Acute kidney injury (AKI) is common in critically ill patients and associated with increased morbidity, mortality, and health care costs,1–3 especially in the context of multiorgan failure.4,5 These patients have numerous physiologic derangements including hemodynamic instability and are therefore being increasingly treated with continuous renal replacement therapy (CRRT). Consequently, considerable effort is being put into identifying prognostic factors and treatment variables that may predict or modify survival in these patients.6–13
One important prognostic factor may be fluid accumulation. Absolute or relative hypovolemia results in decreased cardiac output, blood pressure, and organ perfusion14; hence, volume resuscitation is needed to maintain organ function.15 However, overaggressive volume resuscitation can cause tissue congestion and hypoxia and is associated with worse survival in general intensive care unit (ICU) populations16 and in patients with AKI.17 Because many of these patients will need CRRT for volume management, we evaluated the association between mortality and volume-related weight gain (VRWG) at the time of initiating CRRT in AKI patients treated with CRRT. We addressed this by analyzing demographic, clinical, and survival data from an observational, single-center registry of patients treated with CRRT at our institution.
Study Design, Setting, and Population
The study was approved by the Institutional Review Board of the University of Mississippi Medical Center, Jackson, MS. Adult patients (≥18 years) who were treated with CRRT in our medical, cardiothoracic, and surgical ICUs between January 2003 and June 2004 were prospectively enrolled during or shortly after initial nephrology consultation. The decision to initiate CRRT, as well as the timing, prescribed dose, and modality, was at the discretion of the nephrologist and performed using Gambro Prisma© (Gambro AB, Stockholm, Sweden) machines and AN-69 polyacrylonitrile dialysis membranes. Patients were excluded if they had preexistent end-stage renal disease (ESRD) or if the time from the onset of AKI to initiation of CRRT was ≥2 weeks.
Definitions and Variables of Interest
Patients were considered to have AKI if their serum creatinine increased by 0.5 mg/dl or greater from baseline or if they had an abnormal serum creatinine at presentation with no known baseline value. The creatinine level at initiation of CRRT, the change in creatinine from hospital admission to initiation of CRRT, and the days elapsed from the diagnosis of AKI to initiation of CRRT were recorded. The patients' weights were obtained in a variety of settings: the emergency room, regular nursing floors, and the ICU. Standard hospital scales were used for ambulatory patients and bed scales for nonambulatory or ICU patients. The first available documented weight on the hospital record was taken as the initial weight, the majority of which were in the ICUs. Subsequent daily weights were monitored with bed scales by the nursing staff and recorded on the care flow sheets. Volume-related weight gain was defined as the difference between the initial weight and the weight at initiation of CRRT. From this, we calculated the percent weight gain. Oliguria was defined as an average urine output of <20 ml/h for at least 12 hours before enrollment. The diagnosis of sepsis was obtained from the chart, and Apache II scores were calculated at the time of the renal consult.
The principal outcome was mortality at 30 days. The main comparisons were a) patients with VRWG ≥10% versus those who gained less <10%; and b) those who gained ≥20% versus those gaining <20%. In a separate analysis, we evaluated the mortality in patients gaining <10%, between ≥10% and <20%, and ≥20%. Additional variables included age, gender, chart diagnosis of sepsis, Apache II scores, ICU location, creatinine at CRRT initiation, absolute change of creatinine, and days elapsed (as described in previous section). Cross- sectional analysis of selected variables was conducted for association with mortality. χ2 tests were used for bivariate analysis of association between selected categorical variables and mortality. Independent two-sample t test was performed to assess the association of continuous variables with mortality. Multivariate binary logistic regression analysis was conducted for more complex associations. Data were analyzed using both SPSS (version 15; SPSS Inc., Chicago, IL) and Minitab (version 13; Minitab Inc., State College, PA).
We have previously reported the general characteristics of the survivors versus nonsurvivors of our study cohort in detail.10 Our overall cohort consisted of 81 patients of which 24 were women. Their mean age was 51.4 years (range: 23–85 years) and overall mortality rate was 50.6%. Oliguria was present in 53 patients (65.4%). Of 41 deceased patients, 32 had oliguria; unadjusted odds ratio for death was 3.22 [95% confidence interval (CI): 1.23–8.45; p = 0.018] for these patients. The overall mean VRWG was 8.3 kg (range: −10.5 to +45.9 kg), representing a mean percent weight gain of 10.2% (range: −11% to +81%). Thirty-eight patients (46.9%) had VRWG ≥10% and 13 patients (16%) had ≥20% VRWG. There were no significant associations between oliguria and percent weight gains (p = 0.215), Apache II scores and weight changes (Pearson r = 0.101, p = 0.368), chart diagnosis of sepsis and death (p = 0.557), and gender and death (p = 0.943) on univariate analysis.
We first assessed the association of VRWG with mortality using a VRWG of 10% and 20% as our cutoff points. The cohort statistics stratified with VRWG of <10% and ≥10% are presented in Table 1. The average VRWG was 1.4% ± 4.6% and 20.3% ± 13.3% in the <10% and ≥10% groups, respectively. The group with the VRWG ≥10% had a significantly higher risk of dying than the reference group of <10% [odds ratio (OR) for death 2.62, 95% CI: 1.07–6.44; p = 0.046] that was not associated with differences in age, gender, Apache II scores, or in the presence of sepsis or oliguria. Serum creatinine at the time of initiation of CRRT was lower in the patients with VRWG ≥10% (perhaps reflecting dilution), and there was a tendency for these patients to have more days elapsed from AKI diagnosis to initiation of CRRT (p = 0.06). Table 2 shows the cohort statistics according to VRWG of <20% and ≥20%. The average VRWG was 6.0% ± 7.4% in the <20% group and 32.2% ± 17.1% in the ≥20% group. Odds ratio for death in the patients with a VRWG ≥20% (versus reference group of <20%) was even higher: 3.98 (95% CI: 1.01–15.75; p = 0.049). Otherwise, there were no differences between groups except that a smaller percentage of patients who had ≥20% VRWG were women. As shown in Figure 1, separating the cohort into three categories of VRWG (<10%; ≥10% but <20%; ≥20% VRWG) was associated with a progressive increase of mortality: 39.5% (17 of 43), 56% (14 of 25), and 76.9% (10 of 13). Accordingly, against a reference group of VRWG <10%, OR for death was increased to 1.95 (95% CI: 0.72–5.28; p = 0.191) in the group with intermediate weight gains and to 5.10 (95% CI: 1.22–21.25; p = 0.025) in the group with severe (≥20%) weight gains.
We next performed multivariate modeling to assess the association of other potential risk factors for death in these patients (Table 3). When analyzed together, oliguria (p = 0.021) and ≥10% weight gain (p = 0.042) maintained independent significance. When sepsis and Apache II scores were included in the modeling, both oliguria (OR 3.04, p = 0.032) and ≥10% weight gain (OR 2.71, p = 0.040) maintained significance. The effect of sepsis and Apache II scores remained nonsignificant on multivariate analysis. The combined presence of oliguria and ≥10% weight gain explained approximately 12% of the observed mortality. Including creatinine at CRRT initiation and days elapsed until CRRT into the logistic regression model abolished the association with ≥10% VRWG (p = 0.133; OR 2.14; 95% CI 0.79–5.76) but not with oliguria (p = 0.018; OR 3.64; 95% CI 1.25–10.6) (r 2 = 0.16).
We then analyzed our data according to a three-way separation of the cohort (<10%; ≥10% but <20%; ≥20% VRWG) in logistic regression. The OR of mortality increased 2.17 (95% CI: 1.11–4.26; p = 0.024) for each step increase across VRWG categories as well as for oliguria (OR 2.93; 95% CI 1.06–8.11; p = 0.038) but not for Apache II scores (p = 0.24) and sepsis (p = 0.35). Including creatinine at CRRT initiation and days elapsed until CRRT into logistic regression did not show an independent association with death (p = 0.456 and 0.135, respectively) but abolished the association with VRWG with death (p = 0.079; 95% CI 0.93–3.76), whereas the association with oliguria persisted (p = 0.022; OR 3.53; 95% CI: 1.20–10.34). Finally, we analyzed the OR between the two extreme cohorts (<10% VRWG versus ≥20% VRWG; total of 56 patients) in multiple logistic regression models. With inclusion of oliguria, sepsis, and Apache II scores, OR for death was markedly increased with VRWG ≥20% against the reference group of VRWG <10% (5.13; 95% CI 0.89–21.16; p = 0.069), albeit formal significance was lost. Results with inclusion of multiple covariates results are shown in Table 4.
Volume management is an essential component in maintaining hemodynamic stability, tissue perfusion, and organ function. Several studies have demonstrated that early volume administration is critical to reverse tissue hypoperfusion and influence prognosis.15 However, when volume resuscitation is excessive, it may be detrimental. Indeed, fluid overload increases morbidity and mortality in patients with acute respiratory distress syndrome,18,19 sepsis,20 and surgical ICU patients,21,22 and lesser fluid gains are associated with better outcomes in abdominal compartment syndrome23,24 and after colon resection.21 Because patients with AKI have impaired ability to regulate volume, they may be particularly susceptible to volume-related increases in morbidity and mortality. Some data suggest that this may be true in pediatric patients; fluid overload at the initiation of CRRT is associated with increased mortality,2,7,8 but even less information is available in adult patients with AKI. Recently, Payen et al.17 used the “Sepsis Occurrence in Acutely ill Patients” (SOAP) database to evaluate whether a positive fluid balance is associated with worse outcomes in patients admitted to the ICU. They reported that patients with AKI, nonsurvivors, had a more positive fluid balance than the survivors. The Project to Improve Care in Acute Renal Disease (PICARD) cohort group recently extended these findings.25 They analyzed the data from their cohort of critically ill adult patients with AKI and found that patients with fluid overload had a significantly higher mortality, irrespective of renal replacement therapy.
Our study focused on the sickest of AKI patients: those requiring CRRT. These patients are usually hypotensive and have impaired tissue perfusion and oliguria. Consequently, they usually receive aggressive volume resuscitation putting them at risk of volume overload. In fact, oliguria and fluid gains of ≥10% of body weight were common in our cohort (65% and 47%, respectively). The severity of illness of our patient cohort is underscored by the fact that the overall mortality in these patients was higher (50.6%) than that in the general ICU population with AKI that was analyzed by the SOAP investigators (35.7%). Our central finding was that despite being similar in all other aspects (severity of illness, sepsis, oliguria, etc.), the patients with VRWG ≥10% had a higher mortality than those with <10% (63% vs. 39%). Moreover, the mortality seems to further increase with VRWG ≥20%, suggesting a dose-response effect of progressive fluid accumulation.
Our study could not discern whether VRWG contributed to the increased mortality or selected out those with a higher risk of death. Fluid overload can directly worsen outcomes by increasing interstitial pressure and impairing tissue perfusion/oxygenation. In fact, it is directly associated with adverse clinical endpoints such as increased ventilator dependency, skin breakdown with sacral decubiti, and poor wound healing.21 It also dilutes the serum creatinine, which may delay the detection of AKI and the initiation of therapy; indeed, we observed lower creatinine and a delay in initiating CRRT in the patients with higher VRWG. It is, therefore, tempting to speculate that the excessive mortality observed in the high VRWG was due to volume overload. However, because severely ill patients develop vasodilatation, capillary leak, third spacing,26 and hemodynamic instability, which prompts aggressive fluid resuscitation, we cannot exclude the possibility that excessive VRWG is simply a surrogate of hypotension, capillary leak, and severity of illness. One argument against this possibility is that the impact of VRWG on mortality did not diminish in our multivariate analysis in which we adjusted for severity of illness. Regardless, the severity of illness scoring systems are known to perform poorly in cohorts with AKI,4,27 thus our study may not be robust enough to detect associations between severity of illness and mortality. Therefore, our results must be interpreted cautiously. Further studies are clearly warranted to determine whether excessive VRWG is a culprit or marker of mortality and whether different fluid resuscitation strategies alter mortality in these patients.
Another strong prognostic factor of worse outcomes in our study was oliguria; mortality was 60.4% compared with 32.1% in nonoliguric subjects. This is consistent with previous reports; oliguria is consistently associated with worse outcomes in patients with AKI.3,4,17 However, the mechanism by which oliguria leads to worse outcomes is not known. It is tempting to speculate that oliguric patients have worse outcomes because they are susceptible to developing fluid overload. By the same token, increased mortality in the fluid overload groups may be the result of a higher incidence of oliguria. However, this was not the case in our study because the incidence of oliguria was not different between the groups, yet there was a large difference in mortality. Our results found that oliguria and weight gain were independent predictors of mortality by mechanisms that remain to be elucidated.
The limitations of our study include the relatively small size, single-center design and lack of randomization. Oliguria was not defined based on weight (ml/kg/h) and not identical to the current definition of the Acute Kidney Injury Network. Sepsis was not based on standardized definitions, recovered as “chart diagnosis” only and subject to physicians' bias. Weights were subject to the imprecision frequently encountered in clinical practice. The dichotomous separation of weight gain at 10%, although a meaningful value and quoted in the literature,2,8,22 was, in fact, a post hoc separation of the cohort. The cohort studied is a specific subset of ICU patients, those with AKI receiving CRRT. Thus, our conclusions are strictly limited to this specific cohort and may not be directly extrapolated to other populations or to weight gains taking place after CRRT initiation. The practice of ICU care, CRRT, and fluid management is steadily evolving, posing an important external bias on our observations. In particular, delays in obtaining renal consults may have influenced the timing of CRRT initiation and led to some of the extreme weight gains observed. Further studies are needed to determine a) whether fluid overload actively contributes to the increased mortality, and b) whether targeted strategies that prevent, ameliorate, or reverse fluid overload will improve survival.
This study extends previous ones that suggest that fluid overload (represented by VRWG in this study) is a predictor of survival in critically ill patients with AKI requiring CRRT. The increased mortality in the patients with higher degrees of volume overload was not related to a higher incidence of oliguria or severity of illness scores, suggesting that the fluid overload may be contributing to the worse mortality.
Supported in part by the National Institutes of Health grants RO1-DK073401 (to L.A.J.).
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