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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Critical Care 1/2018

Net ultrafiltration intensity and mortality in critically ill patients with fluid overload

Zeitschrift:
Critical Care > Ausgabe 1/2018
Autoren:
Raghavan Murugan, Vikram Balakumar, Samantha J. Kerti, Priyanka Priyanka, Chung-Chou H. Chang, Gilles Clermont, Rinaldo Bellomo, Paul M. Palevsky, John A. Kellum
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13054-018-2163-1) contains supplementary material, which is available to authorized users.
A comment to this article is available online at https://​doi.​org/​10.​1186/​s13054-018-2298-0.
Abbreviations
AHR
Adjusted hazard ratio
AKI
Acute kidney injury
AOR
Adjusted odds ratio
APACHE
Acute Physiology and Chronic Health Evaluation
CRRT
Continuous renal replacement therapy
CVVH
Continuous venovenous hemofiltration
CVVHD
Continuous venovenous hemodialysis
CVVHDF
Continuous venovenous hemodiafiltration
FO
Fluid overload
IHD
Intermittent hemodialysis
MAP
Mean arterial pressure
RRT
Renal replacement therapy
SCUF
Slow continuous ultrafiltration
UFNET
Net ultrafiltration

Background

Fluid overload (FO) is a common complication of acute illness affecting more than a third of critically ill patients and approximately two-thirds of patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT) [ 1, 2]. Several studies have documented that FO is independently associated with more than 50% mortality among patients receiving RRT [ 3, 4]. Observational studies suggest that fluid removal using net ultrafiltration (UF NET) may be associated with improved outcomes [ 2], and clinical and consensus guidelines recommend UF NET for the treatment of FO in patients with oliguric AKI who are resistant to diuretic therapy [ 5, 6]. However, the optimal intensity of UF NET (i.e., rate and volume of net fluid removal) in critically ill patients remains uncertain more than 70 years after the first clinical use of ultrafiltration [ 7].
Less intensive UF NET, characterized by a slower rate or smaller volume of fluid removed, may be associated with prolonged exposure to tissue and organ edema and increased morbidity and mortality [ 8, 9]. More intensive UF NET with a faster rate or larger volume of fluid removal, however, may be associated with increased hemodynamic and cardiovascular stress [ 10], leading to ischemic organ injury and mortality in critically ill patients [ 11]. Indeed, three observational studies in outpatients with end-stage renal disease suggest that UF NET intensity > 10 ml/kg/h is associated with increased overall [ 1214] and cardiovascular [ 12] mortality.
Understanding the relationship between UF NET intensity and outcome in critically ill patients is essential for two important reasons. First, if more intensive UF NET is associated with lower mortality, then clinical trials could be designed to reduce the risk of death. Second, understanding the intensity–outcome relationship will aid in standardizing UF NET intensity and implementing quality measures [ 15, 16].
In this observational study involving a large heterogeneous cohort of critically ill patients with ≥ 5% FO and receiving RRT, we examined the association between UF NET intensity and its association with risk-adjusted 1-year mortality. Because the magnitude of FO is independently associated with mortality, we hypothesized that intensive UF NET would be associated with lower mortality. However, our null hypothesis was that there is no difference in mortality for an intensive UF NET group compared with a less intensive UF NET group.

Methods

Data source and study population

We conducted a retrospective study using a large tertiary care academic medical center ICU database: the High-Density Intensive Care dataset, details of which have been published elsewhere (Additional file  1: S1) [ 1, 17, 18]. The study population included adults admitted to medical, cardiac, abdominal transplant, cardiothoracic, surgical, neurovascular, neurotrauma and trauma ICUs during July 2000 through October 2008. We included patients with AKI receiving RRT who had a cumulative fluid balance ≥ 5% prior to RRT initiation (Additional file 1: Figure S1). We extracted the daily fluid balance before and for the duration of RRT (Additional file 1: S2), hourly mean arterial pressure (MAP) and vasopressor type and dose (Additional file 1: S3) during RRT. The University of Pittsburgh’s institutional review board approved the study.

Determination of UFNET intensity

For patients receiving continuous renal replacement therapy (CRRT), we first extracted data on the total duration (in hours) of any form of CRRT (i.e., continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD) and slow continuous ultrafiltration (SCUF)). We then determined the UF volume produced and the amount of substitution fluids given each hour for patients receiving CVVHDF and CVVH. The UF NET each hour was calculated as the difference between the UF volume and the volume of substitution fluids [ 19]. For patients receiving CVVHD and SCUF, UF NET corresponded to the UF volume removed. We then calculated the total number of days of CRRT for each patient based on the hourly duration of CRRT and the total UF NET.
For patients receiving intermittent hemodialysis (IHD), we extracted the total number of IHD sessions and the UF volume removed per session from the time of ICU admission to the end of ICU stay. We excluded patients if they received IHD prior to ICU admission. UF NET corresponded to the volume ultrafiltered during each session. We then expressed the total number of IHD sessions as the number of days for each patient. Subsequently, we estimated the UF NET intensity using the equation:
$$ {\mathrm{UF}}^{\mathrm{NET}}\mathrm{intensity}\left(\mathrm{ml}/\mathrm{kg}/\mathrm{day}\right)=\kern0.5em \frac{\mathrm{Total}\ {\mathrm{UF}}^{\mathrm{NET}}\mathrm{volume}\ \left(\mathrm{ml}\right)}{\mathrm{Hospital}\ \mathrm{admission}\ \mathrm{weight}\ \left(\mathrm{kg}\right)\ \mathrm{X}\ \mathrm{RRT}\ \mathrm{duration}\ \left(\mathrm{days}\right)}. $$
For instance, if an 80-kg patient is on CVVH with an UF rate of 2000 ml/h and substitution fluid of 1500 ml/h, the total UF NET produced is 500 ml/h (2000 – 1500 = 500 ml) or 500 × 24 = 12,000 ml/day. The total UF NET produced for 5 days is 12,000 × 5 = 60,000 ml. Thus, the total UF NET intensity is [60,000 / (80 × 5)] = 150 ml/kg/day. During CVVHD and IHD, the UF volume is equivalent to UF NET.

Outcomes

The primary outcome was 1-year mortality from the index ICU admission and mortality data were obtained from the Social Security Death Master File [ 20]. We chose 1-year mortality because our prior work showed that a positive fluid balance was associated with risk of death at 1 year and use of renal replacement therapy was associated with lower risk of death in patients with a positive fluid balance [ 1]. Secondary outcomes included hospital length of stay, hospital mortality and renal recovery. Renal recovery was defined as alive and independent from RRT at 1 year. Dialysis dependence data were obtained from the US Renal Data System [ 21].

Statistical analysis

We stratified UF NET intensity into three groups because of the nonlinear (i.e., J-shaped) association between UF NET intensity and hospital mortality (Additional file 1: Figure S2). We defined UF NET ≤ 20 ml/kg/day as “low” intensity, UF NET > 20 to ≤ 25 ml/kg/day as “moderate” intensity and UF NET > 25 ml/kg/day as “high” intensity. Categorical variables were compared using the chi-squared test, and continuous variables using-one way analysis of variance and the Kruskal–Wallis test. We assessed time-to-mortality censored at 1 year using Kaplan–Meier failure plots.
We used three methods to examine the association between UF NET intensity and mortality. First, we fitted logistic regression and estimated risk-adjusted odds ratios (AORs) for high and moderate intensity, compared with low intensity UF NET (reference), on 1-year mortality. Second, we fitted Gray’s survival model [ 22, 23] to estimate risk-adjusted hazard ratios (AHRs) for time to mortality using four time nodes and five intervals (Additional file 1: S4). We adjusted for differences in age, sex, race, body mass index, history of liver disease and sequela from liver disease, admission for liver transplantation, admission for surgery, baseline glomerular filtration rate, Acute Physiologic and Chronic Health Evaluation (APACHE) III score, presence of sepsis, use of mechanical ventilation, percentage of FO before initiation of RRT, oliguria before initiation of RRT, time to initiation of RRT from ICU admission, MAP on first day of RRT initiation, cumulative vasopressor dose and cumulative fluid balance during RRT, first RRT modality and duration of RRT.
Third, in order to account for indication bias, we conducted a propensity score-matched analysis. Since the mortality associated with moderate (> 20 to ≤ 25 ml/kg/day) vs high (> 25 ml/kg/day) or moderate (> 20 to ≤ 25 ml/kg/day) vs low (≤ 20 ml/kg/day) intensity UF NET was not different (Table  1), we combined the moderate and low-intensity groups into a single low-intensity group (reference). We then matched the low-intensity UF NET (≤ 25 ml/kg/day) with the high-intensity UF NET (> 25 ml/kg/day) using propensity scores on a 1:1 basis without replacement, creating 258 matched pairs (Additional file 1: S5).
Table 1
Baseline characteristics of study population by net ultrafiltration Intensity
 
≤ 20 ml/kg/day ( n = 475)
> 20 to ≤ 25 ml/kg/day ( n = 166)
> 25 ml/kg/day ( n = 434)
p value
Age (years), median (IQR)
61 (52–69)
59 (51–71)
58 (48–70)
0.16
Male sex
301 (63.4)
114 (68.7)
218 (50.2)
< 0.001
Race
 Caucasian
380 (80)
136 (81.9)
335 (77.2)
0.018
 African-American
24 (5.1)
6 (3.6)
43 (9.9)
 Other
71 (14.9)
24 (14.5)
56 (12.9)
BMI (kg/m 2), median (IQR)
28.3 (24.2–34.3)
27.7 (24.2–31.7)
25.1 (21.9–29.3)
< 0.001
Comorbid condition
 Hypertension
169 (35.6)
72 (43.4)
161 (37.1)
0.19
 Diabetes
121 (25.5)
34 (20.5)
97 (22.4)
0.33
 Cardiac disease
84 (17.7)
36 (21.7)
99 (22.8)
0.14
 Heart failure
70 (14.7)
30 (18.1)
86 (19.8)
0.12
 Vascular disease
41 (8.6)
16 (9.6)
43 (9.9)
0.79
 Liver disease
164 (34.5)
47 (28.3)
107 (24.7)
0.005
 Sequela from liver disease
137 (28.8)
43 (25.9)
95 (21.9)
0.056
 Malignancy
23 (4.8)
4 (2.4)
14 (3.2)
0.26
 Liver transplantation
43 (9.1)
13 (7.8)
42 (9.7)
0.77
 Multiple comorbidity
298 (62.7)
93 (56)
252 (58.1)
0.19
Surgical admission
321 (67.6)
122 (73.5)
301 (69.4)
0.72
Medical admission
131 (27.6)
37 (22.3)
112 (25.8)
0.72
Admission for liver transplantation
102 (21.5)
31 (18.7)
53 (12.2)
0.001
Baseline serum creatinine (mg/dl), median (IQR)
1.029 (0.81–1.27)
1.035 (0.83–1.3)
1.032 (0.8–1.3)
0.89
Baseline eGFR (ml/min/1.73 m 2)
  > 90
107 (22.5)
27 (16.3)
91 (20.9)
0.54
 60–90
235 (49.5)
97 (58.4)
212 (48.9)
 30–60
89 (18.7)
30 (18.1)
92 (21.2)
 15–30
34 (7.2)
8 (4.8)
31 (7.1)
  < 15
10 (2.1)
4 (2.4)
8 (1.8)
APACHE III score, median (IQR) a
95 (70–118)
91 (71–116)
91 (69–112)
0.27
Sepsis a
128 (26.9)
39 (23.5)
138 (31.8)
0.08
Mechanical ventilation a
353 (74.3)
129 (77.7)
329 (75.8)
0.66
Vasopressor a
261 (54.9)
87 (52.4)
218 (50.2)
0.36
Oliguria before initiation of RRT b
 Stage 2
50 (10.5)
9 (5.4)
21 (4.8)
0.017
 Stage 3
406 (85.5)
154 (92.8)
402 (92.6)
MAP during RRT (mmHg), mean (SD) c
 All patients
75.1 (0.58)
77.5 (1.19)
79.4 (0.62)
< 0.001
 CRRT only ( n = 386)
72.7 (0.70)
72.4 (1.89)
77.5 (1.01)
< 0.001
 IHD only ( n = 210)
85 (1.84)
84.1 (2.85)
82.1 (1.27)
0.77
 CRRT and IHD ( n = 487)
74.5 (0.91)
79.1 (1.66)
79.7 (0.98)
0.002
Vasopressor dose (NE), median (IQR) c,d
 All patients
0.11 (0.04–0.25)
0.09 (0.03–0.21)
0.09 (0.04–0.25)
0.25
 Patients on CRRT only
0.14 (0.05–0.30)
0.13 (0.03–0.25)
0.10 (0.03–0.28)
0.31
 Patients on IHD only
0.01 (0.01–0.03)
0.06 (0.01–0.11)
0.03 (0.01–0.07)
0.67
 Patients on both CRRT and IHD
0.08 (0.03–0.16)
0.08 (0.02–0.16)
0.07 (0.03–0.19)
0.85
Data presented as n (%) unless stated otherwise
IQR interquartile range, BMI body mass index, eGFR estimated glomerular filtration, APACHE Acute Physiology and Chronic Health Evaluation, RRT renal replacement therapy, MAP mean arterial pressure, SD standard deviation, CRRT continuous renal replacement therapy, IHD intermittent hemodialysis, NE norepinephrine equivalents
aAt intensive care unit admission
bPatients were classified to have developed oliguria according to the maximum Kidney Disease Improving Global Outcome criteria based on urine output [ 5]
cOn the day 1 of RRT
dAll vasopressors were standardized in terms of NE (Additional file 1: S3) [ 3032]
We performed five sensitivity analyses and two subgroup analyses. First, we restricted the UF NET intensity only up to 72 h from initiation of RRT. Second, we used an alternative definition of UF NET intensity moving the threshold down as follows: low, < 15 ml/kg/day; moderate, 15–20 ml/kg/day; and high, > 20 ml/kg/day. Third, we moved the threshold up: low, < 25 ml/kg/day; moderate, 25–30 ml/kg/day; and high, > 30 ml/kg/day. Fourth, we divided the cohort into tertiles: low, ≤ 16.7 ml/kg/day; moderate, 16.7 to ≤ 27.7 ml/kg/day; and high, > 27.7 ml/kg/day. Fifth, we performed quantitative bias analysis to assess the magnitude of a hypothetical unmeasured confounder that would be necessary to account for the association between UF NET intensity and risk-adjusted mortality (Additional file 1: S6) [ 24, 25].
Sixth, we restricted our analyses only to the subgroup of patients with > 20% FO. Seventh, we confined our analysis of UF NET intensity to the hour (i.e., ml/kg/h) instead of the day among the subgroup of patients who only received CRRT as follows: low, < 0.5 ml/kg/h; moderate, 0.5–1.0 ml/kg/h; and high, > 1 ml/kg/h. Statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC, USA), Gray’s model used R 3.2.1, and quantitative bias analysis was performed using STATA 15 (STATCorp., TX, USA). All hypotheses tests were two-sided with a significance level of p < 0.05.

Results

Study population and patient characteristics

Of 45,568 patients, we excluded patients with no available baseline weight ( n = 2214), ICU duration ≤ 48 h ( n = 18,032), death within 72 h of ICU admission ( n = 663), chronic dialysis ( n = 2386), admission for or with history of renal transplantation ( n = 1232), serum creatinine ≥ 3.5 mg/dl within 1 year of hospitalization ( n = 147) and missing data on fluid balance ( n = 2810). Of 18,084 patients in whom cumulative fluid balance data were available, we excluded those with cumulative fluid balance < 5% of body weight ( n = 9900). Of patients with cumulative balance ≥ 5% of body weight ( n = 8184), we excluded those who did not receive RRT ( n = 7023) and patients without data on UF NET ( n = 86) (Additional file 1: Figure S1).
Of 1075 patients, the distribution of low, moderate and high-intensity UF NET groups was 44.2%, 15.2% and 40.4%, respectively. Minor differences were noted among male sex, race and body mass index between the groups (Table  1). There was a higher prevalence of liver disease (34.5%), sequela from liver disease (28.8%) and liver transplantation (21.5%) among those with low-intensity UF NET. There was a higher prevalence of oliguria in those who received moderate and high-intensity UF NET. Patients in the low-intensity UF NET group had lower MAP compared with the moderate and high-intensity UF NET groups (Table  1 and Additional file 1: Table S1).
Cumulative FO before RRT initiation was lowest in the low-intensity group, compared with the moderate and high-intensity UF NET groups (15.6% vs 17.3% vs 21% of body weight, respectively, p < 0.001; Table  2). Following initiation of RRT, the median cumulative FB for the low, medium and high-intensity UF NET groups was 13.5 vs 22 vs 19 l, p < 0.001; Table  2). During RRT, the MAP was lower and the cumulative vasopressor dose was higher in the low-intensity UF NET group compared with the moderate and high-intensity UF NET groups (Table  2 and Additional file 1: Table S1).
Table 2
Fluid balance, RRT characteristics and outcomes by intensity of net ultrafiltration
 
≤ 20
ml/kg/day
( n = 475)
> 20 to ≤ 25
ml/kg/day
( n = 166)
> 25
ml/kg/day
( n = 434)
p value
Fluids administered in the first 24 h of ICU admission (L), median (IQR)
5.3 (3.5–7.9)
5.1 (3.6– 7.8)
5.23 (3.3–8.1)
0.88
Fluid balance after ICU admission (L), median (IQR)
 At 72 h
7.9 (4.4–12)
7.8 (4.7–13.3)
7.6 (4.7–11.6)
0.71
 At 7 days
10.1 (6.7–15.2)
10.5 (6.4–15.7)
10.1 (6.4–15.1)
0.78
 Average before RRT
2.3 (1.2–4.4)
2.7 (1.5–4.3)
2.3 (1.2–4.2)
0.33
 Cumulative before RRT (%)
15.6 (10–25)
17.3 (9.9–28.6)
21 (12.4–33.7)
< 0.001
Duration from ICU admission to RRT (days), median (IQR)
7 (2–13)
5 (3–12)
6 (3–16)
0.27
RRT duration (days), median (IQR)
4.7 (1.5–11.7)
8.7 (4.5–16.7)
7 (3.1–12.7)
< 0.001
Cumulative FB excluding UF NET for duration of RRT (L), median (IQR) a
13.5 (4.2–32.8)
22 (8.9–45.1)
19 (7.3–37.2)
< 0.001
MAP for duration of RRT (mmHg), mean (SD)
75.2 (0.6)
77.4 (0.8)
80.1 (0.53)
< 0.001
Cumulative vasopressor dose for duration of RRT (NE), median (IQR) a
15.7 (4.3–38.6)
11.4 (1.2–34.7)
8.1 (0.9–25.7)
< 0.001
First RRT modality
 IHD
121 (25.5)
52 (31.3)
127 (29.3)
0.25
 CRRT
354 (74.5)
114 (68.7)
307 (70.7)
CRRT duration (days), median (IQR)
3.9 (1.5–7.7)
5.8 (3.6–9.4)
5.9 (2.8–9.5)
< 0.001
UF NET volume during CRRT (L), median (IQR)
3.4 (0.9–10.2)
11.6 (5.4–19.2)
16.2 (7.5–28.4)
< 0.001
IHD duration (days), median (IQR)
2 (5–9)
7 (3–13)
4 (2–8)
0.004
UF NET volume during IHD (L), median (IQR)
5.5 (2.2–13.5)
12.6 (4.4–19.7)
9.2 (4–17.2)
< 0.001
Both CRRT and IHD duration (days), median (IQR)
14.7 (9.7–22.9)
15.2 (9.2–21.9)
10.7 (6.9–18.4)
< 0.001
UF NET volume during CRRT and IHD (L), median (IQR)
19.5 (9.5–33.9)
27.9 (18.5–42.1)
26.6 (17.8–46.1)
< 0.001
Hospital length of stay (days), median (IQR)
32 (17–54)
37.5 (23–65)
37 (23–61)
< 0.001
Hospital mortality
272 (57.3)
70 (42.2)
187 (43.1)
< 0.001
1-year mortality
331 (69.7)
100 (60.2)
258 (59.4)
0.003
Renal recovery at 1 year b
119 (25.1)
48 (28.9)
138 (31.8)
0.078
Renal recovery at 1 year in survivors b
119 (82.6)
48 (72.7)
138 (78.4)
0.25
Data presented as n (%) unless stated otherwise
RRT renal replacement therapy, ICU intensive care unit, IQR interquartile range, FB fluid balance, UF NET net ultrafiltration, MAP mean arterial pressure, SD standard deviation, NE norepinephrine equivalents, IHD intermittent hemodialysis, CRRT continuous renal replacement therapy
aAll vasopressors were standardized in terms of NE (Additional file 1: S3) [ 3032]
bRenal recovery was defined as alive and independent of RRT at 1 year
The median duration of RRT for the low, moderate and high-intensity UF NET groups was 4.7 vs 8.7 vs 7 days, respectively ( p < 0.001). The median duration of CRRT was 3.9 vs 5.8 vs 5.9 days ( p < 0.001) and the median UF NET volume was 3.4 vs 11.6 vs 16.2 L ( p < 0.001). The median duration of IHD was 2 vs 7 vs 4 days ( p = 0.004) and the median UF NET volume was 5.5 vs 12.6 vs 9.2 L ( p < 0.001). The median duration of RRT for patients who received both CRRT and IHD was 14.7 vs 15.2 vs 10.7 days ( p < 0.001) and the median UF NET volume was 19.5 vs 27.9 vs 26.6 L ( p < 0.001). The median hospital length of stay was 32 vs 37.5 vs 37 days ( p < 0.001) (Table  2). This shorter length of stay among patients with low-intensity UF NET was primarily due to higher mortality in this group. However, there was no difference in renal recovery at 1 year (25.1% vs 28.9% vs 31.8%, p = 0.078) as well as within the subgroup of survivors at 1 year (82.6% vs 72.7% vs 78.4%, p = 0.25) between the three groups.

Association between UFNET intensity and mortality

The crude hospital and 1-year mortality was higher among the low-intensity group compared with the moderate and high-intensity UF NET groups: 69.7% vs 60.2% vs 59.4% ( p = 0.003), respectively (Table  2, Fig.  1a). Using logistic regression, high-intensity compared with low-intensity UF NET was associated with lower 1-year mortality (AOR 0.61, 95% CI 0.41–0.93, p = 0.02, C-statistic 0.811; Table  3 and Additional file 1: Table S2). This association persisted using UF NET as a continuous variable (AOR 0.98, 95% CI 0.97–0.99, p = 0.005; Additional file 1: Table S3). Compared with UF NET of 0–5 ml/kg/day, increasing UF NET intensity was associated with a trend toward lower odds of death ( C-statistic – 0.813; Fig.  1b), whereas moderate-intensity compared with low-intensity UF NET was not associated with mortality (AOR 0.81, 95% CI 0.48–1.35, p = 0.41; Additional file 1: Table S2).
Table 3
Association between UF NET intensity and 1-year risk-adjusted mortality
Covariates
Unadjusted odds ratio (95% CI)
p value
Adjusted a odds ratio (95% CI)
p value
Moderate vs low-intensity UF NET (reference)
0.65 (0.42–0.94)
0.024
0.81 (0.48–1.35)
0.41
High vs low-intensity UF NET (reference)
0.64 (0.49–0.85)
0.002
0.61 (0.41–0.93)
0.02
UF NET net ultrafiltration, CI confidence interval, FO fluid overload, RRT renal replacement therapy, ICU intensive care unit
aAdjusted for age, sex, race, body mass index, history of liver disease and sequela from liver disease, admission for liver transplantation, admission for surgery, baseline glomerular filtration rate, Acute Physiology and Chronic Health Evaluation III score, presence of sepsis, use of mechanical ventilation, percentage of FO before initiation of RRT, oliguria before initiation of RRT, time to initiation of RRT from ICU admission, mean arterial pressure on first day of RRT initiation, cumulative vasopressor dose and cumulative fluid balance during RRT, first RRT modality and duration of RRT
Using Gray’s model, high-intensity compared with low-intensity UF NET had variable association with mortality. Early on after ICU admission, high-intensity UF NET was associated with lowest risk of death that was subsequently attenuated over time, but nevertheless persisted up to 39 days after ICU admission (AHR range 0.50–0.73, p < 0.001; Table  4 and Additional file 1: Figure S3A). Subsequently, between 39 and 365 days, high-intensity UF NET was not associated with mortality (AHR range 0.76–1.02). High-intensity compared with moderate-intensity UF NET was only associated with lower risk of death up to 15 days (AHR 0.53, 95% CI 0.33–0.86; Additional file 1: Table S5 and Figure S3C).
Table 4
Association between intensity of net ultrafiltration and time to mortality from Gray’s model
Characteristic
Adjusted hazard ratio (95% CI) by time interval a
p value
5–15 days
15–23 days
23–39 days
39–91 days
91–365 days
 
High vs low UF NET
0.50 (0.35–0.71)
0.62 (0.46–0.82)
0.73 (0.55–0.97)
0.76 (0.56–1.04)
1.02 (0.71–1.47)
< 0.001
High vs moderate UF NET
0.53 (0.33–0.86)
0.69 (0.46–1.02)
0.75 (0.52–1.09)
0.77 (0.518–1.142)
1.16 (0.72–1.85)
0.039
Moderate vs low UF NET
0.98 (0.62–1.57)
0.87 (0.59–1.27)
0.996 (0.69–1.43)
1.01 (0.69–1.47)
0.844 (0.53–1.34)
0.91
Shown are adjusted hazard ratios estimated from Gray’s model for association between intensity of UF NET and mortality for each time interval. Models included five time intervals and four time nodes with the default timing of nodes chosen by the statistical program based on the number of observations within each time interval. Hazard ratio < 1 suggests that UF NET intensity is associated with lower mortality, and hazard ratio > 1 suggests UF NET intensity is associated with higher mortality. p values reported are for the ranges of hazard ratios from the model
CI confidence interval, UF NET net ultrafiltration, FO fluid overload, RRT renal replacement therapy, ICU intensive care unit
aAdjusted for age, sex, race, body mass index, history of liver disease and sequela from liver disease, admission for liver transplantation, admission for surgery, baseline glomerular filtration rate, Acute Physiology and Chronic Health Evaluation III score, presence of sepsis, use of mechanical ventilation, percentage of FO before initiation of RRT, oliguria before initiation of RRT, time to initiation of RRT from ICU admission, mean arterial pressure on first day of RRT initiation, cumulative vasopressor dose and cumulative fluid balance during RRT, first RRT modality and duration of RRT
After propensity matching, 258 matched pairs were created wherein patients with UF NET intensity ≤ 25 ml/kg/day had similar baseline characteristics compared with UF NET intensity > 25 ml/kg/day, except for cumulative vasopressor dose (Additional file 1: Table S4). Patients with UF NET intensity > 25 ml/kg/day compared with ≤ 25 ml/kg/day had lower 1-year mortality (57% vs 67.8%, p = 0.01; Fig.  2), which persisted after adjusting for vasopressor dose (AOR 0.63, 95% CI 0.44–0.90, p = 0.011).

Sensitivity analyses

When UF NET intensity calculation was limited within 72 h of initiation of RRT, high-intensity UF NET was associated with lower mortality (AOR 0.56, 95% CI 0.35–0.88, p = 0.013; Table  5). Using the alternative thresholds of low, moderate and high-intensity UF NET of < 15 ml/kg/h, 15–20 ml/kg/h and > 20 ml/kg/h, respectively, we found UF NET intensity > 20 ml/kg/h was associated with lower mortality (AOR 0.63, 95% CI 0.41–0.97, p = 0.038). Similar results were found moving the threshold up (AOR 0.58, 95% CI 0.34–0.99, p = 0.04; Table  5) and using tertile cutoff values (AOR 0.61, 95% CI 0.39–0.97, p = 0.037; Table  5). The quantitative bias analysis indicated that our results would be robust unless an unmeasured confounder was at least twice as prevalent among patients who received high-intensity UF NET as among those with low-intensity UF NET (Additional file 1: Figure S4). The unmeasured confounder should have an OR < 0.7 (i.e., reduced risk of death by more than 30%) to mask a null association between high-intensity UF NET and risk-adjusted mortality (Additional file 1: S6 and Figure S4).
Table 5
Sensitivity and subgroup analyses of net ultrafiltration intensity and mortality
Characteristic
Net ultrafiltration intensity
Adjusted odds ratio (95% CI) a
p value
Sensitivity analysis
 UF NET up to 72 h after RRT initiation b
High vs low
0.56 (0.35–0.88)
0.013
Moderate vs low
1.10 (0.58–2.11)
0.76
 Alternative UF NET threshold c
High vs low
0.63 (0.41–0.97)
0.038
Moderate vs low
0.91 (0.53–1.58)
0.74
 Alternative UF NET threshold d
High vs low
0.58 (0.34–0.99)
0.044
Moderate vs low
0.66 (0.43–1.01)
0.053
 Alternative UF NET threshold e
High vs low
0.61 (0.39–0.97)
0.0371
Moderate vs low
0.69 (0.45–1.07)
0.096
Subgroup analysis
 UF NET among subgroup of patients with cumulative FB > 20% before RRT f
High vs low
0.52 (0.26–1.05)
0.07
Moderate vs low
0.74 (0.29–1.84)
0.51
 Alternative UF NET threshold among subgroup of patients who only received CRRT g
High vs low
0.41 (0.24–0.71)
0.0013
Moderate vs low
0.68 (0.39–1.18)
0.17
CI confidence interval, UF NET net ultrafiltration, RRT renal replacement therapy, FB fluid balance, CRRT continuous renal replacement therapy, FO fluid overload, ICU intensive care unit
aAdjusted for differences in age, sex, race, body mass index, history of liver disease and sequela from liver disease, admission for liver transplantation, admission for surgery, baseline glomerular filtration rate, Acute Physiology and Chronic Health Evaluation III score, presence of sepsis, use of mechanical ventilation, percentage of FO before initiation of RRT, oliguria before initiation of RRT, time to initiation of RRT from ICU admission, mean arterial pressure on first day of RRT initiation, cumulative vasopressor dose and fluid balance during RRT, first RRT modality and duration of RRT
bUF NET intensity calculated using RRT duration of 72 h as a cutoff value in 1075 patients
cThreshold for low, moderate and high UF NET varied as follows in 1075 patients: low, < 15 ml/kg/day; moderate, 15–20 ml/kg/day; and high, > 20 ml/kg/day
dThreshold for low, moderate and high UF NET varied as follows in 1075 patients: low, < 25 ml/kg/day; moderate, 25–30 ml/kg/day; and high, > 30 ml/kg/day
eThreshold for low, moderate and high UF NET based on stratifying the cohort of 1075 patients into tertiles: low, ≤ 16.7 ml/kg/day; moderate, 16.7 to ≤ 27.7 ml/kg/day; and high, > 27.7 ml/kg/day
fUF NET calculated within subgroup of 465 patients with cumulative FB > 20% before RRT initiation
gThreshold for low, moderate and high UF NET varied among subgroup of 487 patients who only received CRRT as follows: low, < 0.5 ml/kg/h; moderate, 0.5–1.0 ml/kg/h; and high, > 1 ml/kg/h

Subgroup analyses

High-intensity UF NET was associated with a trend toward lower mortality among patients with > 20% FO (AOR 0.52, 95% CI 0.26–1.05, p = 0.07; Table  5). For patients receiving CRRT, UF NET intensity > 1.0 ml/kg/h compared with UF NET intensity < 0.5 ml/kg/h was associated with lower odds of death (AOR 0.41, 95% CI 0.24–0.71, p = 0.0013).

Discussion

We found that UF NET intensity > 25 ml/kg/day, compared with < 20 ml/kg/day, was independently associated with lower risk-adjusted 1-year mortality in critically ill patients with FO. Using Gray’s model, this survival benefit was greater early on after ICU admission and persisted up to 39 days. In the propensity-matched analysis, UF NET > 25 ml/kg/day, compared with ≤ 25 ml/kg/day, was also associated with lower risk of death. To our knowledge, this is the first study in the literature examining the association between UF NET intensity and long-term mortality.
Our finding is somewhat analogous to the association between intensity of solute control and mortality in critically ill patients receiving RRT in which a threshold intensity of at least 20–25 ml/kg/h of effluent dosing in CRRT or KT/V of 1.2–1.4 per session in patients receiving IHD is associated with improved survival [ 26, 27]. However, in contrast to studies on solute control, the optimal “dosing” for UF NET in critically ill patients with fluid overload is unclear. In our study, we first explored whether there was an association between UF NET dose and mortality, and then aimed to determine the overall “average dose” that is associated with a long-term mortality benefit. It is important to note that our finding does not suggest that UF NET should be dosed > 25 ml/kg/day throughout the duration of fluid removal. Day-to-day dosing may vary in patients depending on the severity of fluid overload, patient tolerability and hemodynamics.
In our study only 40% of patients received intensive UF NET, whereas 44% of patients received less intensive UF NET that has implications for care. Unlike a prescription for solute clearance, the concept of a minimum or adequate “dose” for volume clearance is not usually considered in clinical practice. Although patients who received less intensive UF NET were hemodynamically unstable in our study, our findings persisted after accounting for hemodynamics, vasopressor dose and severity of illness, suggesting that less intensive UF NET per se might be associated with mortality. These findings may suggest that failure to tolerate UF NET > 25 ml/kg/day may portend a poor prognosis and, conversely, tolerating UF NET > 25 ml/kg/day may be a predictor of recovery and lower mortality in critically ill patients with fluid overload.
Our study addresses an important knowledge gap not addressed by prior studies. While numerous studies have documented an association between the severity of FO and incremental risk of death [ 3, 4], none examined the UF NET intensity–mortality relationship. Using the Program to Improve Care in Acute Renal Disease (PICARD) study, Bouchard et al. [ 4] found that patients in whom FO was corrected during RRT had lower mortality than those who remained fluid overloaded despite RRT. Using the Randomized Evaluation of Normal versus Augmented Level of Renal Replacement Therapy (RENAL RRT) cohort, Bellomo et al. [ 2] found that a negative fluid balance during RRT was associated with a mortality benefit. However, we asked a different question: does UF NET intensity and a threshold “dose” of UF NET matter in the treatment of FO independent of fluid balance?
There may be several biologic explanations for the association between UF NET intensity and outcome. First, intensive UF NET may reduce prolonged exposure to FO and modify host response, and could reduce the incidence of subsequent organ dysfunction [ 28]. Second, the salutary effects of intensive UF NET may be mediated through unknown marker clearance independent of fluid balance since the association persisted despite controlling for cumulative fluid balance. Third, clinicians who decide to initiate intensive UF NET may select for a unique group of patients to monitor and carefully titrate fluid removal. Fourth, clinicians and nurses may also have a broad variation in how they prescribe and/or practice UF NET in the real world, which may be associated with differences in outcomes [ 29].
The strengths of our study was that it was robust to three different methods of sensitivity analysis. We accounted for confounding due to severity of illness, hemodynamics, vasopressor dose and cumulative fluid balance before and during RRT. Using Gray’s model, we found that high-intensity UF NET was associated with survival only up to 39 days after ICU admission. This finding is in contrast with the logistic model and propensity-matched analyses, which showed mortality benefit up to 1 year. This discordant finding is due to the differences in the models that were used. In Gray’s model, the number of events between high-intensity and low-intensity UF NET groups was not different within the time interval of 39–365 days. Using the logistic regression model, however, a lower odds of cumulative deaths occurred by 1 year in the high-intensity UF NET group compared with the low-intensity UF NET group.
Our study is not without limitations. First, given the observational nature, it is not possible to make causal inferences between UF NET intensity and outcomes. Second, we do not know precisely whether a UF NET threshold > 25 ml/kg/day is associated with better outcomes, although our findings were robust to several sensitivity analyses. Third, our single-center study may not be generalizable to other ICU populations. Nevertheless, our study included patients typical of an academic medical center ICU population. Fourth, we were unable to distinguish whether patients received low-intensity UF NET due to low prescription, failure to remove fluid (e.g., circuit downtime, trip to operating room, etc.) or other variations in practice with respect to fluid removal. Fifth, although the sensitivity analysis indicated that any unmeasured confounder would need to be highly prevalent and have an OR < 0.7 to mask a null association, it is possible that there may be more than one residual confounder and that it may not be a binary variable.

Conclusion

In summary, among critically ill patients with ≥ 5% FO receiving RRT, our study found that UF NET intensity > 25 ml/kg/day is associated with lower risk-adjusted 1-year mortality compared with < 20 ml/kg/day. Whether this association between UF NET intensity > 25 ml/kg/day and lower mortality risk is just a marker for recovery or a mediator needs to be refuted or confirmed in future prospective randomized controlled trials.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available as they belong to the University of Pittsburgh and University of Pittsburgh Medical Center but are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

This project was approved by the University of Pittsburgh Institutional Review Board.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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