Continuous renal replacement therapy addresses unique needs of acute renal failure in the ICU

Continuous renal replacement therapy (CRRT) represents a spectrum of dialysis modalities used specifically for the management of critically ill patients with acute renal failure (ARF).

The development of CRRT more than 25 years ago was prompted by the recognition that critically ill ARF patients are clinically very different from end-stage renal disease (ESRD) patients and renal replacement therapies used in ESRD may not be suitable for the ARF population. The changing demographics of ARF patients in the intensive care unit (ICU) have led to increasing use of CRRT modalities over time. In turn, CRRT technology has undergone an evolution, with Gambro on the forefront of these changes.

This article describes the evolution that has occurred both in the ARF patient population and the CRRT field over the past decade. The clinical characteristics of critically ill ARF patients are discussed, particularly in relation to the ESRD population. Two important issues in ARF patient management, namely timely diagnosis and recovery of renal function after ARF, are highlighted. Finally, the Prisma® System and Prismaflex® System, manufactured by Gambro to meet the unique needs of the ICU ARF patient population, are presented.

ARF routinely develops as part of multi-organ failure

Several decades ago when dialysis was first used regularly for ARF in the ICU, patients commonly had “isolated” ARF, meaning that renal failure was not associated with other organ failures. As such, patients were usually stable from a hemodynamic perspective and typically tolerated conventional hemodialysis well. Over time, however, the characteristics of the ARF patient population in the ICU have changed considerably to the point now that it is exceedingly rare for an ICU patient to have isolated ARF. Instead, ARF now routinely develops in the setting of concomitant cardiac and pulmonary failure (i.e., “multi-organ failure”), usually in the context of sepsis (1). Of note, sepsis is the most common cause of ARF in the ICU and accounts for approximately 50% of cases, as demonstrated in a recent global study (2). Cardiac failure leads to hemodynamic instability, resulting in the need for large volumes of intravenous fluid and vasoactive medications for blood pressure support. In addition, pulmonary failure frequently results in ventilator dependence.

A recently published study involving nearly 30,000 ICU patients from 54 hospitals in 23 countries (including the United States) provides a very insightful characterization of ARF in the ICU (2). In this study, approximately 6% of all patients admitted to an ICU developed ARF and, of these patients, approximately 70% required renal replacement therapy. Furthermore, the clinical factors associated with a high mortality risk included the need for vasoactive (blood pressure-supporting) medications, mechanical ventilation, shock, and combined liver/kidney failure. (It is important to emphasize that patients with these clinical characteristics are those typically treated with CRRT rather than conventional hemodialysis.) Finally, the study reported a hospital death rate of 60%. This latter figure is very consistent with figures reported from numerous other recent studies and is not appreciably different from ARF death rates reported three or four decades ago (3). This is explained by the fact that, although dialysis and other critical care technologies have improved over the past decades, the illness severity of ARF patients has increased substantially during this same time period.

Hemodynamic instability drives CRRT use

As opposed to conventional hemodialysis, which is most widely prescribed to stable end-stage renal disease (ESRD) patients on an outpatient basis, CRRT was developed specifically to address the clinical condition of critically ill ARF patients. The fundamental concept of CRRT is the use of extended treatment time (i.e. continuous therapy) as a way to provide renal replacement in such a manner that hemodynamic perturbations are avoided (4). This is achieved simply because the longer treatment time (relative to conventional hemodialysis) enables much lower fluid removal rates to be used in CRRT. This characteristic of CRRT addresses the tenuous hemodynamic state of most of these patients. Indeed, many experts consider conventional hemodialysis to be an unsuitable therapy in the ICU due to its propensity to exacerbate the hemodynamic instability so common in ARF patients.

In addition to fluid removal, the solute removal requirements are much greater for a critically ill ARF patient than an ESRD patient treated with conventional hemodialysis. The common clinical conditions leading to ARF, such as sepsis, trauma, and certain surgical procedures, create a highly catabolic state in which there is an accelerated breakdown of tissues in the body. This tissue breakdown leads to a high generation rate of toxins and retention of these toxins leads to the rapid appearance of uremic signs and symptoms. The cumulative (i.e., daily or weekly) removal capabilities are significantly greater in CRRT than in conventional hemodialysis. Again, this advantage is explained largely by the significantly longer treatment times provided by CRRT (5, 6).

As indicated previously, many experts feel that a large percentage of critically ill ARF patients cannot be managed adequately with conventional hemodialysis. Indeed, over the past several years, as the nephrology and critical care communities have increasingly recognized the clinical advantages of CRRT, its global utilization has also increased significantly. In the global multi-center trial discussed above, CRRT was the initial modality used in 80% of patients requiring dialysis (2). These data indicate CRRT is indispensable in the management of ARF patients.

RIFLE helps diagnosis AFR

One of the difficulties that clinicians face in managing critically ill ARF patients is the inability to make the diagnosis in a timely manner. In isolation, interpretation of the blood chemistry typically used to estimate renal function (creatinine) is difficult in this population for several reasons. A new approach to defining and diagnosing ARF, designated the RIFLE system (7), has been validated clinically in several studies and now is being incorporated rapidly into clinical practice. RIFLE is an acronym, for which the components are: R=Risk of kidney injury; I=kidney injury; F=kidney failure; L=loss of kidney function; and E=End-stage renal disease. For each letter, there are two defining criteria: kidney function (as assessed by the change in blood creatinine concentration from baseline) and urine output.

In the clinical validation of the RIFLE system, multiple studies have confirmed that RIFLE class severity is associated with increasing ICU and hospital length of stay, greater need for dialysis, and higher mortality. A particularly revealing study indicated that ARF patients reaching the “F” class had a hospital mortality rate that was five-fold higher than similar ICU patients not having ARF (8). Moreover, only 14% of these patients received any form of renal replacement therapy, suggesting the possibility of systematic underutilization of dialysis in this population.

Finally, the “E” class of the RIFLE system highlights the clinical reality that a significant percentage of patients do not recover renal function after an episode of ARF in the ICU. The resulting need for chronic dialysis support has both patient quality-of-life and health economic implications. A recent cost analysis compared annual healthcare costs in the subsequent year after hospital discharge in groups of patients who did or did not recover renal function after ARF. Largely reflecting the costs of chronic dialysis therapy, annual healthcare costs were a striking seven-fold higher in the patients failing to recover renal function (9). These data have important implications in light of two recent observational studies, involving nearly 3500 patients, demonstrating a significantly higher rate of renal recovery after ARF in patients treated with CRRT compared to conventional hemodialysis (10, 11). Although these results await further confirmation, they suggest an important advantage for CRRT (12).

Gambro Prisma and Prismaflex® Systems for CRRT

Gambro has been the undisputed market leader in the development and maturation of CRRT, with the global introduction of Prisma® in 1995 being a milestone in this process. The major recognition in the design of the Prisma® system was that the critically ill ARF population has unique needs and simply applying technology developed for ESRD patients is not appropriate. One of the Prisma® features developed to meet these needs was the possibility for the clinician to prescribe a broad range of modalities, depending on the specific clinical condition of a given patient. These modalities include continuous venovenous hemodialysis (CVVHD), continuous venovenous hemofiltration (CVVH), and continuous venovenous hemodiafiltration (CVVHDF) (13). Another major development breakthrough with Prisma® was an integrated fluid balance system which allowed for controlled fluid removal at a specified rate consistent with a patient’s hemodynamic status.

Recent clinical outcome data have indicated that patient survival in the CRRT population is directly related to the dose of therapy provided (14). In response to these data, CRRT fluid exchange rates and blood flow rates have increased over the past several years. The Prismaflex® (Figure 1) is Gambro’s next-generation CRRT system with extended fluid exchange and blood flow rate capabilities, enabling delivery of high-dose CRRT and the possibility to influence patient outcome positively. The system was introduced in Europe in 2004 and now is used on a global basis (15).

Summary

First described 25 years ago, CRRT is being increasingly applied in the ICU as the complexity and number of critically ill ARF patients increase. Gambro is the recognized leader in the CRRT field and revolutionized the therapy with the introduction of the Prisma® system in 1995. Gambro’s second-generation CRRT system, the Prismaflex®, addresses the ARF patient population’s changing therapy requirements in response to clinical outcome studies. For many reasons, it is expected that growth in CRRT utilization will continue to increase in the future (16, 17).

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