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Re: Lack of renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure un
- Anne H Ristikankare, T.Kuitunen, A.Kuitunen, L.Uotila, A.Vento, R.Suojaranta-Ylinen, M.Salmenperä, R.Pöyhiä (20 April 2007)
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Lack of renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure underg
- Patrick G Morgan, Maria Georghiou, Fidelma Flynn, Sian Jaggar (13 March 2007)
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Lack of renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure underg
- Anne H. Ristikankare, T.Kuitunen, A.Kuitunen, L.Uotila, A.Vento, R.Suojaranta-Ylinen, M.Salmenperä, R.Pöyhiä (27 November 2006)
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A premature conclusion
- Yahya Shehabi, University New South Wales (27 October 2006)
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Anne H Ristikankare , T.Kuitunen, A.Kuitunen, L.Uotila, A.Vento, R.Suojaranta-Ylinen, M.Salmenperä, R.Pöyhiä
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A response to the letter by Patrick G.Morgan Lack on renoprotective effect of i.v. N-acetylcysteine in patients with chronic renal failure undergoing cardiac surgery A.Ristikankare, T.Kuitunen, A.Kuitunen, L.Uotila, A.Vento, R.Suojaranta-Ylinen, M.Salmenperä, R.Pöyhiä We thank Dr. Morgan and his colleagues for their interests in our paper. They brought up some interesting points, which we would like to comment briefly. In 2000 Tepel and co- workers published very promising results of NAC as a renoprotective drug in radio contrast induced renal failure1. Thereafter a number of new clinical trials about the use of NAC for renal protection has been published. Unfortunately in these further studies NAC has not proved to protect kidneys in that extent neither in contrast induced nephropathy nor cardiac surgery 2. In our study we included patients who had plasma creatinine above normal limits which are above 90 µmol/l for women and 100 µmol/l for men in our hospital. At the department of clinical chemistry in our hospital, serum creatinine is analyzed using an enzyme based method with NORIP scaling, which is widely used in Scandinavian countries. It gives 10-15% lower values and it is considered more specific than Jaffe-method. We also calculated estimated GFR before operation and in each time point of renal evaluation but did not choose to publish it in accordance with our referee in this article. At the time of inclusion of the patients their GFR was 58 ± 18 ml min-1 and after the induction of anaesthesia it was 68 ml min-1 in both groups. In the resent study, where GFR was found to be a better marker than creatinine to assess patients at risk of postoperative renal failure, the preoperative renal insufficiency was defined as 60 ml min-1 or less3. It is true that the patients had rather mild but also definitive preoperative renal failure. Furthermore, in both groups the patients suffered renal injury after the operation. We agree that the number of the patients in the study could have been greater. None of the patients had NSAIDs during the study or one day prior of the operation. In general NSAIDs are rarely used in this group of patients in our hospital. We were also surprised of the great volumes of fluid that was needed to maintain adequate hydration according to our protocol. The fluid therapy might have been excessive with some patients because to avoid hypovolemia we kept the pulmonary wedge pressure carefully between 10-14 mmHg during the 24 hours of study period. We believe that patients in the NAC-group received more fluids than the control-group do the vasodilatory effect of NAC. None of the patients were haemofiltrated during the CPB. If dialysis is needed after cardiac surgery ICU doctors and consultant nephrologists initiates continuous renal replacement therapy (CRRT) or intermittent haemodialysis (IHD) depending of the haemodynamic status of the patient. In our study we recorded the length of the stay in ICU but we did not control it in anyway. The longer ICU time in NAC-group might be a result of the greater fluid input but it was not determined in our study. Three patients who died had a multiorgan failure do the complications of the surgery. In the recent clinical study with patients undergoing abdominal aortic reconstruction NAC had anticoagulant and platelet-inhibiting properties, which should be considered if it is administered to patients with increasing bleeding risk. 1 Tepel M, van der Giet M, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343: 180-4 2 Burns KEA, Chu MWA, Novick RJ, et al. Perioperative N- acetylcysteine to prevent renal dysfunction in high-risk patients undergoing cabg surgery: a randomized controlled trial. JAMA 2005; 294: 342-50 3 Wijeysundera DN, Karkouti K, Beattie WS, et al. Improving the identification of patients at risk of postoperative renal failure after cardiac surgery. Anesthesiology 2006; 104: 65-72 4 Niemi TT, Munsterhjelm E, Poyhia R, et al. The effect of N- acetylcysteine on blood coagulation and platelet function in patients undergoing open repair of abdominal aortic aneurysm. Blood Coagul Fibrinolysis 2006; 17: 29-34 Conflict of Interest:None declared |
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Patrick G Morgan Royal Brompton Hospital, Maria Georghiou, Fidelma Flynn, Sian Jaggar
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Editor We read with interest the paper by Risikankare et al regarding the lack of renoprotective effect of N-acetylcysteine (NAC) in patients with pre-existing renal failure undergoing cardiac surgery. We feel that several aspects of this study require further comment. Firstly a recent meta-analysis of the use of NAC to prevent contrast induced nephropathy in patients with renal impairment was inconclusive(1), therefore reducing the evidence base for the rational use of NAC. We would also wish to question the inclusion of patients with plasma creatinine greater than 100 µmol litre-1, which is below the upper limit of normal for many laboratory results in the UK. Therefore it seems likely this study may have included patients with normal renal function. We suggest it would have been more appropriate to identify patients with established renal impairment using a more specific parameter than plasma creatinine, such as Glomerular Filtration Rate or estimated Creatinine clearance(2). The power analysis was aimed at detecting a difference in N-acetyl-b- D-glucosaminidase (NAG) and not for any of the other outcome measures. Having powered for 40 patients per group, not reaching this due to the exclusion of three patients reduced the reliability of the results. Post-operatively the patients in the NAC arm bled significantly more than the placebo group we are unclear whether the results were skewed due to large losses from a small number of patients, or a small but significant increase in all. In any event we wonder about the effect of Non- steroidal anti-inflammatory drugs (NSAIDs) In our practice NSAIDs are avoided as soon as a diagnosis of renal impairment is made. They would certainly not be continued up until the day preceeding surgery, rather being managed in the same way as aspirin. The published fluid balance shows very large intravenous fluid administration in the first 24 hours following surgery. Clearly fluid load requirements are different between Coronary Artery Bypass Graft (CABG) and valvular surgery and the inclusion of just CABG patients would have been preferable. There are a number of questions pertaining to the study that we feel are unclear. Firstly whether haemofiltration was employed during Cardiopulmonary Bypass for these patients with plasma creatinine greater than 100 µmol litre-1. It was unclear whether the trend towards longer Intensive Care Unit (ITU) stays in the NAC arm was due to physiological or resource reasons. We are interested in what the criteria for commencing renal replacement therapy were and regarding the patients who died what the cause of death was and whether it was related to renal impairment? We feel that as this paper was powered for the efficacy of NAC and since there was more bleeding in the NAC arm, questions regarding the safety of NAC have surfaced due to its inherent anticoagulant properties and thus the need for larger fluid requirements. 1. Zagler A, Azadpour M, Mercado C, Hennekens C H. N-Acetylcysteine and contrast induced nephropathy: a meta-analysis of thirteen randomised trials. American Heart Journal. 2006; 151 140-145. 2. Wang F, Dupuis JY, Nathan H, Williams K. An analysis of the association between preoperative renal dysfunction and outcome in cardiac surgery: estimated creatinine clearance or plasma creatinine level as measures of renal function. Chest. 2003; 124(5) 1852-62. Conflict of Interest:None declared |
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Anne H. Ristikankare , T.Kuitunen, A.Kuitunen, L.Uotila, A.Vento, R.Suojaranta-Ylinen, M.Salmenperä, R.Pöyhiä
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A.Ristikankare, T.Kuitunen, A.Kuitunen, L.Uotila, A.Vento, R.Suojaranta-Ylinen, M.Salmenperä, R.Pöyhiä We thank Dr. Shehabi for his interest in our paper. In his letter, Dr. Shehabi rises important issues but some misunderstandings need to be addressed. Firstly, the definition of renal dysfunction is a complex issue. As an inclusion criteria we used the elevated plasma creatinine value, which albeit affected by age and muscle mass, has still been proven to be a reliable estimate of renal dysfunction in cardiac surgery.(1) In addition and as stated in our paper, we included patients with mild preoperative renal dysfunction (mean creatinine > 127 mol l-1) because it has been shown to be an important predictor of poor outcome in patients undergoing cardiac surgery.(2) We calculated estimated GFR before operation and every time when plasma creatinine or serum cystatin C were measured. Before the induction of anaesthesia estimated GFR was 68 ml min-1 1.73m2 -1 in both groups. Secondly, the patients did not receive any intravenous fluid therapy before operation but the adequate haemodynamics and normovolemia were carefully monitored and kept throughout the study period. Indeed, maintaining normovolemia is the most important strategy in the perioperative care of patients with renal impairment.(3) Thirdly, Dr. Shebabi is concerned about the frequent use of vasoactive medications in our patients. We are not aware on which study Dr. Shebabi bases his argument that using such medications would not be usual medical practice in cardiac anaesthetic patients. Actually, there is not much reliable information how vasoactive medications are used during and after cardiac surgery nor is there valid scientific evidence which medications should be used. The selection of inotropes or vasopressors seems to be based much on variable clinical practice and history of using medications. According to a recent survey, epinephrine and PDE inhibitors are commonly used in cardiac surgical patients, which may be quite surprising for an intensivist but certainly not for an experienced cardiac anaesthetist. (4) The indications for the vasoactive medications in our study were clearly described in the method section of our paper and need not to be repeated. Fourthly, regarding the assessment of postoperative renal function, we wish to refer to the study by Kuitunen and co-workers.(1) In addition, we agree with the opinions of one of the referees of BJA who pointed out that estimated GRF is reliable only in steady state conditions and is not recommended to be used in situations such as our study. We also measured plasma cystatin C and urine N-acetyl beta-D-glucosaminidase, a sensitive marker of tubular dysfunction. Thus we believe that we have covered quite comprehensively both glomerular and tubular functions of kidney. Finally, there were no differences in the postoperative complications of the patients in the two groups. In conclusion, we think we have targeted a right population, patients with mild preoperative renal dysfunction who certainly are in risk to develop postoperative renal damage and assessed their renal function with adequate methods. In our study the renal function deteriorated after cardiac surgery similarly after N-acetylcysteine (NAC) and placebo. Our results agree with the previous study by Burns and co-workers.(5) On the basis of current evidence, NAC does not seem to work in the fight against postoperative renal deterioration. Would the role of NAC change as a preventive medication, needs to be shown in a randomized and controlled study. We look forward to see if Dr. Shebabis study will provide new evidence that would change the current concepts. References 1 Kuitunen A, Vento A, Suojaranta-Ylinen R, et al. Acute renal failure after cardiac surgery: evaluation of the RIFLE classification. Ann Thorac Surg 2006; 81: 542-6 2 Zakeri R, Freemantle N, Barnett V, et al. Relation between mild renal dysfunction and outcomes after coronary artery bypass grafting. Circulation 2005; 112: I270-5 3 Sear JW. Kidney dysfunction in the postoperative period. Br J Anaesth 2005; 95: 20-32 4 Kastrup M, Markewitz A, Spies C, et al. Current practice of hemodynamic monitoring and vasopressor and inotropic therapy in post- operative cardiac surgery patients in Germany: results from a postal survey. Acta Anaesthesiol Scand 2006 5 Burns KEA, Chu MWA, Novick RJ, et al. Perioperative N- acetylcysteine to prevent renal dysfunction in high-risk patients undergoing cabg surgery: a randomized controlled trial. JAMA 2005; 294: 342-50 Conflict of Interest:None declared |
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Yahya Shehabi, Director Intensive Care & Research Prince of Wales Hospital Sydney, University New South Wales
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The question of renal protection by N-acetylcysteine (NAC) is yet to be answered, most studies so far have been in a relatively small number of patients and have left many questions unanswered, in particular regarding the dose and timing of NAC administration. The study by Ristikankare A and colleagues addressed the question of dosage and timing using a relatively higher dose than any of the previous studies, and also NAC was given shortly before the planned insult. However, The authors have made some serious omissions and wrong assumptions to the extent that conclusions from this study are questionable. 1. The definition of mild to moderate renal failure included any patient with a serum creatinine greater than 100umol/l. Taking into account the high body mass index of patients included, the number of patients included with normal creatinine clearance or glomerular filtration rate GFR (greater than 50 ml/min) is unknown and therefore not all patients have renal impairment. 2. It is not clear what preoperative hydration patients in either groups received. 3. The study was supposed to compare NAC group with usual medical practice, the level of inotrope and vasopressors used in either group is disproportionate to the left ventricular ejection fraction (LVEF). Levels of LVEF of 45% are reasonable function and in most centre a nor- epinephrine infusion and milrinone infusion in almost every patients is not usual medical practice. 4. Assessment of post operative kidney function should have included creatinine clearance or an estimate of GFR. 5. There is a possible chance that the NAC group had higher post op complications than placebo for reasons unrelated to the NAC infusion and therefore had an unexpected unaccounted for negative effect on outcome of renal function. In conclusion, this study whilst used a high dose NAC immediately before bypass insult, has failed to include the appropriate eligible target group and therefore the conclusions are questionable. Conflict of Interest:No financial competing interest. However, I am the Principal Investigator of a similar study near completion. |
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