Continuous dialysis is superior to intermittent dialysis in acute kidney injury of the critically ill patient ：在危重病人伴急性肾损伤时CRRT优于IHD
AUTHOR: Claudio Ronco
RESOURCE:Nature Clinical Practice Nephrology (2007) 3, 118-119

CONTENT:

Acute kidney injury (AKI) affects 5–7% of hospitalized patients and continues to be associated with poor outcomes despite technological advances.1 Patients who would previously have died from other causes now survive long enough to develop AKI and complex physiological derangements, which are associated with high mortality. AKI is frequent in the intensive care unit (ICU); the reported incidence is 1–25%2 depending on the population studied and the definition used. Thus, we observe two separate syndromes. Uncomplicated AKI can be managed outside the ICU and usually carries a good prognosis (disease-related mortality <10%). By contrast, complicated AKI in the ICU develops as part of multiple organ dysfunction syndrome and is associated with 50–70% mortality during the ICU stay.3 The average outcome of these two syndromes has caused AKI mortality rates to falsely appear constant over the past few decades.

Increasing complexity of patients in ICUs has led to continuous renal replacement therapy (CRRT) techniques being developed. Continuous arteriovenous hemofiltration was safe and well tolerated but lacked efficiency. Machines introduced subsequently have made it possible to perform continuous venovenous hemofiltration with hemodialysis and hemodiafiltration, thus maintaining good clinical tolerability but allowing adequate blood purification.4

Has CRRT really modified the clinical course of AKI? Comparisons of continuous and intermittent therapies have so far failed to demonstrate the superiority of any one technique in terms of survival. On the other hand, a recent meta-analysis shows that several of these comparisons were performed before 2000, when a standard treatment dose for CRRT was established, and in most of the studies patients with higher severity scores were allocated to CRRT.5 Data published in 2000 indicated a correlation between CRRT dose and outcome.6 One could thus speculate that populations treated with CRRT before 2000 were highly underdialyzed and that comparisons with intermittent modalities in that period were, therefore, flawed. More-recent studies in which adequate doses are delivered demonstrate a possible superiority of CRRT over intermittent therapies.7, 8 One can also try to compare physiological end points.

The complexity of the patient who has AKI associated with multiple organ failure implies that CRRT should probably be the first-line treatment in ICU settings. Furthermore, clinical conditions other than AKI, such as congestive heart failure, respiratory distress syndrome, and cerebral edema, will probably benefit from such treatment when oliguria or early signs of renal insufficiency are present.

The patient with severe hemodynamic instability cannot be controlled with intermittent treatments such as hemodialysis or hemodiafiltration, which are carried out for 3–4 h/day. The slow continuous fluid removal achieved with CRRT is generally better tolerated and an optimum hydration status can be reached relatively swiftly, with adequate maintenance of measured hemodynamic parameters. Direct measurements of blood volume during intermittent treatment have shown that even small volumes of ultrafiltration can lead to a notable drop in circulating blood volume in patients receiving such therapy.9 This phenomenon is not observed in CRRT and can seriously hinder recovery from AKI, as the recovering kidney is extremely sensitive to small variations in perfusion pressure and blood flow. Recent data from Uchino et al.7 show a higher chance of renal recovery in AKI patients treated with CRRT than in those who received intermittent therapy.

CRRT can also correct various forms of acidosis. Intermittent hemodialysis produces a dramatic alkalinization, frequently followed by a rebound of acidosis; however, CRRT slowly generates a steady-state concentration of both uremic solutes and organic acids in blood. Unlike CRRT, intermittent treatments can worsen the clinical conditions of patients with cerebral edema, because of a postdialytic influx of fluid into the brain.

Several mechanisms have been proposed to explain the improvement of acute respiratory distress syndrome engendered by CRRT. The continuous withdrawal of fluid from the interstitium as a result of progressive vascular refilling represents a major advantage of the technique. Modulation of vascular inflammation via clearance or adsorption of a specific proinflammatory substance onto the dialysis membrane has also been suggested as a contributing factor. This mechanism has also been invoked as a means of improving clinical conditions in patients with systemic immuneresponse syndrome or septic shock. Numerous ex vivo, animal and human studies have shown that synthetic filters can extract nearly every substance involved in sepsis to some degree.10

With regard to sepsis and septic shock, neither one-off interventions nor those directed at a single mediator appear appropriate. Some studies have shown CRRT to have no influence on cytokine plasma levels. On the other hand, noteworthy clinical benefits in terms of hemodynamic improvement have been achieved even without measurable decreases in cytokine plasma levels.10 Nevertheless, such benefits have generally been disappointing. Attempts have been made to improve the efficiency of soluble mediator removal by increasing the amount of plasma water exchange, with improved clinical effects.11

There is a reason why the human kidney works 24 hours a day: to maintain homeostasis and to keep biological parameters under tight control. Intermittent forms of renal replacement therapy that attempt to correct in a few minutes physiological derangements that have developed over hours or days are aggressive and unphysiological. Such techniques have limited efficiency in eliminating waste products, and result in severe hemodynamic intolerance, high risk of brain edema and worsening of inflammatory conditions, and fail to maintain acid–base balance or keep electrolytes in a steady state. By contrast, CRRT corrects derangements gently and slowly, like the native kidneys.

In CRRT, the life span of the circuit can sometimes be shorter than 24 h; however, most such technical complications can be prevented by ensuring adequate prescription, monitoring and dose delivery, and appropriate training of personnel. Nevertheless, in some cases extended daily treatments offer the right compromise between logistical considerations and clinical tolerability.

The authors of a recent retrospective study, which failed to demonstrate the superiority of either continuous or intermittent therapy, candidly admit that they could not control for many of the variables present in the ICU. Surprisingly, they suggest conducting a study that includes only patients who could benefit from either treatment modality, excluding the very patients in whom CRRT is most often used and in whom intermittent therapies are contraindicated or not feasible.12 Comparing intermittent and continuous therapies can be misleading. Besides the difficulty of conducting a well-designed, adequately powered, randomized trial (requiring at least 1,200 patients), we believe that continuous and intermittent therapies represent a continuum in the management of AKI; thus, sicker patients would derive greater benefit from CRRT, whereas less severely ill patients might take advantage of daily extended or intermittent treatments.

It must be highlighted that our preference for CRRT applies only to critically ill patients with AKI, in whom intermittent dialysis can be problematic or even impossible. For patients in renal wards who have uncomplicated AKI, daily hemodialysis might be adequate. Even in these cases, however, an intermediate form of renal replacement therapy between fully intermittent and fully continuous regimens is strongly advisable, as patients with AKI are very different from those on chronic hemodialysis.

关于CRRT与IHD的讨论

TITLE:Continuous dialysis is not superior to intermittent dialysis in acute kidney injury of the critically ill patient ：在危重病人伴有急性肾损伤时CRRT并不优于IHD
AUTHOR:Jonathan Himmelfarb
RESOURCE:Nature Clinical Practice Nephrology (2007) 3, 120-121
CONTENT:
Kramer and colleagues pioneered the concept of continuous renal replacement therapy (CRRT) in the intensive care unit (ICU) in 1977.1 CRRT was introduced after it was commonly observed that intermittent hemodialysis (IHD) frequently worsened hemodynamics in critically ill patients, who were often hypotensive, in shock, and on pressor support.2 CRRT offered continuous regulation of volume and solute homeostasis, which promised greater hemodynamic and metabolic stability.3 In the ensuing three decades, many clinicians and investigators caring for critically ill patients with severe acute kidney injury (AKI) have continued to regard CRRT as an inherently superior therapy, and thus the treatment of choice in the ICU. Indeed, in a recent international epidemiologic survey, more than 80% of patients with AKI who were critically ill received CRRT, compared with only 17% who received IHD.4

Four recently published randomized clinical trials and one multicenter observational study call into question whether outcomes with CRRT are superior to those of IHD, as previously assumed.5, 6, 7, 8, 9 None of these studies shows a superior outcome for CRRT compared with IHD, and several imply a worse outcome with CRRT. Mehta et al.5 randomized 166 critically ill patients with severe AKI to either CRRT or IHD. There was a significantly higher ICU mortality rate in subjects randomized to CRRT (60% vs 42%; P = 0.02). After post hoc adjustment for differences in severity of illness, the increased risk attributed to CRRT was no longer statistically significant (odds ratio 1.6). Within each tertile of severity of illness score, however, randomization to CRRT was associated with a trend toward higher rather than lower risk. In a single-center trial, 125 patients were randomized to CRRT or IHD. In-hospital mortality rates did not differ significantly by treatment assignment (47% vs 51%; P = 0.72).6 In another single-center, prospective trial, 80 patients were randomized to CRRT or IHD.7 There were no differences in survival or renal functional recovery between groups. Most recently, the Hemodiafe Study Group reported the results of a randomized multicenter study comparing CRRT with IHD in 360 critically ill patients with AKI.8 Overall, there was no significant difference in the primary end point of 60-day survival (33% with CRRT vs 32% with IHD). The authors did, however, note an unexpected and significant increase in survival rates within the IHD group over time (relative risk of mortality 0.67 per year; P <0.0001), which was not seen in the CRRT group. This somewhat surprising result implies that over the course of the trial there was a learning curve for optimizing the results of IHD within the study centers. Had IHD been optimized from the onset, the trial might have reported better survival with this modality than with CRRT.

Recently, the Program to Improve Care in Acute Renal Disease (PICARD) group compared the outcomes of different renal replacement therapy modalities.9 For the first time, this analysis incorporated multiple centers, multivariable regression analysis, and a propensity score approach to address residual confounding. Within the PICARD cohort, use of CRRT was associated with a significantly higher relative risk of mortality than was use of IHD. Thus, the totality of evidence available from recently published clinical trials and observational studies does not support a better outcome for CRRT versus IHD, and in fact several of these studies indicate a possibly worse outcome.

The results of the above studies are surprising and certainly do not support the long-standing, widely held belief that CRRT provides better outcomes than IHD. In critically reassessing this hypothesis, two important corollaries should be considered. First, has IHD become safer and more efficacious with contemporary dialytic techniques? Second, might CRRT be less safe and/or efficacious than previously considered?

The concept that CRRT can provide more hemodynamic stability, more-effective volume homeostasis, and better blood pressure support than IHD has been the basis for the assumption that CRRT is a superior therapy. Over the past two decades, however, technical advances in the delivery of IHD have dramatically decreased the propensity of IHD to cause intradialytic hypotension. These advances include the introduction of volume-controlled dialysis machines, the routine use of biocompatible synthetic dialysis membranes, the use of bicarbonate-based dialysate and the delivery of higher doses of dialysis. Notably, in the only randomized crossover study of IHD and continuous venovenous hemofiltration reported to date, the hemodynamic responses to the two therapies were similar.10 In an important study, Schortgen et al. demonstrated that there was a lower rate of hemodynamic instability and better outcomes after implementation of a clinical practice algorithm designed to improve hemodynamic tolerance to IHD.11 Recommendations included priming the dialysis circuit with isotonic saline, setting dialysate sodium concentration at above 145 mmol/l, discontinuing vasodilator therapy, and setting dialysate temperature to below 37 °C. Thus, the original rationale for the widely held assumption that CRRT is a superior therapy may have dissipated over time.

Although considerable attention has focused on the perceived benefits of CRRT, there has been less emphasis on the possibility that CRRT might confer increased risk. As a continuous extracorporeal therapy, CRRT often requires continuous anticoagulation, which can increase bleeding risk. Conversely, clotting of the extracorporeal circuit also occurs frequently with CRRT, which might contribute to blood loss and could exacerbate anemia in critically ill patients. The increased solute transfer associated with the use of CRRT might enhance removal of amino acids, vitamins, catecholamines, and other solutes with a beneficial function in critically ill patients. Also of concern are recent reports that technical problems with the delivery of CRRT, including machine malfunction, medication errors, and compounding errors, might contribute to increased patient morbidity and mortality.12 Detection of safety problems and/or adverse events is particularly difficult when there are high rates of expected morbidity and mortality in the population undergoing a procedure, as is the case with CRRT in critically ill patients with AKI. Currently, few available studies in the nephrology literature provide substantive information on the safety or adverse effects of CRRT or IHD in the critically ill population.

After the introduction of new technology and devices into medical practice, there is a natural tendency to assume that the novel therapeutic approach is providing benefit. This is especially the case when there are modest clinical improvements over time, as in the treatment of AKI. Given that CRRT has now been in clinical use for three decades, it is fair to ask whether research-based evidence supports the use of this more complex and expensive technology in preference to IHD. Examining the results of recently published observational studies and randomized trials reveals no convincing evidence to support superiority of CRRT over IHD in the management of most critically ill patients with AKI.5, 6, 7, 8, 9 .