Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 7  |  Issue : 1  |  Page : 19-26

N-acetylcysteine for renal protection in patients with rheumatic heart disease undergoing valve replacement


Department of Anesthesia and Intensive care, Faculty of Medicine, Assiut University, Assiut, Egypt

Date of Submission08-Jan-2013
Date of Acceptance14-Feb-2013
Date of Web Publication26-Jun-2014

Correspondence Address:
Fatma A Abd El Aal
MD, Department of Anesthesia and Intensive Care, Faculty of Medicine, Assiut University, 71526 Assuit
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJCA.0000430356.13405.00

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  Abstract 

Objective

Acute kidney injury (AKI) after cardiac surgery is associated with increased morbidity and mortality. The aim of the study is to assess the effect of N-acetylcysteine (NAC) on postoperative AKI in patients with rheumatic heart disease undergoing valve replacement while excluding other risk factors (clinical trials gov identifier NCT01704482).

Patients and methods

In this prospective, randomized, placebo-controlled, double-blinded clinical trial, conducted in Assiut University Hospital, 60 patients with rheumatic valvular heart disease who underwent heart surgery were randomized to either group N (n=30) 24 h of high dose N-acetylcysteine infusion (300 mg/kg body weight in 5% glucose) or group C (n=30) equivalent volume of 5% glucose over the same period. The primary outcome was maximum change in creatinine from baseline within 5 days after surgery. The secondary outcome and other data collected were: operative time, bypass time, clamping time, intraoperative urine output, invasive mean arterial blood pressure (5 min after induction, before going on bypass, lowest on bypass and before discharge to ICU), colloids and crystalloids given at the first 24 h, blood products given in the first 48 h, furosemide for the first 48 h, urine output for the first 48 h post-operatively, duration of mechanical ventilation, length of ICU stay and hospital stay.

Results

Creatinine increased in both groups (32.26±29 μmol/l in group N vs. 39.97±29.38 μmol/l in group C, P=0.32) and peaked on postoperative day 3. Acute kidney injury occurred in 25 patients (9 patients in group N vs. 16 patients in group C; P=0.07). There was no difference in lengths of stay in the intensive care unit, hospital stay, and duration of mechanical ventilation. There were no significant differences between both groups as regard operative time, bypass time, clamping time, intraoperative urine output, invasive mean arterial blood pressure, colloids and crystalloids given at the first 24 h, blood products given in the first 48 h, furosemide for the first 48 h and urine output for the first 48 h post-operatively.

Conclusion

NAC was no more effective than placebo in decreasing acute renal dysfunction in patients with Rheumatic Heart disease undergoing valve replacement.

Keywords: N-acetylcysteine, renal, rheumatic heart


How to cite this article:
Abd El Aal FA, Abbas MS. N-acetylcysteine for renal protection in patients with rheumatic heart disease undergoing valve replacement. Egypt J Cardiothorac Anesth 2013;7:19-26

How to cite this URL:
Abd El Aal FA, Abbas MS. N-acetylcysteine for renal protection in patients with rheumatic heart disease undergoing valve replacement. Egypt J Cardiothorac Anesth [serial online] 2013 [cited 2020 Feb 26];7:19-26. Available from: http://www.ejca.eg.net/text.asp?2013/7/1/19/135458


  Introduction Top


Acute kidney injury (AKI) is a common and serious postoperative complication of cardiopulmonary bypass (CBP) and may affect 25–50% of patients 1. AKI carries significant costs 1 and is independently associated with increased morbidity and mortality 2. Even minimal increments in plasma creatinine levels are associated with an increase in mortality 3,4.

Multiple causes of CBP-associated acute renal dysfunction have been proposed, including ischemia–reperfusion, generation of reactive oxygen species, hemolysis, and activation of inflammatory pathways 5,6.

Oxidative stress can be attenuated by N-acetylcysteine (NAC), which directly scavenges reactive oxygen species and reduces oxidative stress during CPB 7. NAC protects from contrast-induced nephropathy, especially at high doses and in high-risk patients 8, possibly by reducing the oxidative stress generated on exposure to a radiocontrast 9.

Intravenous NAC administered in patients with different risk factors after surgery did not reduce AKI risk 10–13.

However, preoperative renal dysfunction, valvular surgery, redo surgery, belonging to NYHA class IV, a decreased left ventricular ejection fraction, or insulin-dependent diabetes mellitus are all different risk factors with different pathophysiologies, suggesting that preventive intervention may be required against each risk factor for a statistically significant reduction in the risk of AKI after cardiac surgery.

Aim of the work

We aimed to investigate the efficacy of NAC to attenuate acute renal dysfunction (defined as a postoperative increase in the serum creatinine concentration >25% from baseline during the first 5 postoperative days) in patients with rheumatic heart disease undergoing CBP for single valve replacement.


  Patients and methods Top


After approval by the local ethics committee of Assiut University and obtaining written informed consent from all patients, 60 adult patients undergoing elective open heart surgery for valve replacement were included. The patients were randomly allocated into two equal groups – group N (NAC group) (n=30) and group C (control group) (n=30) – to investigate the efficacy of NAC in attenuating acute renal dysfunction [defined by an increase in the serum creatinine level >0.5 mg/dl (44 μmol/l) or a 25% increase from baseline within the first 5 postoperative days] in patients with rheumatic heart disease undergoing CBP for single valve replacement.

Exclusion criteria

Patients with pre-existing renal impairment (preoperative plasma creatinine concentration >120 μmol/l), those who had undergone redo cardiac surgery, those who had type 2 diabetes and were on insulin therapy, those requiring emergency cardiac surgery, those who had chronic inflammatory disease and were on immunosuppressors, those who were on chronic moderate-to-high-dose corticosteroid therapy (≥10 mg/day prednisone or equivalent), and those who were 18 years of age or younger were excluded from the study.

All patients were premedicated with diazepam (5 mg) the morning of the operation. After placement of electrocardiographic leads and a pulse oximeter, a peripheral intravenous cannula was inserted. The left radial artery was cannulated with a 20-G indwelling catheter with the aid of local anesthesia to monitor arterial blood pressure invasively. A central venous catheter was also inserted into the internal jugular vein with the aid of local anesthesia.

Anesthesia was induced with propofol (2 mg/kg), cisatracurium (0.15 mg/kg), and fentanyl (5 μg/kg), intravenously. After intubation, anesthesia was maintained with inhalation of isoflurane, together with fentanyl (1 μg/kg/h) and cisatracurium (0.03 mg/kg) every 20 min. The lungs were mechanically ventilated with a mixture of oxygen and air. Mechanical ventilation was maintained until the start of the CPB. Standard hypothermic CBP (28–32πC) surgeries were performed.

Immediately after the induction of anesthesia, before the first surgical incision, group N was administered NAC at an intravenous dose of 150 mg/kg in 250 ml of 5% glucose over 15 min, followed by a continuous intravenous infusion of 50 mg/kg in 250 ml of 5% glucose over 4 h and then 100 mg/kg in 1000 ml of 5% glucose over 20 h (total dose=300 mg/kg body weight over 24 h). Group C was administered an equivalent volume of 5% glucose over the same period.

Cardiopulmonary bypass technique

After heparin administration at a dose of 3–5 mg/kg, aortic and right heart cannulation was performed. CPB was established once the activated clotting time was greater than 450 s. CPB was instituted with a nonpulsatile heart–lung machine, with the blood flow maintained at 2–2.4 l/min/m2. The prime volume comprised mannitol, nonglucose-containing solutions, and heparin. The body temperature during bypass was maintained between 28 and 30πC. The cardioplegic solution was mixed with autologous blood obtained from the extracorporeal circuit.

Patient characteristics such as age, sex, weight, height, body surface area, and type of operation were recorded.

Preoperative variables including the heart rate, mean arterial blood pressure (before induction), central venous pressure, temperature, hemoglobin level, serum urea level, serum creatinine level, creatinine clearance (using Cockcroft–Gault equation) rate, and ejection fraction were recorded.

Data collection

Operative data including the operative time, bypass time, clamping time, intraoperative urine output, and invasive mean arterial blood pressure (5 min after induction, before going on bypass, the lowest reading during bypass, and before discharge to ICU) were recorded.

Intraoperative and postoperative interventions including administration of blood products for the first 48 h, furosemide for the first 48 h, and colloids and crystalloids for the first 24 h were recorded.

Postoperative levels of serum creatinine were derived from routine measurements in the ICU or in the normal ward of care for the first 5 postoperative days.

Urine output for the first postoperative 48 h, the duration of mechanical ventilation, and the length of ICU stay and hospital stay were also recorded.

Discontinuation of mechanical ventilation and discharge protocols

While in the ICU, the patients were routinely kept sedated with a continuous infusion of fentanyl (1 μg/kg/h) and propofol (0.5 mg/kg/h).

The patients were extubated when they fulfilled the criteria of extubation. Thereafter, they were transferred out of the ICU when the following criteria were met: an SpO2 greater than 90% at an FiO2 less than 0.5 through a facemask, adequate cardiovascular stability with no hemodynamically significant arrhythmia, chest tube drainage less than 50 ml/h, urine output greater than 0.5 ml/kg/h, no intravenous inotropic or vasopressor therapy, and no seizure activity.

Statistical analysis and power of the study

All continuous variables are expressed as mean±SD or median (interquartile range), and discrete variables are presented as frequencies and percentages. Analysis of categorical variables was performed using the &khgr;2-test. Analysis of continuous variables was performed using the independent samples t-test. A P value of 0.05 or less was considered statistically significant. Statistical analyses were performed using the SPSS package, version 16.0 statistical software (SPSS Inc., South Wacker Drive, Chicago, Illinois, USA). Using data available from other studies, we expected a mean increase in serum creatinine concentrations from baseline to peak of 50 μmol/l in the control group, with a SD of 40 μmol/l. Given these changes, we calculated that 30 patients per group were needed to have an 80% power of detecting a 30 μmol/l difference (minimally clinically important difference) between the control and the intervention group at an α of 0.05.


  Results Top


Patient characteristics

There were no significant differences observed between the studied groups with regard to patient characteristics (age, sex, weight, height, body surface area, and type of operation performed) [Table 1].
Table 1: Patient characteristics in the two studied groups

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Preoperative variables

There were no significant differences observed between the studied groups with regard to preoperative heart rates, mean arterial blood pressures, central venous pressures, temperatures, hemoglobin levels, serum urea levels, serum creatinine levels, creatinine clearance rates, and ejection fraction%.

The mean values of preoperative variables of patients in the studied groups were all within the normal ranges [Table 2].
Table 2: Preoperative variables in the two studied groups

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Intraoperative variables

The mean bypass duration for group N was 97.00±9.35 and was 94.50±9.02 for group C. Statistical analysis showed no significant differences between both mean values [Figure 1].
Figure 1: Box plot (10th, 25th, 50th, 75th, and 90th) percentile showing the bypass duration for the studied groups. o represent outliers (those with more or less than 2/3 times of upper or lower quartile). The number represent patient's number.

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The duration of aorta cross-clamping and operative time for the studied groups also varied insignificantly [Figure 2] and [Figure 3].
Figure 2: Box plot (10th, 25th, 50th, 75th, and 90th) percentile showing the clamping duration for the studied groups. o represent outliers (those with more or less than 2/3 times of upper or lower quartile). The number represent patient's number.

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Figure 3: Box plot (10th, 25th, 50th, 75th, and 90th) percentile showing the clamping duration for the studied groups. o represent outliers (those with more or less than 2/3 times of upper or lower quartile). The number represent patient's number.

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The independent t-test was used to test the difference between the groups for mean arterial blood pressure, as measured before induction, 5 min after induction, before bypass, at the time of the lowest value during bypass, and at discharge to the ICU [Figure 4].
Figure 4: Mean arterial blood pressure (MAP) changes over time in the studied groups.

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In group N, the mean blood pressure measured invasively was 85.43±4.66 before induction, with a minimum value of 62.03±3.40, which was lowest on bypass.

In group C, the mean blood pressure measured invasively was 83.40±3.55 before induction, with a minimum value of 59.27±11.36, which was lowest on bypass.

There were no significant differences in MAP between the two groups during the study at a given time point [Table 3].
Table 3: Intraoperative variables

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Intraoperative and postoperative intervention

As regards blood product administration to patients, 37 of the 60 patients in our study received fresh blood during the first 48 h (about 62% of all patients in the study): 17 in group N and 20 in group C. The &khgr;2-test revealed no significant difference between the two groups.

Moreover, 28 of the 60 patients in our study received fresh frozen plasma (about 47% of all patients in the study): 16 in group N and 12 in group C. Again, this was statistically insignificant.

The total amount of furosemide administered during 0–24 h was 54.67±13.83 mg for group N and 60.67±16.17 mg for group C, and there was no significant difference between the values of the two groups.

The total amount of furosemide administered during 24–48 h was 9.33±17.21 mg for group N and 6.67±15.16 mg for group C, and again there was no significant difference between the two groups.

The total amount of colloids and crystalloids administered during 0–24 h was 5117±1150 ml for group N and 4883±1298 ml for group C, and there was no significant difference detected between the two groups [Table 4].
Table 4: Intraoperative and postoperative intervention

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Postoperative outcomes

In group N, the mean absolute increase in the serum creatinine concentration was 32.26±29.93 μmol/l, and in group C it was 39.97±29.38 μmol/l. The difference between the two groups in terms of an absolute change in serum creatinine concentrations from baseline to peak during the first 5 postoperative days was statistically insignificant (P=0.32). The perioperative serum creatinine concentrations are shown in [Figure 5].
Figure 5: Mean serum creatinine levels at baseline and during the first 5 postoperative days for the studied groups

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There was no statistically significant differences between the two groups in terms of the number of patients with more than 25% increase in serum creatinine concentrations from baseline during the first 5 postoperative days (nine patients of group N and 16 patients of group C group; P=0.07).

There was no statistically significant differences between the two groups in terms of the number of patients with more than 44 μmol/l increase in serum creatinine concentrations above baseline during the first 5 postoperative days (six patients in group N and 10 patients in group C; P=0.24).

The urine outputs during 0–24 h for group N and group C were 3541±467 and 3435±480 ml, respectively. The urine outputs during 24–48 h for group N and group C were 2491±271 and 2455±205 ml, respectively. No statistically significant difference between the mean values of the two groups could be detected [Figure 6] and [Figure 7].
Figure 6: Box plot (10th, 25th, 50th, 75th, and 90th) percentile showing the urine output during 0–24 h for the studied groups. o and * represent outliers (those with more or less than 2/3 times of upper or lower quartile). The number represent patient's number.

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Figure 7: Box plot (10th, 25th, 50th, 75th, and 90th) percentile showing the urine output during 24–48 h for the studied groups.

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As regards the duration of ventilation, it was 4.90±1.79 h for group N and 5.63±4.08 h for group C. As for the duration of ICU stay, it was 3.00±0.83 days for group N and 3.47±1.14 days for group C. As regards the hospital stay, it was 9.00±0.83 days for group N and 9.57±1.45 days for group C. There was no statistically significant differences between the two groups as regards the mean values of the three above-mentioned outcome variables [Table 5].
Table 5: Postoperative outcomes

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  Discussion Top


Acute kidney injury after cardiac surgery is associated with serious sequelae including a higher risk of infection, prolonged hospitalization, increased costs, and a higher risk of short-term and long-term mortality 14,15. In particular, patients who require postoperative dialysis have an exceedingly high short-term mortality risk 15. Those who survive to hospital discharge often remain dialysis-dependent and have a 10% survival rate at 1 year 16.

However, at present, there are no therapies proven to reduce the incidence of postoperative AKI. In this regard, studies examining diuretics, vasoactive agents, steroids, clonidine, and diltiazem have not shown a conclusive benefit 14.

The pathogenesis of AKI after cardiac surgery involves an intricate interaction between the susceptible host and preoperative, intraoperative, and postoperative factors. Ischemia–reperfusion injury, oxidative stress, and systemic inflammation are factors considered to play a significant role in the development of AKI after cardiac surgery 10, 14, 17. NAC has the potential to be useful in this setting because it reduces the production of oxygen free radicals 7,18 and proinflammatory cytokines 19 and has been shown to reduce the degree of ischemic AKI in animal studies 20,21.

In a recent meta-analysis, Sisillo and Marenzi 22 concluded that data on the efficacy of NAC are conflicting. Therefore, the use of NAC for prevention of postoperative AKI in cardiac surgery patients cannot be considered conclusive and needs further investigation.

In the present study, 60 patients with rheumatic heart disease undergoing elective open heart surgery for single valve replacement were investigated for the efficacy of NAC to attenuate acute renal dysfunction (defined as a postoperative increase in the serum creatinine concentration more than 25% from baseline during the first 5 postoperative days).

The results of our study revealed that there was no significant difference between the studied groups as regard patient characteristics and preoperative variables. Furthermore, we found no difference in terms of an absolute change in serum creatinine levels from baseline to peak during the first 5 postoperative days; in addition, there were no changes in other study outcomes such as the length of ICU stay, hospital stay, and duration of mechanical ventilation.

High-dose NAC is routinely used in the clinical treatment of acetaminophen overdose-induced acute liver failure 23 and has also been administered for experimental use in the treatment of acute liver failure in critically ill patients 24.

In two previous studies, NAC was used in the prevention of CPB-related acute renal dysfunction, achieving conflicting results. In one study, moderate-dose intravenous NAC was found to have beneficial effects on renal function 25; however, the authors determined serum creatinine levels as an indicator for renal function before surgery and at 1 day after surgery only, although an increase in serum creatinine concentrations can also be detected later on. More importantly, in a placebo-controlled RCT of 295 patients, no effect of NAC on renal function in high-risk cardiac surgery patients was detected. In this setting, however, low-dose intravenous NAC, at a dose routinely administered for the prevention of contrast-induced nephropathy (4×600 mg in 24 h), was used without weight adjustment and preoperative intravenous loading, thus minimizing the chance of success and increasing the chance of type II error due to underdosing 10. Accordingly, in our study, the NAC dose was 10 times greater, was adjusted for body weight, and was applied with the use of preoperative intravenous loading.

Prasad et al. 26 studied the efficacy of NAC in preventing postoperative renal dysfunction after off-pump coronary artery bypass graft. There was no significant difference in the incidence of renal dysfunction between patients in the NAC group (8.6%) and those in the control group (11.4%) (P=1.00). They concluded that NAC does not have any beneficial effect on renal function in high-risk patients undergoing off pump coronary artery bypass.

Haase et al. 11 studied 60 cardiac surgery patients at high risk with more than one criterion for risk (creatinine >1.36 mg/dl, age >70 years, NYHA class III/IV or ejection fraction <50%, diabetes mellitus, and valvular or complex or redo surgery). They studied the absolute change in serum creatinine concentrations from baseline to peak values during the first 5 postoperative days and concluded that high-dose NAC was no more effective than placebo in attenuating CBP-related acute renal failure in high-risk cardiac surgery patients.

Ristikankare et al. 12 studied 80 patients with mild-to-moderate renal failure undergoing elective heart surgery with a CBP. All patients received either an intravenous NAC (n=38) or a placebo (n=39) at induction of anesthesia and then for up to 20 h. In addition, they concluded that prophylactic treatment with intravenous NAC had no renoprotective effect in patients with pre-existing renal failure undergoing cardiac surgery.

Another study by Adabag et al. 13 evaluated 102 patients with chronic kidney disease who underwent heart surgery. The patients were randomized either to receive NAC (n=50) (600 mg oral twice daily) or placebo (n=52) for a total of 14 doses (three preoperative). The primary outcome was a maximum change in creatinine concentrations from baseline within 7 days after surgery. The secondary outcome was AKI (i.e. >0.5 mg/dl or ≥25% increase in creatinine concentrations from baseline). Again, more than one risk factor was included in the inclusion criteria, and they concluded that prophylactic perioperative NAC administration does not prevent AKI after cardiac surgery.

To date, no RCT has been carried out to selectively investigate the effect of high-dose NAC on the renal outcome in cardiac surgery patients undergoing CPB with a single risk factor for AKI, which was valve replacement in our study.

The strengths of this study include its randomized placebo-controlled design and inclusion of at risk patients who were likely to develop AKI. Indeed, 41% of our study patients developed AKI. Another notable strength in our study was that the NAC dose was high, was adjusted for body weight, and was applied with the use of preoperative intravenous loading, thus increasing the chance of success and minimizing the chance of type II error due to underdosing.

In contrast, some limitations of this study are also noteworthy. First, in this investigation, the diagnosis of AKI was primarily based on an increase in serum creatinine concentrations, which may not accurately reflect the GFR during a nonsteady state of AKI because of tubular secretion and resorption 27.

Reports suggest that newer markers such as cystatin C may be superior to creatinine in estimating the GFR 28. However, serum creatinine is clinically relevant, and even a minimal increase in levels of serum creatinine, and the dimension of this increase, is associated with increased morbidity and mortality 3,4. Moreover, it was the outcome measure used in the largest RCT on the prevention of acute renal dysfunction in cardiac surgery to date 10 and thus was also used in the present study.

There are several possible explanations why a treatment effect was not observed:

First, NAC may simply not be effective in preserving renal function in cardiac surgery patients exposed to CPB. Adding to this, in a previous study, it was observed that high-dose NAC was also ineffective in preventing renal injury in abdominal aortic surgery 29.

Second, although the dose chosen was well above that used in a previous RCT 10 and for the prevention of contrast-induced nephropathy 8, 30, the optimal dose of NAC to reduce CPB-induced oxidative stress is unknown. It may be that even our high dose was insufficient to reduce CPB-induced oxidative stress and renal injury.

Third, we used a loading dose of NAC (50% of the total dose) at the induction of anesthesia before the commencement of CPB and continued a high-dose infusion for 24 h. Theoretically, such high-dose NAC might have been excessive and might have paradoxically diminished the level of radical oxygen species, thus attenuating their potentially positive role in the regulation of intracellular signaling 31. However, we cannot confirm or negate this possibility, as we did not perform the corresponding measurements.

Fourth, although we considered the studied infusion regimen theoretically optimal, it may be that earlier administration is required for NAC to develop a complete cellular protective effect. In addition, the 24-h duration of NAC infusion may have been too brief for any ongoing potential renal protection. However, there is evidence that markers of ischemic renal injury become detectable within 2 h after commencement of CPB 32 and remain high for up to 24 h. This renders a 24-h treatment schedule a reasonable initial approach.

Finally, NAC might have effectively prevented CPB-induced oxidative injury but failed to protect the kidney because it did not counteract other, perhaps more important, postoperative mechanisms of renal injury.

In conclusion, NAC was no more effective than placebo in decreasing acute renal dysfunction in patients with rheumatic heart disease undergoing valve replacement. Other renal protection strategies in this setting should be investigated.[32]

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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Abstract
Introduction
Patients and methods
Results
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Introduction
Patients and methods
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