Strategies for the Treatment of Acute Renal Failure in Intensive Care Units: The Aspect of Dosing

Abstract

Despite all the medical progress, the mortality rate in intensive care units for patients with acute renal failure (ARF) remains high, among specific patient populations, up to 88% [Letourneau I, Dorval M, Belanger R, Legare M, Fortier L, Leblanc M. Acute renal failure in bone marrow transplant patients admitted to the intensive care unit. Nephron Apr 2002; 90(4), 408–12.]. Recent trial results indicate that patient survival may be improved by adequate renal replacement therapy. In particular, the dose of intermittent and continuous renal replacement therapies has proved to be a significant factor affecting patient survival. Daily intermittent hemodialysis, e.g., is superior to alternate‐day intermittent hemodialysis, and with continuous therapies, survival is related to the filtration rate. Further relevant factors include early initiation of renal replacement therapy, choice of biocompatible membranes and the application of bicarbonate‐buffered replacement solutions for defined patient groups. The advantages offered by continuous techniques could be demonstrated for individual patient groups; in meta‐analyses, advantages were shown for the total population of patients with ARF. Other than for patients with chronic renal failure (NKF—DOQI. Clinical practice guidelines for hemodialysis adequacy. Am J Kid Dis 1997; Vol. 30, 515–566.), there are no current clinical guidelines for a standard treatment of intensive care patients with ARF. Therefore, such a treatment standard still needs to be determined.

• Acute renal failure
• Continuous renal replacement therapy
• Filtration volume
• Uremia
• Kt/V

Introduction

Manifestation of ARF in critically ill patients in intensive care drastically deteriorates the patient's prognosis. Compared to patients without ARF, patients with ARF and a similar degree of severity measured by common prognostic scoring systems such as APACHE III or MOF, carry a markedly poorer prognosis.[1] It is noteworthy that since 1950, the mortality of patients with ARF in intensive care units has remained equally high despite the introduction of dialysis treatment, continuous renal replacement therapy and all the other medical advances that have been made during the last decades.[2] It is unclear whether the existing modalities are adequate, and thus maximum renal replacement therapy has always been adequately used. Numerous trials of ARF management in intensive care units support the assumption that survival may be related to the use of different treatment modalities. The following factors have been shown to significantly influence the survival of patients: timing of renal replacement therapy, membrane characteristics, type of buffer solution used for CVVH, hemodialysis time interval and dialysis dose. The following sections will specifically address the issue of dosage for renal replacement techniques in the management of ARF in intensive care units.

Timing of Renal Replacement Therapy

With acutely impaired renal function, the timing of renal replacement therapy has a high prognostic value. Gettings et al. retrospectively examined the clinical course of 100 trauma patients with ARF in relation to the timing of renal replacement therapy.[3] The survival rate in the early treatment group was 39% compared to only 20% in the late treatment group. Late initiation of continuous renal replacement therapy was associated with a mean BUN of 94.5 mg/dL as opposed to a mean BUN of 42.6 mg/dL with early treatment initiation. Whereas treatment started in the early treatment group on day 10, the late treatment group did not begin treatment until day 19. This trial provides clear evidence for the benefit of an early initiation of renal replacement therapy. In this study, the early treatment group had a mean BUN of 42.6 mg/dL. The Austrian Society for Internal and General Intensive Medicine (ÖGIAIM) also recommends starting renal replacement therapy with BUN values of 30–50 mg/dL.[4] Considering the urea kinetics of patients with ARF, this value appears reasonable. Patients with sepsis have a high level of catabolism with a degradation of 1.75–1.95 g protein per kg body weight. The elimination of urea from protein degradation requires a urea clearance of 25 mL/ kg body weight.[5], [6] Given a linear relation of body weight, urea clearance and resulting serum BUN, a serum BUN of 50 mg/dL can be expected with this clearance of urea. If renal replacement therapy is started with a higher BUN, it may require several days—even with appropriate dosing—before this value will be achieved. Therefore, renal replacement therapy should be initiated on the clinical indication of a BUN of 50 mg/dL.

Dosage

Since the introduction of renal replacement therapies, treatment intensity, and thus, dosage have been increased. This applies to both intermittent and, in particular, continuous renal replacement techniques. Whereas Kramer[7] introduced continuous hemofiltration using a filtration volume of 8 L/24 h, the current standard amounts to 48 L/24 h.[12] On the whole, survival rates have improved with an increased intensity of dialysis. Storck et al. compared CAVH and CVVH and were able to demonstrate that survival rates of patients undergoing continuous hemofiltration have markedly improved with CVVH.[8] This may be attributed to a higher filtration rate made possible by the application of a blood pump. Paganini examined the mortality rate of patients with ARF in intensive care units in relation to the severity of the underlying disease and in relation to the dialysis dose as measured by Kt/V.[9] The results of this study demonstrate that the mortality rate is not only determined by the severity of the underlying disease but also by the dialysis dose. Patients with moderate severity of disease showed a notably improved survival with a higher dose, measured by Kt/V, than patients receiving a lower dialysis dose. The prognosis of patients with severe or mild severity of disease was dose independent. This indicates that a high dialysis dose in severely ill patients, who had a mortality rate of 100%, and in less severely ill patients, who had a survival rate of 100%, does not exert any influence on their prognosis, though this is the case with most other patients.

In a prospective randomized multicenter trial, Ronco examined 425 patients with ARF in intensive care units and demonstrated that CVVH using a filtration volume of 35 mL/h/kg body weight is superior to a filtration volume of 20 mL/h/kg body weight.[10] Compared to the group with 20 mL/h/kg body weight and a survival rate of only 41%, the survival rate in the group using 35 mL/h/kg body weight was significantly better (57%). These data indicate that standard treatment using 20 mL/h/kg body weight is not adequate and present clear evidence for the importance of dosing in continuous renal replacement techniques.

It could also be demonstrated for intermittent techniques that an increased dialysis dose leads to a reduction in mortality. In a prospective randomized trial, Schiffl et al. examined whether there was a difference in mortality between two groups of patients, one of which received daily and the other alternate‐day hemodialysis.[11] Mortality was significantly reduced in the group with daily dialysis, where the weekly Kt/V urea of 5.8 was markedly higher than the weekly Kt/V urea of 3.0 in the alternate‐day hemodialysis group. This trial, conducted in 160 patients with ARF in intensive care units, shows that although intermittent hemodialysis also represents an appropriate renal replacement therapy, patients with ARF in intensive care units require a more intensive treatment than patients with chronic renal failure. (For an overview of the mentioned studies, refer to Table 1).

Table 1. Studies About the Influence of the Dose of Dialysis Therapy in the Treatment of Patients with Acute Renal Failure

Author	Therapy	Dose	Result
Storck et al.[8]	CHF	15.7 l v. 7.0 l FV/day	29.4% v. 12.5% mortality rate
Paganini et al.[9]	CHF/IHD	IHD: KtV ≤ 1 v. KtV ≥ 1	Improved survival rate in dependence of the severity of the underlying disease
		CHF: TAC ≤ 45 mg/dL v. TAC > 45 mg/dL
Ronco et al.[10]	CHF	20 mL/kg/h v. 35 mL/kg/h v.	41% v. 57% v. 58% survival rate
		45 mL/kg/h FV
Schiffl et al.[11]	IHD	daily v. alternate day HD	28% v. 46% mortality rate
Phu et al.[13]	CHF/PD	CHF 25l FV/day v. 70 l /day PD (30‐min dwell time 2 l exchange volume)	5% v. 17% mortality rate

Abbr.: CHF: Continuous hemofiltration, FV: Filtrationvolume, IHD: Intermittent hemodialysis, Kt/V: Urea‐clearance × time/volume, PD: Peritoneal dialysis, TAC: Time averaged urea concentration.

The reasons for better survival rates of patients receiving a higher dialysis dose are still unclear. It seems likely, though, that the higher removal rate of uremic toxin contributes substantially to improving survival. Increasing the filtration rate does not only result in a better control of uremia, but also in a clearly improved acid–base balance. In contrast to a filtration rate of 1,000 mL, a higher filtration rate of 1,500 mL/h leads to a much more rapid correction of existing metabolic acidosis.[12]

Patients without sepsis treated with a filtration rate of 1,500 mL/h showed a considerably more rapid correction of existing metabolic acidosis than a group of patients with sepsis, which means that compared to patients without sepsis, those with sepsis need a higher dialysis dose in order to compensate for metabolic acidosis. Patients with sepsis and ARF particularly benefit from increased dialysis doses. Investigations by Ronco et al. found a trend towards a better prognosis in a subgroup of patients with sepsis and a filtration rate of 45 mL/h/kg body weight. Compensation for acidosis might thus be an additional factor contributing to improved survival rates, which are associated with increased dialysis doses.

Further evidence for this hypothesis is given by the study of Phu et al.[13] In this randomized prospective study, CVVH was compared to Peritoneal Dialysis (PD) in the treatment of patients with acute renal failure due to sepsis or malaria. The authors showed that with the used regime of PD, the decline of creatinine levels was much slower than in the CVVH group and the patients were more and long‐lasting acidic than the patients on CVVH. Furthermore, the PD group had to be dialyzed for a longer period and the mortality was higher than in the CVVH group. The CVVH treatment was not adequate with a filtration volume of 25 l/day, but the PD treatment with a volume of 70 l and very short dwell time of 30 minutes was much more ineffective, this resulted in an increased mortality rate, underlining again the importance of uremia control and compensation of metabolic acidosis.

Also, the type of replacement solution must not be ignored in this context. Commonly used lactate‐buffered replacement solutions might cause problems in critically ill patients. Hyperlactatemia may be responsible for disturbed hemodynamics. An initial increase of plasma lactate was observed with patients treated with a filtration rate of 1,500 mL, indicating that degradation in the liver is disturbed by an increased production and simultaneous intake of lactate. Thus, bicarbonate‐buffered solutions should be preferred with high‐volume replacement. Barenbrock demonstrated that the use of bicarbonate‐buffered solutions for the management of patients with ARF in intensive care units leads to more stable hemodynamics. In patients with concurrent coronary heart disease, a higher mortality rate could be observed in the group treated with lactate.[14] Overall, these data favor the use of bicarbonate‐buffered solutions in intensive care units.

New Techniques

Apart from continuous and intermittent renal replacement techniques, new methods such as prolonged daily dialysis have been developed.[15], [16], [17] These methods, also known as hybrid techniques, merely prolong common intermittent hemodialysis to a period of 6–8 or even 18 hours at low flow rates. They offer the advantages of intermittent techniques such as clearly decreased anticoagulation requirements. At the same time, critically ill patients hemodynamically tolerate them, as they allow for a slow rate of fluid removal. In addition, these techniques are extremely effective with regard to the dialysis dose, as the dialysate can be processed by the machine itself and expensive dialysates or replacement solutions need not be purchased. This enables a highly efficient therapy at relatively low costs. However, the evidence for the benefit of these techniques must still be evaluated.

Summary

Renal replacement therapy in intensive care units must be tailored to the individual patient. Not all the patients with ARF can be treated intermittently, and on the other hand not all patients require continuous renal replacement. Adequate application of renal replacement therapy is important, in particular, a sufficient dose of dialysis. With intermittent hemodialysis, treatment should be provided daily. Continuous hemofiltration requires an appropriate filtration rate, i.e., 2,000 mL/h or rather, 35 mL/h/kg body weight. Bicarbonate‐buffered solutions should be preferred for renal replacement. The aim is to start renal replacement therapy early.