|Year : 2019 | Volume
| Issue : 2 | Page : 214-219
Intravenous N-acetylcysteine versus intravenous theophylline in the prevention of contrast-induced nephropathy in critically ill patients: a prospective randomized clinical trial
Sherif G Anis, Rafik Y Atallah
Department of Anesthesia and Intensive Care, Ain Shams University, Egypt
|Date of Submission||12-Oct-2017|
|Date of Acceptance||12-Dec-2018|
|Date of Web Publication||12-Jun-2019|
Sherif G Anis
Source of Support: None, Conflict of Interest: None
Aim Despite the use of several agents for prophylactic agents, contrast-induced nephropathy (CIN) remains a crucial clinical problem. The aim was to compare the efficacy of intravenous N-acetylcysteine (NAC) and intravenous theophylline in the prevention of CIN in critically ill patients.
Patients and methods A total of 90 patients were admitted to the ICU with at least one risk factor for CIN and randomly divided into three groups. All patients received the regular management of renal protection with good hydration, to maintain adequate intravenous volume expansion with isotonic crystalloids (normal saline: 1–1.5 ml/kg/h) 3–12 h before the procedure, and it was continued for 6–24 h afterward. In the first group, patients received 6 mg theophylline intravenously over 30 min as a loading dose, followed by a maintenance dose of 0.5 mg/kg/h intravenously, to be started after the loading dose (group T). In the second group, patients received the full course of treatment with NAC (group A), which comprised three consecutive intravenous infusions: first infusion as initial loading dose of 150 mg/kg body weight infused in 200 ml over 1 h, followed by the second infusion of 50 mg/kg in 500 ml over the next 4 h, followed by the third infusion of 100 mg/kg in 1 l over the next 16 h (to be completed on the day of the examination). Control group: in this group, 30 patients received no additional drug before administration of radiocontrast medium. They only received the regular management of renal protection with good hydration.
Results Despite the inclusion of ICU patients at high risk for CIN, we found a significant lower incidence of CIN and a lower incidence of patients requiring dialysis among patients under prophylaxis of intravenous NAC and intravenous aminophylline, as creatinine concentration was elevated by 25% in only four patients in the NAC group and only in three patients in the aminophylline group, and the incidence of CIN and patients requiring dialysis were significantly lower (P<0.045) than that in the control group.
Conclusion We concluded that the administration of intravenous NAC or intravenous theophylline around the time of contrast administration prevents renal injury in equal efficacy compared with patients receiving no additional drugs at the time of contrast administration as regards incidence of nephropathy and incidence of dialysis among study patients.
Keywords: contrast nephropathy, critically ill, N-acetylcysteine, prevention, theophylline
|How to cite this article:|
Anis SG, Atallah RY. Intravenous N-acetylcysteine versus intravenous theophylline in the prevention of contrast-induced nephropathy in critically ill patients: a prospective randomized clinical trial. Res Opin Anesth Intensive Care 2019;6:214-9
|How to cite this URL:|
Anis SG, Atallah RY. Intravenous N-acetylcysteine versus intravenous theophylline in the prevention of contrast-induced nephropathy in critically ill patients: a prospective randomized clinical trial. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2019 Jul 18];6:214-9. Available from: http://www.roaic.eg.net/text.asp?2019/6/2/214/260149
| Introduction|| |
Contrast-induced nephropathy (CIN) is defined as an acute deterioration in renal function after exposure to, and as a result of, contrast media (CM) . However, acute renal failure (ARF) occurring after procedures associated with contrast administration may be caused by several different factors including volume depletion, atheroembolic disease, and congestive heart failure. Because it is not always possible to clinically differentiate the cause of the renal dysfunction, it may be more appropriate to term this condition as contrast-associated nephropathy .
Consequences of exposure to CM may include renal vasoconstriction and redistributed blood flow, tubular epithelial cell toxicity with disruption of cell integrity, oxygen radical generation, and apoptosis, intratubular obstruction, and hemoglobin oxygen saturation curve shifts .
A variety of therapeutic agents such as N-acetylcysteine (NAC), theophylline, low-dose dopamine, and statins aimed at ameliorating these changes have been studied. Despite the use of several prophylactic agents, such as low-dose NAC, ascorbic acid, mannitol, frusemide, and sodium bicarbonate administration, CIN remains a crucial clinical problem . A confusing plethora of clinical–chemical parameters has recently been replaced by the definition by Barrett and Parfrey  of CIN as an increase in serum creatinine concentration of at least 0.5 mg/dl within 48 h after the administration of CM. The reported incidence varies greatly, between less than 1% to more than 50%, depending on several risk factors .
Marked protective effects of NAC against oxidative stress-induced tubular damage might involve various chemical mechanisms. First, NAC directly scavenges superoxide radicals. Second, as a precursor of glutathione synthesis, NAC significantly increases intracellular redox potential and, likely, improves the reductive status of critical regulatory protein thiol groups. Third, NAC may combine with nitric oxide (NO), leading to the formation of S-nitrosothiols, which are a more stable storage form of NO and display potent vasodilator properties .
In our study, we compared the protective effect of intravenous NAC with that of intravenous theophylline, in patients who were admitted to ICU with at least one risk factor for CIN.
| Aim|| |
Our aim was to compare the protective effect of intravenous NAC and intravenous theophylline in patients receiving only good hydration with no additional drug who were admitted to the ICU with at least one risk factor for CIN and who will receive at least 100 ml of iodinated CM.
| Patients and methods|| |
Institutional ethics review board approval and informed consents were obtained from all patients or their legal guardians before enrollment in the study. A total of 90 patients were admitted to the ICU from October 2015 to August 2016 at Ain Shams University Hospitals with at least one risk factor for CIN, and they were randomly divided using computer-generated random number tables with closed sealed envelopes prepared by a blinded assistant into three groups: group T included 30 patients assigned to receive intravenous theophylline, group A included 30 patients assigned to receive intravenous NAC, and a control group included 30 patients who received no additional drug before contrast administration. All patients received the regular management of renal protection with good hydration to maintain adequate intravenous volume expansion with isotonic crystalloids (normal saline: 1–1.5 ml/kg/h) 3–12 h before the procedure, and it was continued for 6–24 h afterward.
Risk factors for CIN were defined as follows:
- Impaired renal function.
- Diabetes mellitus (metformin is used in type 2 diabetes mellitus to decrease the amount of glucose produced by the liver and to increase the body’s response to insulin). Metformin in isolation is not considered a risk factor for CIN, but particular attention must be paid to patients taking metformin who are scheduled to undergo contrast-enhanced examination. In patients with renal failure (acute or chronic), the renal clearance of metformin is decreased, and there is an associated risk of lactic acidosis, which has a mortality rate of up to 50%. Some patients who receive intravenous contrast may experience a deterioration of renal function (CIN).
- There is some controversy about when to stop and restart metformin for patients scheduled to undergo intravenous contrast-enhanced examinations. The guidelines from The European Society of Urogenital Radiology advocates stopping metformin 48 h before computed tomography for patients with an estimated glomerular filtration rate (eGFR) of less than 45 ml/min.
- High dose of CM (CM>2 ml/kg body weight).
- Nephrotoxic medications: aminoglycosides, vancomycin, diuretics, and chemotherapeutic agents.
- Dysfunction of other organs: liver and heart (New York Heart Association grade 3 or higher). Chronic heart failure (CHF) poses a particular challenge. Patients with compensated CHF should still be given volume, but at lower rates. Uncompensated CHF patients should undergo hemodynamic monitoring, if possible, and diuretics should be continued.
The inclusion criteria were as follows:
- Patients having a minimum of one of the risk factors for CIN.
- At least 100 ml of low osmolarity CM.
- Age, 18 years or over.
In the first group, in addition to the regular management of renal protection with good hydration, 30 patients received 6 mg theophylline intravenously over 30 min as a loading dose, followed by a maintenance dose of 0.5 mg/kg/h intravenously , to be started after the loading dose, and it was continued for 21 h before CM administration (group T).
In the second group, in addition to the regular management of renal protection with good hydration, thirty patients received the full course of treatment with NAC (group A), which comprised consecutive intravenous infusions:
- Initial loading dose of 150 mg/kg body weight infused in 200 ml over 1 h.
- 50 mg/kg in 500 ml over the next 4 h.
- 100 mg/kg in 1 l over the next 16 h.
- To be completed on the day of the examination (group A).
- The patient should, therefore, receive a total of 300 mg/kg over a 21 h period .
- Body weight estimate (75).
Control group: 30 patients received no additional drug before administration of radiocontrast medium. Only receiving the regular management of renal protection with good hydration to maintain adequate intravenous volume expansion with isotonic crystalloids, normal saline (1–1.5 ml/kg/h), 3–12 h before the procedure and continued for 6–24 h afterward, reaching a central venous pressure of 12–15 and keeping urine output more than 100 ml/h.
- High-grade arrhythmia (arrhythmia resulting in circulatory instability within 24 h before the administration of CM).
- Theophylline allergy, pregnancy.
- In case of ARF (increase in creatinine concentration of 0.5 mg/dl or more since admission), patients were eligible if the increase in creatinine concentration over the previous 48 h was 0.5 mg/dl or less.
- Chronic renal failure, as in patients already on dialysis, the commonly cited issues with contrast administration include volume load and direct toxicity of contrast to the remaining nonfunctional nephrons and nonrenal tissues. These issues underlie the perceived need for emergent dialysis and contrast removal.
The risk of acute damage from contrast is, therefore, greatest in patients with chronic kidney disease. This can be explained by the increase in single-nephron eGFR and thus the filtered load of contrast per nephron. This is akin to a double hit to the remaining nephrons: increased contrast load and prolonged tubular exposure. While this may not seem to be a concern in patients with end-stage renal disease who are already on dialysis, residual renal function, in fact, plays a big role in their outcome, more so in patients on peritoneal dialysis. Its preservation is, therefore, important.
Eligible patients undergoing 90 consecutive low osmolarity CM-enhanced radiographic procedures in our medical ICU received theophylline or NAC infusions, or only received good hydration, before the administration of CM.
The following parameters were examined:
- Serum creatinine and blood urea nitrogrn concentrations (0, 12, 24, and 48 h after contrast administration).
- Urine volume and fluid balance (at 12 h interval).
Fluid balance was calculated as the difference between fluid supplies and fluid losses. Fluid supplies include all fluids administrated enterally and parenterally; this includes antibiotics, all drugs administrated by syringes, and flushing solutions. Fluid losses include urine, vomiting and fluid losses via drainages.
Urine analysis and renal ultrasound were evaluated as dichotomous values (pathological finding: yes/no). Any deviation from normal ultrasound findings (normal sizes of both kidneys, normal diameter and echogenicity of renal parenchyma, absence of dilatation of renal pelvis) or from the normal urine analysis was considered pathological and excluded from the study.
Study outcome measures
The primary outcome measure was the incidence of CIN as classically defined as an increase in 25% or more of creatinine levels within two days following contrast injection. Additional endpoints were the incidence of ARF requiring dialysis within 48 h after administration of CM and the comparison of serum creatinine levels at 12, 24, and 48 h after administration of CM with baseline levels.
Statistical presentation and analysis of this study were conducted using the mean, SD, analysis of variance (ANOVA) test and χ2-tests by SPSS, version 20 (IBM Corp, Armonk, NY, USA).
ANOVA test was used for comparison among different times in the same group in quantitative data.
Pearson’s χ2 and likelihood-ratio χ2. Fisher’s exact test and Yates’ corrected χ2 are computed for 2×2 tables.
Sample size was calculated using Epicalc 2000 software with the following input: the minimal sample size was 90.
- Type I error (α)=5% with confidence level 95% and study power 90% (power of test) with type II error of 10% (β).
- The significance level (α) was at 0.05.
| Results|| |
Baseline patient characteristics
There were a total of 90 patients (mean age: 58.5±14.8 years; 47 women, 43 men) at randomization; patients’ demographic and clinical characteristics were similar between the three treatment groups. Treatment medications were also similar between the groups. All baseline parameters are shown in [Table 1] and [Table 2]. Mean eGFR according to Modification of Diet in Renal Disease was 42 ml/min/1.73 m2.
The individual time courses of serum creatinine concentration for the patients under NAC and theophylline in comparison with control groups showed that the elevation in creatinine concentration was significantly lower 12 h after CM in patients treated with NAC 134±22.7 μmol/l and in patients treated with theophylline 135±24 μmol/l than before when compared with the control group (148.4±24).
Serum creatinine is elevated 24 and 48 h after CM in patients under NAC and theophylline, with a significantly lower percentage of change than before in the control group under no prophylaxis.
The occurrence of contrast nephropathy (CN) and incidence of ARF in the three groups are shown in [Table 3] and [Table 4].
|Table 3 Mean increases in serum creatinine at 12, 24, and 48 h compared with baseline serum creatinine in the three groups|
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|Table 4 Incidence of contrast nephropathy and incidence of acute renal failure in the three groups|
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Despite the inclusion of ICU patients at high risk for CIN, we found a significantly lower incidence of CIN according to Barrett and Parfrey, as there was a 25% increase in serum creatinine and a lower incidence of patients requiring dialysis using intravenous NAC and intravenous aminophylline.
Among 90 patients with risk factors including impaired renal function and diabetes, creatinine concentration was elevated by 25% in only four patients in the NAC group and only in three patients in the theophylline group, and the incidence of CIN and patients requiring dialysis was significantly lower (P<0.045) than that in the control group.
| Discussion|| |
CIN is an important cause of ARF and is associated with increased morbidity and mortality in hospitalized patients.
Our analysis suggests that administration of NAC or theophylline around the time of contrast administration prevents renal injury.
Classically, CN is defined as an increase in 25% or more, or as an absolute increase of 44 µmol/l of creatinine levels within two days following contrast injection . Recently, Acute Kidney Injury Network (AKIN) and Risk, Injury, Failure Loss and End-stage kidney disease (RIFLE) criteria have emerged to standardize the diagnosis of AKI in hospitalized patients .
In patients undergoing elective radiological or cardiologic procedures, CN can be prevented by hydration and withdrawal of diuretics and/or nephrotoxic drugs. Its prevalence has, therefore, declined over the recent years . The occurrence of CN is, however, consistently higher in diabetic patients, congestive heart failure patients, volume-depleted patients, critically ill patients and, especially, in patients suffering from chronic kidney disease . Emergency computed tomography with contrast injection in patients with renal impairment (eGFR<60 ml/min) remains an important cause of CN given the lack of sufficient time for hydration and the lack of renal functional reserve .
Bursts of oxidative stress occur naturally, and the body cells and tissues possess antioxidant systems to protect against oxidative damage. After exposure to CM, there is a surge in oxidative stress that may overwhelm these systems and result in tissue injury . NAC is an acetylated derivative of the amino acid cysteine. The chemical formula is C5H9NO3S, the molecular mass is 163.2 g/mol, and the most plausible mechanism of NAC protective effect against CIN is supplementation of the body’s antioxidant capacity . NAC might work by inducing glutathione synthesis. Glutathione plays a central role in the body’s defense against cellular oxidative damage . It generally cannot enter cells; instead, it must be synthesized intracellularly from glycine, glutamate, and cysteine. Cysteine is the moiety that supplies glutathione’s active sulfhydryl group and plays a critical role as the rate-limiting factor in glutathione synthesis .
Vasoconstriction has often been considered as a factor contributing to the pathogenesis of CIN. By stabilizing NO, NAC may have a vasodilatory effect in certain situations . In addition, NAC’s sulfhydryl group may inhibit angiotensin-converting enzyme, reducing the production of the vasoconstrictor angiotensin II .
The mechanism by which theophylline induces diuresis is unknown. Theophylline is a nonspecific phosphodiesterase inhibitor at high concentrations and a nonspecific adenosine receptor antagonist at lower concentrations. Theophylline could potentially induce renoprotective or diuretic effects through either of these mechanisms .
Phosphodiesterase inhibition causes increased accumulation of cyclic adenosine monophosphate (cAMP) by inhibiting hydrolysis of cAMP to AMP and ultimately adenosine. If phosphodiesterase inhibition were important to theophylline’s diuretic effects, then increased cAMP in the kidney and the subsequently increased cAMP excretion in the urine would be observed .
A particular strength of our study was our analysis of two separate outcome measures, both showing a benefit from NAC and theophylline administration. Our use of a second outcome measure was particularly important given the varying definitions of CIN used in the studies. Some studies reported CIN as a rise in creatinine of 0.5 mg/dl, such as the study carried out by Huper and colleagues, whereas others reported CIN as a 25% increase in serum creatinine, as in the study carried out by Durham . Differing definitions of CIN make a comparison between studies more difficult. Having a change in creatinine as a second outcome measure allowed us to validate the findings of our first outcome measure and provided an outcome measure that may be easier to interpret for most clinicians.
However, one limitation of our study is the focus on the short-term changes in creatinine rather than on longer-term outcomes such as the length of hospitalization, and the rate of progression to end-stage renal disease after discharge. Only a few studies reported information on the length of hospitalization, such as the study carried out by Huper and colleagues, and none of the studies reported the effect of NAC or theophylline on overall costs or outcomes after discharge.
| Conclusion|| |
Our analysis suggests that administration of intravenous NAC or intravenous theophylline around the time of contrast administration prevents renal injury in equal efficacy compared with patients receiving no additional drugs at the time of contrast administration as regards incidence of nephropathy and incidence of dialysis among study patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]