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The Authors Reply: Chiti and colleagues confuse the criteria for inclusion in the observational monitoring study SITS-MOST1 with the criteria for treatment with intravenous thrombolysis, which are provided in the most recent guidelines for the treatment of acute ischemic stroke.2 The criteria for treatment with intravenous thrombolysis are modeled on those of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial, and they define no upper age limit for intravenous thrombolysis. As we mentioned in our article, a post hoc subgroup analysis of the NINDS rt-PA Stroke Study showed no significant differences in the benefit from rt-PA among subgroups of patients categorized according to age.3 Unfortunately, the number of patients older than 80 years of age included in randomized trials of intravenous thrombolysis has been too small for definitive conclusions, but observational studies other than SITS-MOST have not shown an increase in the risk of intracranial hemorrhage among these patients.4 To our knowledge, the only published information on tenecteplase and desmoteplase for acute ischemic stroke comes from small phase 2 trials. For this reason, these agents cannot be recommended for use outside clinical trials. With regard to the issue of osmotherapy raised by Mumoli and Cei, as we mentioned in our article, no medical therapy — including osmotherapy — has proved to be effective for the treatment
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of life-threatening edema in acute ischemic stroke. To our knowledge, there have been no randomized clinical trials testing this treatment strategy, and there is no other firm indication that osmotherapy improves functional outcome.5 As mentioned in the guidelines that Mumoli and Cei refer to, any recommendation regarding the use of osmotherapy for life-threatening edema is therefore based on expert opinion rather than evidence.2 H. Bart van der Worp, M.D., Ph.D. Jan van Gijn, F.R.C.P. University Medical Center Utrecht 3584 CX Utrecht, the Netherlands
[email protected] 1. Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with
alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-82. [Erratum, Lancet 2007; 369:826.] 2. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 2007;115(20):e478-e534. 3. Generalized efficacy of t-PA for acute stroke: subgroup analysis of the NINDS t-PA Stroke Trial. Stroke 1997;28:2119-25. 4. Sylaja PN, Cote R, Buchan AM, Hill MD. Thrombolysis in patients older than 80 years with acute ischaemic stroke: Canadian Alteplase for Stroke Effectiveness Study. J Neurol Neurosurg Psychiatry 2006;77:826-9. 5. Hofmeijer J, Van der Worp HB, Kappelle LJ. Treatment of space-occupying cerebral infarction. Crit Care Med 2003;31:61725.
Normotensive Ischemic Acute Renal Failure To the Editor: In his review of normotensive ischemic acute renal failure (Aug. 23 issue),1 Abuelo mainly emphasizes altered glomerular hemodynamics and a reduced glomerular filtration rate in the pathogenesis of normotensive ischemic acute renal failure. However, most often, primary hypoxic or toxic tubular injury initiates upstream tubuloglomerular feedback mechanisms that lead to altered glomerular hemodynamics and to secondary reduction of the glomerular filtration rate. Tubular oxygenation and viability depend on these regulatory mechanisms, which control and match both regional supply and consumption of oxygen for tubular transport.2 These regulatory mechanisms are altered by nephrotoxins such as nonste-
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roidal antiinflammatory drugs or contrast medium and by predisposing factors such as chronic renal insufficiency or diabetes, which explains medullary ischemia and the frequent development of acute kidney failure under these conditions.3,4 Glomerular hemodynamics not only affect the downstream oxygen supply but also markedly regulate solute delivery for distal tubular transport. Reduction of the glomerular filtration rate improves medullary oxygenation and contributes to tubular preservation, since tubular transport declines.2 Thurau and Boylan’s term “acute renal success”5 emphasizes the concept that a reduced glomerular filtration rate is a reasonable adaptation to hypoxic injury. It is therefore important to re-
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alize that maneuvers enhancing the glomerular Rinaldo Bellomo, M.D. filtration rate in patients with acute renal failure Austin Hospital Melbourne 3084, Australia have the potential to increase tubular damage.
[email protected] Christian Rosenberger, M.D. John A. Kellum, M.D. Charité University Clinic 133353 Berlin, Germany
University of Pittsburgh Medical Center Pittsburgh, PA 15261
Seymour Rosen, M.D. Beth Israel Deaconess Medical Center Boston, MA 02215
Samuel N. Heyman, M.D. Hadassah University Hospital, Mt. Scopus 91240 Jerusalem, Israel
[email protected] 1. Abuelo JG. Normotensive ischemic acute renal failure. N Engl
J Med 2007;357:797-805. 2. Brezis M, Rosen S. Hypoxia of the renal medulla — its implications for disease. N Engl J Med 1995;332:647-55. 3. Rosenberger C, Rosen S, Heyman SN. Renal parenchymal oxygenation and hypoxia adaptation in acute kidney injury. Clin Exp Pharmacol Physiol 2006;33:980-8. 4. Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal disease. J Am Soc Nephrol 2006;17:17-25. 5. Thurau K, Boylan JW. Acute renal success: the unexpected logic of oliguria in acute renal failure. Am J Med 1976;61:30815.
To the Editor: Dr. Abuelo’s review does not consider some important topics; as reported in the same issue of the Journal,1 a systolic blood pressure of 90 to 100 mm Hg is not “normal” in older patients (normal level, approximately 140 mm Hg). Also, mean arterial pressure can differ at the same systolic blood pressure: a blood pressure of 100/70 mm Hg is equivalent to a mean arterial pressure of 80 mm Hg, whereas a blood pressure of 100/40 mm Hg is equivalent to a mean arterial pressure of 60 mm Hg. In the latter case, at a high right atrial pressure, the renal venous pressure can be more than 20 mm Hg, and the renal perfusion pressure can be less than 40 mm Hg. A consensus definition of acute renal failure has now been validated in more than 60,000 patients,2 and a systematic assessment of urinalysis in patients with sepsis (the most common cause of acute renal failure) showed that the procedure lacked diagnostic or predictive value.3 Finally, recent animal models suggest that, in hyperdynamic sepsis, there may not be renal ischemia at all.4 Outside of specific cases of nephrotoxic kidney injury, acute renal failure is seldom “normotensive.” Moreover, in hyperdynamic sepsis, acute renal failure may not even be ischemic.
Sean M. Bagshaw, M.D. University of Alberta Edmonton, AB T6G 2B7, Canada 1. Chobanian AV. Isolated systolic hypertension in the elderly.
N Engl J Med 2007;357:789-96. 2. Kellum JA, Bellomo R, Ronco C. Classification of acute kidney injury using RIFLE: what’s the purpose? Crit Care Med 2007; 35:1983-4. 3. Bagshaw SM, Langenberg C, Bellomo R. Urinary biochemistry and microscopy in septic acute renal failure: a systematic review. Am J Kidney Dis 2006;48:695-705. 4. Langenberg C, Wan L, Egi M, May CN, Bellomo R. Renal blood flow in experimental septic acute renal failure. Kidney Int 2006;69:1996-2002.
The Author Replies: Rosenberger et al. state that the reduced glomerular filtration rate in ischemic acute tubular necrosis reduces the sodium load that the tubules must transport, as well as their consumption of oxygen. Their warning that attempting to increase the glomerular filtration rate may be harmful seems overly speculative, since they provide no examples of tubular damage caused in this manner. The treatment of acute tubular necrosis aims to increase renal perfusion by raising the blood pressure and by reducing any renal vasoconstriction. This increases oxygen supply, which may make up for the increased filtration and delivery of sodium to the tubules. Typically, recovery of the glomerular filtration rate ensues without any clinical evidence of increased tubular injury. Bellomo et al. state that a systolic blood pressure of 90 to 100 mm Hg is not normal in older patients; however, my article refers to pressures greater than 90 to 100 mm Hg and my intention was to encompass adults of all ages, not just older adults. As to the statement by Bellomo et al. that acute renal failure is seldom “normotensive,” Hou et al. reported that 52% of cases of postoperative renal failure were not hypotensive.1 Also, 10 to 21% of adults 50 years of age or older have blood pressures of less than 120/80 mm Hg.2 Ischemic acute renal failure occurs rather commonly in patients with a systolic blood pressure in the range
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of more than 100 to less than 120 mm Hg. Thus, role of ischemia in the pathogenesis of this conit seems fair to call it normotensive. Neverthe- dition. less, in an older patient, a blood pressure under 120/80 mm Hg is often below its usual level and J. Gary Abuelo, M.D. should be compared with previous readings. My Rhode Island Hospital Providence, RI 02903 concern with the definition of “acute kidney in-
[email protected] jury” is that it does not yet specify which causes of renal failure are included. For example, Zhou 1. Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospital-acquired renal insufficiency: a prospective study. Am J et al. do not include cases due to acute glomeru- Med 1983;74:243-8. 3 lonephritis or systemic lupus erythematosus. Al- 2. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hyperthough Bellomo et al. state that urinalysis lacks tension in the US adult population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. diagnostic value for renal failure due to sepsis, the Hypertension 1995;25:305-13. 4 report they cite actually concluded that there were 3. Zhou H, Hewitt SM, Yuen PST, Star RA. Acute kidney injury few data on this question and that good studies biomarkers — needs, present status, and future promise. Nephrology SAP 2006;5:63-71. are needed. My experience is that urinalysis usu- 4. Bagshaw SM, Langenberg C, Bellomo R. Urinary biochemisally correlates well with the clinical picture. The try and microscopy in septic acute renal failure: a systematic finding of both high and low renal blood flows review. Am J Kidney Dis 2006;48:695-705. 5. Langenberg C, Wan L, Egi M, May CN, Bellomo R. Renal in studies of experimental septic acute renal fail- blood flow in experimental septic acute renal failure. Kidney Int 5 ure calls into question but does not rule out the 2006;69:1996-2002.
Mirror Therapy for Phantom Limb Pain To the Editor: Phantom limb pain occurs in at least 90% of limb amputees.1 Such pain may be induced by a conflict between visual feedback and proprioceptive representations of the amputated limb.2 Thus, illusions or imagery of movement of the amputated limb might alleviate phantom limb pain. Mirror therapy has been used with some success in patients who have had a hand or an arm amputated.3 Since the critical component of mirror therapy may be the induction of limb imagery, we conducted a randomized, sham-controlled trial of mirror therapy versus imagery therapy involving patients with phantom limb pain after the amputation of a leg or foot. We randomly assigned 22 patients to one of three groups: one that viewed a reflected image of their intact foot in a mirror (mirror group), one that viewed a covered mirror, and one that was trained in mental visualization. The patients were told that each therapy was being examined for efficacy, and each patient provided written informed consent. Eighteen subjects (six in each group) completed the study. Patients in the mirror group attempted to perform movements with the amputated limb while viewing the reflected image of the movement of their intact limb. Patients in the covered-mirror group attempted to perform movements with both their intact and amputated limbs when the mirror was 2206
covered by an opaque sheet. Patients in the mental-visualization group closed their eyes and imagined performing movements with their amputated limb. Under direct observation, patients performed their assigned therapy for 15 minutes daily. They also recorded the number and duration of pain episodes and the intensity of pain with the use of a 100-mm visual-analogue scale; they also recorded the number and duration of pain episodes. The primary end point was the severity of pain after 4 weeks of therapy. Baseline scores on the visual-analogue scale were similar among the groups (P = 0.62). Pain intensity decreased with mirror treatment (Fig. 1), as did the number and duration of pain episodes. After 4 weeks of treatment, 100% of patients in the mirror group reported a decrease in pain (median change on the visual-analogue scale, –24 mm; range, –54 to –13), but two patients had brief reactions (
