcysteine than in those who received acetylcysteine alone.

For patients in group A, serum creatinine levels obtained 12 hours (1.28 mg/dL ± 0.75; P = .46), 24 hours (1.25 mg/dL ± 0.77; P = .78), and 48 hours (1.27 mg/dL ± 0.84; P = 1.00) after the administration of contrast medium did not change compared with baseline (1.25 mg/dL ± 0.74).

In contrast, serum creatinine levels for patients in group T decreased 12 hours (1.19 mg/dL ± 0.58; P = .008) and 48 hours (1.16 mg/dL ± 0.55; P = .034) after the administration of contrast medium compared with baseline (1.25 mg/dL ± 0.61). In group AT, serum creatinine levels significantly decreased 24 hours (1.21 mg/dL ± 0.74; P = .003) and 48 hours (1.17 mg/dL ± 0.69; P < .001) after the administration of contrast medium compared with baseline (1.28 mg/dL ± 0.74).

Blood urea nitrogen levels were stable in groups T and A but decreased in group AT 12 (33.02 mg/dL ± 19.76; P = .009) and 24 (31.27 mg/dL ± 17.34; P = .014) hours after the administration of contrast medium compared with baseline (34.3 mg/dL ± 20.0).

Multiple regression analysis of risk factors.—The multiple regression analysis demonstrated that prophylactic agent (P = .014), age (P = .019), and hypertension (P = .049) were independent risk factors for the maximal increase in serum creatinine after contrast medium injection compared with baseline. Among the three different groups, patients who received acetylcysteine alone had a significantly higher maximal increase in serum creatinine (P = .014) compared with those who received theophylline alone or in combination with acetylcysteine.

Proteinuria.—Complete proteinuria diagnostics could be performed in 119 cases (42 in group T, 44 in group A, and 33 in group AT). Baseline levels for all five proteinuria markers were comparable in all three treatment groups (Table 2). For all patients, there was no increase in any proteinuria marker at any time. In contrast, urinary total protein concentration decreased significantly after 12 hours (P = .028), and urinary albumin concentration decreased significantly after 12 hours (P = .006) and 48 hours (P = .031).


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  		Table 2. Time Course of Proteinuria after Contrast Material Administration

 
Comparing the three different treatment groups yielded an increase in {alpha}-1-microglobuline (P = .032) and N-acetyl-ß-glucosaminidase (P = .007) after 12 hours in group AT; this increase was not observed in the other two treatment groups. Additionally, total protein concentration decreased after 12 (P = .034) and 24 (P = .031) hours in group A but not in the two other groups. In group T, there was no change in any proteinuria marker at any time.

Characteristics and outcomes of patients with contrast-induced nephropathy.—Table 3 summarizes the characteristics of patients with and those without contrast-induced nephropathy. Comparisons of the incidences and means of risk factors for contrast-induced nephropathy between patients with and those without contrast-induced nephropathy reveal that the mean baseline values for creatinine, blood urea nitrogen, and Cigarroa quotient were significantly higher in patients with contrast-induced nephropathy (Table 3). Furthermore, the prevalence of sepsis and the use of catecholamines were significantly more frequent among patients with contrast-induced nephropathy. Patients with and those without contrast-induced nephropathy, however, were not different with regard to the amount and application (intravenous or intraarterial) of contrast medium or the prevalence of diabetes and hypertension.


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  		Table 3. Characteristics of Patients with Contrast-induced Nephropathy and Comparison with Baseline Values

 
Figure 5 shows the time course for the nine patients with contrast-induced nephropathy according to the definition by Barrett and Parfrey (10). A total of four patients died after contrast medium administration: one after 2 days (group AT), one after 5 days (group A), one after 10 days (group A), and one after 12 days (group A). The overall mortality of patients with contrast-induced nephropathy (four [44%] of nine patients) was significantly higher (P < .001) than that of patients without contrast-induced nephropathy (three [4%] of 82 patients).


Figure 5
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  		Figure 5: Time course for serum creatinine in patients with contrast-induced nephropathy. Values for serum creatinine can be converted to micromoles per liter by multiplying by 88.4.

 
In one patient with contrast-induced nephropathy and anuric acute renal failure, dialysis was started 2 days after contrast medium administration and continued until death, which occurred 10 days after contrast medium administration. The other three of four lethal cases were caused by malignant diseases (esophageal carcinoma, cholangiocellular carcinoma, and multiple myeloma). With respect to the underlying malignancies and written declarations of all three patients, no dialysis was performed. All three patients had clinical and laboratory signs of oliguric or anuric acute renal failure at the time of death.

Two of the five surviving patients recovered from contrast-induced nephropathy and were discharged with normalized serum creatinine levels. One of them died 4 months after the administration of contrast medium. Among the four patients who survived long term, three were discharged with increased serum creatinine levels (0.3, 0.7, and 0.8 mg/dL) compared with baseline. In two of these patients, long-term follow-up demonstrated normalization of renal function within 4 weeks. Mean serum creatinine levels were not significantly increased compared with baseline values at discharge or death (2.84 mg/dL ± 1.77 vs 2.09 mg/dL ± 1.02; P = .110).

Side effects.—None of the patients developed side effects that required therapeutic interventions. Particularly, there were no malignant arrhythmias after treatment with theophylline and no allergic side affects attributable to acetylcysteine.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
The overall incidence of contrast-induced nephropathy in our study (6%) is low compared with the results of several other studies in patients at similar risk, including studies performed with no prophylaxis except hydration. The incidence of contrast-induced nephropathy among the hydrated control groups for Tepel et al (9), Shyu et al (20), Diaz-Sandoval et al (22), and Koch et al (8) was 21%, 25%, 45%, and 52%, respectively. Thus, a beneficial effect of at least one of the three different prophylactic approaches in our study is highly probable.

In general, the incidence of contrast-induced nephropathy was significantly associated with more severe renal impairment before contrast medium administration, sepsis, or the use of catecholamines. All these risk factors were comparable within the three study groups. A comparison of the three different groups in our study shows an advantage for those receiving theophylline alone or in combination with acetylcysteine compared with those receiving acetylcysteine alone. The incidence of contrast-induced nephropathy among patients receiving theophylline alone (2%) was significantly lower than the incidence of contrast-induced nephropathy among patients receiving acetylcysteine alone (12%) (P = .047). This effect is even more pronounced in patients with creatinine levels of more than 1.5 mg/dL (P = .008). Mean serum creatinine levels decreased in the two groups that received theophylline alone or in combination with acetylcysteine. Serum creatinine levels, however, did not decrease in group A.

The decrease in creatinine for patients in groups T and AT, despite the administration of contrast medium, can be explained by the benefits of radiographic diagnosis and intervention: The benefits of demonstrating sepsis and performing consecutive therapy on the source of sepsis may outweigh the potential noxious side effects of the contrast medium. This phenomenon has been previously described in patients who were admitted to the intensive care unit (17), as well as in other studies on contrast-induced nephropathy (9,21,22).

The multiple regression analysis demonstrated a significant reduction in the maximal increase in serum creatinine levels within 48 hours after contrast medium administration in patients who received theophylline (group T and group AT) compared with those who received acetylcysteine (group A). The time course for blood urea nitrogen levels was significantly more favorable among patients in group AT than among those in groups T or A. The latter might be a hint for an additive effect of the two agents. Both agents interfere with crucial steps of the multifactorial pathophysiologic process of contrast-induced nephropathy.

Contrast media cause renal vasoconstriction and medullary ischemia due to modulation of renal synthesis and the release of several vasoactive mediators such as nitric oxide (33), prostaglandins (8,34), and endothelin (35). One of the most important vasoconstrictive mediators is adenosine, which increases in renal concentration after the administration of contrast material (36–38). Theophylline is a nonselective adenosine A1 and A2 receptor antagonist that has prevented contrast-induced and adenosine A1 receptor–mediated afferent renal vasoconstriction in several experimental studies (37,38). The results of a number of clinical studies have shown substantial prophylactic effects after the administration of contrast material, especially in patients with impaired renal function (5,6,16–18,39–41). In addition to medullary ischemia, contrast material can induce postischemic reperfusion injuries that are mediated by reactive oxygen metabolites in the kidneys (42–44). Therefore, antioxidants such as superoxide dismutase, acetylcysteine, and allopurinol have been successfully used in experimental (45) and clinical trials (9,20–23,46).

The less pronounced prophylactic effect of acetylcysteine compared with theophylline in our study might be related to several reasons: To date, at least 16 randomized controlled studies on acetylcysteine prophylaxis have been published (9,20–32). Only five of these studies reported a significant benefit (9,20–23). The largest trial (32), which included 397 patients, and the most recent meta-analysis (31), which included 20 studies with a total of 2195 patients, did not show a statistically significant benefit for acetylcysteine prophylaxis. By contrast, another meta-analysis (19) demonstrated a significant reduction of contrast-induced renal impairment with theophylline (P = .004). Nevertheless, acetylcysteine might be effective in patients who receive smaller amounts of contrast medium (between 75 and 140 mL), as suggested by the results of three studies (9,20,21) and two subgroup analyses (24,31). The mean amount of contrast medium in our study, however, was 157 mL.

Theophylline, on the other hand, was effective in two studies that included patients who received larger amounts of contrast medium (207 and 249 mL) (5,18). Furthermore, the results of a previous study (47) demonstrate that acetylcysteine might interfere with the analysis of serum creatinine concentrations. These results suggest that acetylcysteine artificially decreases serum creatinine levels without improving renal function, as determined by superior parameters such as cystatin C. Creatinine metabolism is affected by acetylcysteine, either through direct activation of creatinine kinase or through reversal of inhibition by free radicals (48). Therefore, the authors classified the preventive effects of acetylcysteine as "questionable" (47).

Another explanation of the lower prophylactic efficiency of acetylcysteine might be the emergency setting of our study, which deliberately included patients who underwent contrast- enhanced procedures immediately after randomization. Therefore, only 28 (56%) of 50 cases that were randomized to receive acetylcysteine could be pretreated 24 hours before contrast medium administration, as suggested by the protocols of three trials with effective acetylcysteine prophylaxis (9,20,21). Other patients received only two doses of 600 mg acetylcysteine on the day of examination (16 [32%] of 50 cases) or two doses of 600 mg acetylcysteine on the day of the examination and three doses of 300 mg acetylcysteine on the day before the examination (six [12%] of 50 cases) (three doses of 300 mg acetylcysteine is the standard mucolytic regimen in our intensive care unit).

Among the six patients who developed contrast-induced nephropathy despite acetylcysteine administration, only three received four doses of acetylcysteine starting 24 hours before the examination; the other three received acetylcysteine only two or three times but at least once before contrast medium administration. Comparisons of the incidence of contrast-induced nephropathy among patients who received four doses of acetylcysteine (three [11%] of 28 cases) and the incidence of contrast-induced nephropathy among patients who received theophylline (one [2%] of 51 cases) did not yield a statistically significant difference (P = .090). However, the incidence among the patients who received two or three doses of acetylcysteine (three [14%] of 22 cases) was significantly higher than that among patients who received theophylline alone (one [2%] of 51 cases, P = .044) and among all patients who received theophylline (ie, group T and AT together) (three [3%] of 100 patients, P = .037). Nevertheless, this subgroup analysis was not a prospective endpoint of the study.

Furthermore, a clinical study should be as close to clinical praxis as possible, including emergency examinations with high amounts of contrast material. Many of the emergency contrast-enhanced procedures in the intensive care unit cannot be delayed for 24 hours. Therefore, the immediate effect of theophylline given once 30 minutes before contrast medium injection is one of the main advantages of using this agent compared with 24-hour pretreatment with acetylcysteine. Additionally, the intensive care setting included patients with paralytic ileus and doubtful gastrointestinal absorption, which required rapid intravenous administration of both prophylactic agents. The efficiency of oral (18) and intravenous theophylline (5,6,17) has been demonstrated. Acetylcysteine was effective in four studies (9,20–22) with oral administration and in one trial with intravenous administration (23). Therefore, it is not likely that the lower prophylactic efficiency of acetylcysteine resulted from intravenous administration.

Patients who underwent repeat examinations were deliberately included because repeat exposure to contrast medium is an important risk factor for contrast-induced nephropathy. Excluding patients with higher risk does not make sense in a study on prophylaxis. From a pathophysiologic viewpoint, a combination of theophylline and acetylcysteine might be superior to the administration of each agent alone. Indeed, the time course for serum creatinine and blood urea nitrogen levels was most favorable among the patients who received both agents, although these patients had significantly higher baseline blood urea nitrogen levels than those in the other two groups. The latter might be a bias induced by our randomization procedure given the opportunity to include patients who were pretreated with theophylline or acetylcysteine. Acetylcysteine is used frequently in the intensive care unit to liquefy mucus. Therefore, a large number of patients would have been withdrawn from the study if those who had undergone this treatment were excluded.

Nevertheless, a greater number of patients in group AT (38 [77%] of 49 cases) than in groups A and T (24 [24%] of 101 cases) had been pretreated with one of the prophylactic agents. Therefore, one might argue that these patients might have been more seriously ill than those in the other two groups. However, all other baseline characteristics, including the prevalence of multiple organ failure, catecholamine therapy, emergency examination, and baseline creatinine levels, were comparable.

Another limitation of our study might be the number of patients included. Despite the inclusion of a greater number of patients than most of the previous clinical studies concerning contrast-induced nephropathy, the statistical power is low with regard to the primary endpoint, especially for comparisons between groups T and AT. However, to detect a difference between these two groups, which had incidences as low as 2% and 4%, with sufficient statistical power would require a study population of 1626 in each group ({chi}2 test; power of 90% [nQuery, version 4.0; Statistical Solutions]).

Nevertheless, our study gives several hints for better prophylactic efficacy with theophylline versus acetylcysteine. Until studies that include the above-mentioned number of patients are available, prophylaxis of contrast-induced nephropathy should include theophylline, if possible in combination with acetylcysteine twice daily on the day before the contrast-enhanced procedure. Another limitation might be the absence of a strict hydration regimen for all patients. This, however, would have been unethical in patients who were admitted to the intensive care unit with a variety of different requests for fluid and electrolyte substitution. Nevertheless, our data concerning fluid balance and urine output demonstrate sufficient volume support, with a mean of more than 2.5 L/d over the complete observation period of 48 hours after contrast medium administration, which is much longer than the suggested hydration of more than 12 hours at 1 (mL · kg–1)/h. The mean amounts of urine output and fluid balance were comparable for all three groups; thus, a bias is not likely.

In addition to the prophylactic effect of theophylline, the overall low incidence of contrast-induced nephropathy (6%) might be partly the result of thorough hydration according to clinical, radiographic, hemodynamic, and laboratory data, which are usually unavailable in patients who are admitted to the intensive care unit. With respect to the absence of a control group without any medical prophylaxis, a prophylactic effect of acetylcysteine cannot be excluded. Finally, all our patients were white. There are, however, no data on ethnic susceptibility to contrast-induced nephropathy or racial differences with regard to the efficacy of theophylline or acetylcysteine.

In conclusion, for prophylaxis of contrast-induced nephropathy in patients who are admitted to the intensive care unit and who receive 100 mL or more of contrast medium, theophylline is superior to acetylcysteine.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 
Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, W.H., F.E., A.W., U.H., R.M.S.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, W.H., F.E., H.R., A.W., D.S., R.F.; clinical studies, W.H., F.E., H.R., A.W., D.S., A.S., R.H., C.S., A.M., R.S., R.F.; statistical analysis, W.H., F.E., M.H.; and manuscript editing, W.H., F.E., M.H., A.W., C.S., A.M., R.S., P.H., U.H., R.M.S.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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