No early respiratory benefit with CVVHDF in patients with acute renal failure and acute lung injury
Eric A. J. Hoste1,,
Raymond C. Vanholder2,
Norbert H. Lameire2,
Carl D. V. K. Roosens1,
Johan M. A. Decruyenaere1,
Stijn I. Blot1 and
Francis A. Colardyn1
1 Intensive Care Unit, and
2 Renal Division, Ghent University Hospital, Ghent, Belgium
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Abstract
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Background. There is debate as to whether, in patients with acute lung injury, continuous renal replacement therapy has beneficial effects on pulmonary gas exchange by mechanisms other than fluid removal. Because continuous renal replacement therapy is associated with potential morbidity and mortality, it seems unethical to perform a randomized trial in patients with acute lung injury without renal failure. Therefore, the effects of continuous venovenous haemodiafiltration with zero volume balance on gas exchange were evaluated in patients with acute renal failure and acute lung injury. Because haemofilter conditions should be comparable between patients, we opted for an evaluation of the effects during a 24-h period. Results of this trial can guide future studies in non-renal patients with acute lung injury.
Methods. In all 37 patients with acute renal failure and acute lung injury, treated with continuous venovenous haemodiafiltration with zero fluid balance during a 1 year period, ventilatory and haemodynamic parameters were measured every 8 h during the 24 h preceding therapy and during the first 24 h of therapy.
Results. We found a slight, although not statistically significant, increase in the PaO2/FIO2 ratio and the oxygenation index, in the total group of patients, and in the subgroups of patients with acute lung injury of extrapulmonary and pulmonary causes.
Conclusions. During the first 24 h of treatment, continuous venovenous haemodiafiltration with zero volume balance did not result in a significant improvement of the respiratory status in patients with acute renal failure and acute lung injury, nor in the subgroups of patients with acute lung injury with extrapulmonary causes.
Keywords: acute kidney failure; adult respiratory distress syndrome; haemodiafiltration; haemodialysis; inflammation; multiple organ failure
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Introduction
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Continuous renal replacement therapy (CRRT) is frequently used as a mode of dialytic treatment in intensive care unit (ICU) patients with acute renal failure. It has been claimed that CRRT improves oxygenation in patients with acute renal failure and respiratory failure [17]. CRRT has even been used in non-acute renal failure patients with acute respiratory failure [1,3,4,8,9]. However, other authors observed either no improvement, or found conflicting results regarding pulmonary gas exchange of patients with respiratory failure treated with CRRT [813]. All studies, however, suffer from a number of drawbacks. All but four of these studies evaluated an arteriovenous, non-pump-driven form of CRRT [1,2,48,1012]. At present, the application of these systems has been abandoned, mainly because of a lack of efficacy [14]. Most of these studies were undertaken in patient populations not exceeding 20 in number [26,8,9,12,13], and/or did not clearly specify whether the patients fulfilled the definition for acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) [15] as it is applied at present [17,10,12,13]. Finally, some of these studies have not been published as full papers [7,9].
This study attempts to evaluate whether CRRT, as it is currently performed, does not exert negative effects on the evolution of ALI, or indeed has potential as therapy in patients with ALI, irrespective the presence of acute renal failure.
The beneficial effects of CRRT on pulmonary function, if any, can be explained by the removal of water that has accumulated in the pulmonary parenchyma, or by other intrapulmonary mechanisms, with potential beneficial effect on gas exchange, such as the improvement of the metabolic status, reduction of oxidative stress and/or the continuous removal of inflammatory mediators. In patients with ALI but without acute renal failure, removal of fluid overload can easily be obtained by administration of diuretics. Therefore, if CRRT provides some benefits for ALI in patients without acute renal failure, these effects should be mediated by other additional mechanisms than fluid removal.
In our opinion, a prospective trial regarding the effects of CRRT in patients with ALI but without a renal indication for CRRT is at this moment not ethical because of the potential morbidity and mortality associated with CRRT, and the absence of proof of benefit in patients with ALI and acute renal failure. Therefore, we chose to perform an intervention study in patients with ALI, and acute renal failure and an indication for CRRT. Respiratory status was compared before and after institution of CRRT with zero fluid balance. This study design allows the evaluation of the effect of CRRT by mechanisms other than those caused by fluid removal. It also clarifies whether prospective randomized trials in ALI patients without renal failure have at least a reasonable chance of success.
Potential mechanisms responsible for beneficial effects such as adsorption of inflammatory mediators to the membrane, ultrafiltration, and clearance are all related to the characteristics of the haemofilter, and therefore vary over time because of clotting and biofilm formation on the membrane. On the other hand, when the clotted haemofilter is replaced, additional beneficial effects can be anticipated. This is illustrated by the fact that complement factor D and cytokine concentration decreases only during the first 1213 h after initiation of CRRT [13,16]. These findings could both be explained by the fact that clearance of complement and cytokines depends mainly on adsorption and less on convective forces. These examples illustrate that it is crucial that all patients are studied under the same haemofilter conditions. Bearing in mind that a significant proportion of filters tend to clot after 24 h of treatment, and because the spontaneous' evolution of ALI, and other factors beyond our control could influence the results, we chose a 24 h observation time frame before intervention with CRRT, and a 24 h time frame after this.
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Subjects and methods
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All patients treated during a 1 year period in the ICU of the Ghent University Hospital were evaluated for inclusion. Patients with acute renal failure, being treated with CRRT, and who met to the criteria for ALI according to the AmericanEuropean Consensus Conference [acute onset, PaO2/FIO2 <300, pulmonary artery occlusion pressure (PAOP) <18 mmHg or no clinical evidence of raised left atrial pressure, and bilateral pulmonary infiltrates on chest radiography] were included [15]. All patients were in the acute phase of the disease (PaO2/FIO2 <300, with start of ALI less than 72 h before CRRT). Post-cardiac-surgery patients and those with <8 h of treatment with CRRT were excluded. Patients who needed fluid removal for medical reasons were also excluded.
Renal replacement therapy (either intermittent or continuous) was instituted in patients with acute renal failure fulfilling at least one of the following criteria: serum urea >200 mg/dl, fluid overload, bicarbonate <15 mEq/l, potassium >6.0 mmol/l and/or oligoanuria (<400 ml/day). CRRT was chosen above intermittent renal replacement therapy when patients were haemodynamically unstable. During the study period different methods of CRRT were performed: continuous arteriovenous haemofiltration (CAVH), continuous venovenous haemofiltration (CVVH), and continuous venovenous haemodiafiltration (CVVHDF). Because these different methods of CRRT can have different effects, and the majority of patients were treated with CVVHDF, we choose to include only patients treated with CVVHDF.
CVVHDF was performed with a flow-controlled blood roller pump (BSM22-VPM Hospal, Lyon, France), and a biocompatible AN69 plate haemofilter (Hospal, Lyon, France). A bicarbonate-buffered electrolyte solution (Clearflex D6, Bieffe Medital, Grossotto, Italy), was used as dialysate/substitution fluid. Dialysate flow was 1.0 l/h, and blood flow was set at 100 ml/h. Ultrafiltration was not pump controlled. Standard heparin was used as anticoagulant; the dose was titrated according to the activated partial thromboplastin time (6080 s). All patients had an indwelling arterial line; 27 patients underwent a semi-continuous cardiac output measurement (Vigilance, Baxter Healthcare Corporation, McGaw Park, IL, USA); six patients had intermittent cardiac output measurements (Edwards SwanGanz, Baxter Healthcare Corporation, McGaw Park, IL, USA).
Data were collected at 8 h intervals the day preceding CVVHDF (T=-1 to -3), and at 8 h intervals during the 24 h following institution of CVVHDF (T=1 to 3). The APACHE II score [17] was calculated on data from the first day of ICU admission. Patients were classified as having ALI of either pulmonary or extrapulmonary origin [18]. The lung injury severity score (LIS) was calculated on data collected 24 h before the start of CVVHDF, and after 24 h [19]. The oxygenation index was calculated as 100xFIO2xmean inspiratory pressure/PaO2, and the dynamic respiratory compliance as tidal volume/(peak inspiratory pressure-PEEP).
Statistical analysis
The data are expressed as means (SD). The Friedman test was used to compare the means of the parameters for the entire study period, when significant the Wilcoxon signed-ranks test was used to evaluate differences at specific time points. Fisher's test was used for comparison of discrete variables. The MannWhitney U test was used for comparison of patients with pulmonary and extrapulmonary ALI. Significance was accepted for a P value <0.05. In order to obtain a power for the study of 80%, a minimum of 32 patients should be included to detect a 20% rise in PaO2/FIO2 in a population with a mean PaO2/FIO2 of 150. The statistical software SPSS 10.0.5 for Windows (SPSS Inc. Chicago, IL, USA) was used.
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Results
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During the 1 year study period, 155 patients with acute renal failure were dialysed in the ICU. Fifty-seven patients were dialysed intermittently with a conventional dialysis monitor, two patients were treated with CAVH, 14 with CVVH, and 82 patients were treated with CVVHDF. Forty-five of these 82 patients fulfilled the inclusion criteria. One patient was excluded because he died 5 h after initiation of CVVHDF, one patient because a negative volume balance was initiated, and six patients because they developed acute renal failure and acute lung injury after cardiac surgery. This left 37 patients available for the study.
The baseline characteristics of the population are summarized in Table 1
.
There was no significant change in PaO2/FIO2 during the 24 h preceding CRRT. The respiratory, ventilatory and haemodynamic data of the total patient group before the start of CVVHDF, and in the first, second, and third 8 h interval after the start of CVVHDF are summarized in Table 2
. Despite a trend for improved PaO2/FIO2 (Figure 1
) none of the respiratory parameters changed significantly. Regarding the ventilatory data, only a decrease in FIO2 was observed. All other parameters remained unaltered.

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Fig. 1. Evolution of PaO2/FIO2 (mean±SE) in all patients (n=37). T=-3 to -1 is at 8-h intervals during the 24 h preceding CVVHDF, and T=1 to 3 is at 8-h intervals during the first 24 h of CVVHDF.
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Over the observation period there was also no change in the haemodynamic parameters. There was no significant change in the dose of the individual vasopressors. Only six patients were not on a vasopressor dose of vasoactive medication (all doses of noradrenaline, adrenaline, vasopressin, dobutamine, or dopamine in excess of 5 µg.kg-1.min-1) before the start of CVVHDF. Three of these six patients needed treatment with a vasoactive drug during the first 8 h of CVVHDF treatment. On the other hand, fewer patients needed vasoactive drugs during the remaining treatment period, although this decrease was not significant.
The number of patients with oliguria was not significantly different over the first 24 h of CVVHDF; neither was the urinary volume of the patients without oliguria (Table 3
). Furthermore there was a gradual decline in ultrafiltration volume over the three intervals observed. The CVVHDF treatment resulted in an improvement of acidosis, as is illustrated by the increase in pH, base excess, and plasma bicarbonate level.
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Table 3. Urinary volume, ultrafiltrate and evolution of acidosis before and at the three intervals after start of CVVHDF
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In a second analysis, the 37 patients were divided between those with a pulmonary (n=18), and those with an extrapulmonary aetiology of ALI (n=19), and the respiratory and ventilatory evolution was evaluated. There was no difference in the number of patients receiving vasopressors (dopamine, noradrenaline, adrenaline, dobutamine or vasopressin) nor in the administered doses (data not shown) between the two groups. Beside a higher PaCO2 at T=-3 and T=-1, and a lower peak inspiratory pressure at T=-3 for the patients with ALI from pulmonary causes, there was also no difference in the ventilatory or pulmonary characteristics of both groups before CVVHDF, as illustrated in Table 4
. In both variants of ALI, the patients had a significant decline of the FIO2, whereas there was no change in any of the other parameters. The evolution of the PaO2/FIO2 in both groups is also illustrated in Figure 2
. In both groups, no significant change in the evolution of this parameter could be detected, although there was a trend to improvement in the group with ALI of extrapulmonary cause.
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Table 4. Changes in respiratory and ventilatory data the first 24 h after initiation of CVVHDF for patients with pulmonary (P) (n=18) or extrapulmonary (EP) origin (n=19)
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Fig. 2. Evolution of PaO2/FIO2 (mean±SE) in patients with ARDS of pulmonary aetiology (n=18) (solid line), and extrapulmonary aetiology (n=19) (broken line). T=-3 to -1 is at 8 h intervals during the 24 h preceding CVVHDF, and T=1 to 3 is at 8 h intervals during the first 24 h of CVVHDF.
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Discussion
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This analysis explores whether CVVHDF had any beneficial effects on the ventilatory and respiratory status of patients with ALI in the acute phase, by mechanisms other than fluid removal. By this, we could delineate if this technique could be evaluated in a randomized trial with longer observation periods in patients with ALI without acute renal failure.
No significant changes in respiratory parameters were observed, at least during the first 24 h after the initiation of CVVHDF. Although the administered FIO2 decreased, this was not the result of an improvement in gas exchange, as illustrated by an unaltered PaO2/FIO2, and oxygenation index.
Beneficial effects on respiratory parameters can be mediated by several mechanisms other than fluid removal, for example better metabolic control, and/or continuous modulation of inflammation. A whole range of known and unknown mediators are thought to play a role and to interact with each other in the pathophysiology of ALI: pro-inflammatory mediators (e.g. macrophage-inhibiting factor, platelet activating fac<1?show=[fo]>tor, interleukin 8, tumour necrosis factor-
), anti-inflammatory mediators (e.g. interleukin 1 receptor antagonist, soluble tumour necrosis factor-
receptor, and antibodies against interleukin 8, 10 and 11), neutrophils, surfactant, and factors responsible for activation of the coagulation cascade [20]. It seems therefore virtually impossible to delineate the several processes involved in the impaired gas exchange by measurement of serum levels of mediators. To further elucidate whether modulation of inflammation could be clinically relevant, patients with ALI due to an extrapulmonary cause were compared with patients with a pulmonary cause. ALI of extrapulmonary or pulmonary origins have different pathogenetic characteristics: oedema and alveolar collapse due to capillary leak and systemic inflammation play a central role in extrapulmonary ALI, whereas consolidation secondary to pneumonia and lung inflammation is essential in pulmonary ALI [18]. If CVVHDF has a beneficial systemic anti-inflammatory effect resulting in a decrease of extravascular lung water, a more substantial improvement of respiratory compliance and of PaO2/FIO2 particularly in patients with an extrapulmonary cause of ALI should be expected. There was only a trend to improvement in PaO2/FIO2 in patients with ALI of extrapulmonary aetiology, and no statistically significant differences in both subgroups of patients with ALI were found.
Compared with previous work on the effects of CRRT on pulmonary function, the present study contains the largest number of patients, and was adequately powered to detect a 20% increase of PaO2/FIO2. Thus it remains uncertain if a larger study population would alter the conclusions.
The study was designed to evaluate specifically the effects of regular CVVHDF therapy under as stable haemofilter characteristics as possible, whilst still allowing sufficient exposure time for treatment. It remains unclear whether haemofiltration alone, higher ultrafiltration rates, and/or longer treatment times, would have resulted in a different outcome. Adsorption seems to play an important role in the clearance of mediators of inflammation, as is evidenced for complement factor D and various cytokines [13,16]. Therefore, different membranes and/or frequent membrane changes could lead to differences in outcome. Additionally, CVVH seems to have differing effects on circulating inflammatory mediators compared with CVVHD, and leads, in contrast to CVVHD, to reduction of tumour necrosis factor-
levels [21]. However, it remains uncertain whether this leads to different effects of CVVH and CVVHD on the evolution of organ dysfunction. Finally, a higher ultrafiltration rate, compared to that usually used, can possibly lead to improvement of gas exchange. A randomized controlled study evaluating the effects of 48 h of CVVH with an ultrafiltration rate of 2 l/h, could, as in this study, not reveal improvement of organ dysfunction in patients with early severe sepsis or septic shock [22]. On the other hand, patients treated with CVVH with an ultrafiltration rate of 35 ml/kg/h, or ±2.4 l/h, had a better survival compared to patients treated with CVVH with an ultrafiltration rate of 20 ml/h [23]. Additionally, in an uncontrolled study of patients with septic shock, high-volume ultrafiltration (35 l during a 4-h treatment period) followed by CVVH with an ultrafiltration rate of 1 l/h led to improved haemodynamic status [24].
In summary, this intervention study could not find a statistically significant improvement of pulmonary gas exchange during the first 24 h of treatment with CVVHDF with zero fluid balance, in the whole patient group with ALI, nor in the subgroups of patients with ALI from either pulmonary or extrapulmonary origin. On the other hand, no negative effects of CRRT on the evolution of ALI were observed. This leaves, at least in our opinion, room for a prospective randomized trial with another form of CRRT, in non-acute renal failure patients with ALI. According to the data mentioned above, CVVH with an ultrafiltration rate of 35 ml/h seems the most appropriate procedure for such a trial.
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Acknowledgments
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We wish to thank Mr Georges Van Maele, statistician of the Department of Medical Informatics and Statistics in our hospital for his review of the statistical analysis of this manuscript, and Mr C. Danneels for his much appreciated technical assistance.
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Notes
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Correspondence and offprint requests to: Eric A. J. Hoste, Intensive Care Unit, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Email: erik.hoste{at}rug.ac.be 
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Received for publication: 17. 5.02
Revision received 22. 7.02.