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Prolonged Frusemide Use and Strong Ion Difference
- Awori J Hayanga (28 July 2006)
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Strong ion difference in relation to frusemide use
- Kwok M HO (29 July 2006)
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Equipose on whether frusemide can improve outcome in acute renal failure
- Sean M Bagshaw, Anthony Delaney, and Rinaldo Bellomo (2 August 2006)
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Use of frusemide in acute renal failure
- Kwok M Ho (3 August 2006)
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Frusemide in Acute Renal Failure
- Saul Blecker, Nirav R. Shah (15 September 2006)
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Frusemide to prevent or treat acute renal failure
- Marlies Ostermann, Rene Chang, Consultant Transplant Surgeon, St George's Hospital, London SW17 0QT (9 October 2006)
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Awori J Hayanga, Critical Care / Surgery Fellow University of Michigan Medical Center
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Meta analysis is considered the highest order of evidence and the definitive source of conclusive data. Ho and Sheridan [1] failed to report on a more practical and common side effect of prolonged intravenous frusemide use, namely the acid –base abnormality that was previously considered under a Henderson-Hasselbach understanding as a “contraction alkalosis.” This alkalosis is maintained by volume contraction, decreased glomerular filtration rate and hypokalemia and can be corrected by the use of a carbonic anhydrase inhibitor.[2] This alkalosis has, however, more recently been elucidated by the Strong Ion Difference theories and the Stewart Model. [3,4] A preoccupation with the lesser observed and even lesser described side effect of ototoxicity appears to have diverted the author’s attention from what would have been a more practical and clinically relevant discussion about this side effect that would have been of greater clinical value not just within Critical Care but clinical practice at large. REFERENCES 1 Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ. 2006 Jul 21; [Epub ahead of print] 2 Gattinoni L, Carlesso E, Cadringher P, Caironi P. Strong ion difference in urine: new perspectives in acid-base assessment. Crit Care. 2006 Apr 7;10(2):137 [Epub ahead of print] 3 Derksen R, Scheffer GJ, van der Hoeven JG. Quantitative acid- base physiology using the Stewart model. Does it improve our understanding of what is really wrong?Eur J Intern Med. 2006 Aug;17(5):330-3 Competing interests: None declared |
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Kwok M HO, ICU Consultant Intensive Care Unit, Royal Perth Hospital, Perth WA 6000, Australia
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Thank you for the question raised by Dr. Hayanga regarding the possibility of contraction alkalosis caused by prolonged frusemide infusion. First, acid base status was seldom reported in many trials in which frusemide was evaluated. It was impossible to pool results that were not reported in individual clinical trials together in a meta-analysis. Second, biochemical complications such as alkalosis or hypokalaemia induced by frusemide, either by a bolus injection or by a prolonged infusion, are not patient orientated outcomes. They are amendable to correction by avoiding hypovolaemia or by replacing the potassium deficiency, respectively. Furthermore, for the trials that evaluated frusemide as a preventive agent in patients at risk of acute renal failure, hypovolaemia was prevented by infusing intravenous fluid and there was no significant difference in the changes of the total body weight before and after treatment with either the placebo and frusemide. And as such, contraction alkalosis was unlikely to be a significant biochemical complication in these patients. On the other hand, ototoxicity is a patient orientated clinical outcome and the associated symptoms can be very disturbing to our patients, especially if they are irreversible. Finally, there was no signficant improvement in the proportion of patients with persistent oliguria in patients who already had acute renal failure as shown by our meta-analysis. Therefore, it would be unlikely that frusemide infusion in the pooled studies could induce significant alkalosis as the urine output did not increase significantly. Contraction alkalosis would not have happened after the use of frusemide if hypovolaemia was not induced in these patients. Competing interests: None declared |
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Sean M Bagshaw, Intensivist Austin Hospital, Studley Road, Heidelberg, Victoria, 3084, Australia, Anthony Delaney, and Rinaldo Bellomo
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Dear Editors: We read with interest the meta-analysis by Ho et al regarding the use of frusemide in the prevention or treatment of acute renal failure.1 We would like to raise several concerns we have with their meta-analysis. First, the reporting of a pooled analysis of trials that use frusemide both for the prevention and for the treatment of acute renal failure may have the consequence of generating confusion and lead to erroneous conclusions. Second, the authors have failed to adequately acknowledge the limitations of the included trials. These trials inconsistently report both on primary outcomes and adverse effects. Likewise, all patients in two trials and the majority in another were already receiving renal replacement therapy at inclusion, thus making pooled estimates on this outcome invalid.2-4 Furthermore, these trials are generally small and of poor overall quality. Lastly, most of these trials were published several decades ago.2 4 5 The approach to, and technical capabilities for, management of acute renal failure have evolved. Third, the authors failed to specify a priori criteria for trial inclusion. As a result, the trial by Brown et al 5 has been included in their pooled analysis. This trial is a comparison of two frusemide regimens rather than with a placebo control. They have duplicated the patients allocated to control in a study by Cantarovich et al for the assessment of hospital mortality.2 Both of these will unduly influence the event rates and summary effect estimates. Finally, when assessing need for renal replacement therapy or the proportion of patients remaining oliguric, the authors have failed to account for or consider the observed heterogeneity across studies. From these findings, we can only conclude that it is not possible to draw any strong conclusions and that a more cautious interpretation is warranted, in particular for those trials examining whether treatment with frusemide impacts outcome. These discrepant findings taken with those from larger observational studies, suggest there exists a genuine equipoise on the efficacy of frusemide.6 7 Thus, a large and suitably power multi-centre randomized controlled trial is needed to definitively resolve the question of the role of frusemide in the management of acute renal failure. Such a trial should ideally incorporate clinically relevant and patient-centered outcomes as well as important secondary outcomes addressing issues of harm, physiologic effects (i.e. urine output) and dose-response. Sean M Bagshaw, MD, MSc Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia Rinaldo Bellomo, MD Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, Australia Anthony Delaney, MBBS, MSc Department of Intensive Care, Royal North Shore Hospital, St. Leonards, New South Wales, Australia References: 1. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ 2006. 2. Cantarovich F, Fernandez JC, Locatelli A, Perez Loredo J. Frusemide in high doses in the treatment of acute renal failure. Postgraduate Medical Journal 1971;47:Suppl:13-7. 3. Cantarovich F, Rangoonwala B, Lorenz H, Verho M, Esnault VL. High- dose furosemide for established ARF: a prospective, randomized, double- blind, placebo-controlled, multicenter trial. Am J Kidney Dis 2004;44(3):402-9. 4. Kleinknecht D, Ganeval D, Gonzalez-Duque LA, Fermanian J. Furosemide in acute oliguric renal failure. A controlled trial. Nephron 1976;17(1):51-8. 5. Brown CB, Ogg CS, Cameron JS. High dose frusemide in acute renal failure: a controlled trial. Clinical Nephrology 1981;15(2):90-6. 6. Mehta RL, Pascual MT, Soroko S, Chertow GM, Group PS. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002;288(20):2547-53. 7. Uchino S, Doig GS, Bellomo R, Morimatsu H, Morgera S, Schetz M, et al. Diuretics and mortality in acute renal failure. Crit Care Med 2004;32(8):1669-77. Competing interests: None declared |
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Kwok M Ho, ICU Consultant ICU, Royal Perth Hospital, Perth, WA 6000
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Thank you for their interest in our meta-analysis and the questions raised by Drs. Bagshaw, Delaney and Bellomo. First, the trials that evaluated frusemide in the prevention or treatment of acute renal failure were stratified in the meta-analysis with the results separately reported in the forest plots. Both prevention and treatment trials were considered in this meta-analysis because there is experimental evidence to support the use of frusemide before acute renal insult occurs. The interaction between the results of the two strata of trials (prevention or treatment) was tested statistically and the results were not significantly different. Second, contrary to their interpretation of the meta-analysis, we have acknowledged the limitations very clearly in the method, result, and discussion section of the meta-analysis. We specified a priori criteria for trial inclusion in this meta-analysis and as such, we had included a study of single dose of frusemide compared with prolonged continuous infusion (as stated on line 8 in the method section) in the initial analysis. However, this study was excluded in the sensitivity analysis and this did not change the magnitude and direction of the results. Heterogeneity was observed in all outcomes except hospital mortality and ototoxicity (as stated on the first line of the third paragraph in the result section) and also the I2 values (which signify the degree of inconsistency) were reported in the results. Furthermore, we also made it very clear that the sample size of pooled studies (n=204) in this meta- analysis might still be too small to exclude a small protective effect (relative risk <30%) of frusemide on the risk of renal replacement therapy. This point was discussed when the limitations of the meta- analysis were discussed in the discussion section of the paper. Meta- analyses are prone to bias. A separate sensitivity analysis that included higher quality studies with adequate allocation concealment could not demonstrate beneficial effects of frusemide in the setting of acute renal failure. Third, frusemide had been evaluated to prevent acute renal failure and treatment of early phase and also in established phase of acute renal failure in the included studies. Frusemide has been shown to be useful in preventing renal tubular injuries in isolated perfused kidney. The limited data available in the literature, however, do not suggest frusemide is more useful in a specific phase of acute renal failure. Fourth, it might be argued that a correction should be made to the overall significance level and confidence interval to account for the pairwise comparisons between the three treatment arms in one study. Use of a Bonferroni correction would result in widened confidence intervals and a rejection of the null hypothesis at smaller p values. In the present study, which used a nominal 5% level with Bonferroni correction, a test of the relative risk being different from 1 would be regarded as significant only if p<0·017 (ie, 0·05 divided by 3). Based on this method, the significance of all p-values would remain the same for the outcomes that included this study. Finally, we agree with Dr. Bagshaw, Delaney, and Bellomo that a large randomised controlled trial is needed to confirm the results of our meta- analysis. Until we have the results of a large randomised controlled trial, clinicians should be cautious when high doses of frusemide (1 to 3.4g per day) are used to treat acute renal failure. Competing interests: None declared |
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Saul Blecker, Physician New York University School of Medicine, New York, NY 10016, Nirav R. Shah
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Acute renal failure in the hospital is associated with a high rate of mortality. As oliguric renal failure is considered a poor prognostic sign, many clinicians administer diuretics to increase urine output despite a lack of evidence demonstrating true benefit.(1) In their recent meta- analysis, Ho and Sheridan conclude that frusemide does not have significant benefit in prevention or treatment of acute renal failure and may lead to ototoxicity. (2) These results are based on a number of small randomized control trials and are in agreement with a larger observational study which found that diuretics may cause harm. (1) These conclusions also echo a recent meta-analysis on another unproven pharmacotherapy for acute renal failure: low dose dopamine. In that study, Friedrich et al. showed that low dose dopamine increases urine output but has no effect on overall renal function or mortality.(3) The message appears to be that while both frusemide and dopamine may increase urine output, neither confers clinical benefit. Although diuretics may not provide renal protection or improved survival, experts have recommended such treatment for fluid management in oliguric acute tubular necrosis (4) with a presumed goal of shorter time to discharge. Ho and Sheridan conclude that frusemide actually increases hospital stay, although this data was based on only two studies, both on prevention rather than treatment of renal failure. We believe that this conclusion requires further study in studies of treatment before it is substantiated by data. Finally, we have some concern regarding statistical heterogeneity in the meta-analysis. The authors report significant heterogeneity for outcomes other than in-hospital mortality and ototoxicity. However, they report I-squared of 0% both for the number of dialysis sessions required and for the length of hospital stay. More importantly, the proportion of patients requiring renal replacement therapy – one of the primary outcomes measured – and proportion of patients who remain oliguric had I-squared values of 64% and 91%, respectively, representing significant heterogeneity. The authors do not address possible causes of this heterogeneity and proceed with pooling of these potentially very different trials in meta-analysis. While we laud the author’s attempts at reporting as much data as possible, such differences should be explored further and interpreted with caution. (5) Saul Blecker, MD Nirav R. Shah, MD, MPH Department of Internal Medicine, New York University School of Medicine References (1) Mehta RL. Pascual MT. Soroko S. Chertow GM. PICARD Study Group. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA. 2002;288:2547-53. (2) Ho KM. Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ. 2006;333:420, doi:10.1136/bmj.38902.605347.7C (3) Friedrich JO. Adhikari N. Herridge MS. Beyene J. Meta-Analysis: Low-Dose dopamine increases urine output but does not prevent renal dysfunction or Death. Ann Inten Med. 2005; 142:510-524. (4) Rose, BD. Pathogenesis and prevention of postischemic acute tubular necrosis. In: UpToDate, Rose, BD (Ed), Waltham, MA, 2006. (5) Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5 [updated May 2005]. http://www.cochrane.org/resources/handbook/hbook.htm. Accessed 5th Sept 2006. Competing interests: None declared |
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Marlies Ostermann, Consultant in Nephrology and Critical Care Guy's & St Thomas' Hospital, London SE1 9RE, Rene Chang, Consultant Transplant Surgeon, St George's Hospital, London SW17 0QT
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Dear Editors, we read with interest the meta-analysis by Ho et al regarding the role of frusemide in the setting of acute renal failure.1 Although we do not disagree with the conclusion that frusemide does not cure or prevent acute renal failure, we have some concerns about how this conclusion was reached and the overall message it sends to medical practioners. Firstly, none of the studies used the same criteria for the definition of acute renal failure. As a result, patients with different degrees of renal failure were included, ranging from patients with a serum creatinine < 177 micromol/L to patients already on renal replacement therapy. Previous studies, including our own, have shown that outcome of acute renal failure clearly depends on how it is defined and the timing of its onset.2-4 Secondly, it is important to acknowledge that frusemide still has a role in the treatment of patients with acute renal failure who are fluid overloaded. In this situation, treatment with a diuretic will not cure acute renal failure and may also not avoid renal replacement therapy completely but it may induce diuresis, prevent life-threatening pulmonary oedema and hyperkalaemia and overall make acute renal failure more manageable. This is particularly important in situations when renal replacement therapy is not immediately available. Being able to induce diuresis can buy enough time to transfer a patient safely to a setting (occasionally to another hospital) where renal replacement therapy can be provided. Finally, the meta-analysis is based on the results of 9 studies of which 4 were conducted more than 25 years ago and may not be relevant to modern clinical practice any longer. We feel strongly that these points should be remembered before frusemide gets abandoned from the management of patients with acute renal failure. References 1. Ho KM, Sheridan DJ. Meta-analysis of frusemide to prevent or treat acute renal failure. BMJ 2006:333;420-425 2. Novis BK, Roizen MF, Aronson S, Thisted RA. Association of Preoperative Risk Factors with Postoperative Acute Renal Failure. Anesth Analg 1994;78: 143-149 3. Ostermann ME, Chang RW. Prognosis of acute renal failure: an evaluation of proposed consensus criteria. Intensive Care Med 2005;31:250- 256 4. Guerin C, Girard R, Selli JM, Perdrix JP, Ayzac L. Initial versus Delayed Acute Renal Failure in the Intensive Care Unit. Am J Respir Crit Care Med 2000;161: 872-879 Competing interests: None declared |
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