Fluid removal intensity in intermittent hemodialysis for acute kidney injury: net ultrafiltration rate characterization and outcomes

Introduction: Hematocrit monitoring during continuous renal replacement therapy (CRRT) allows the continuous estimation of relative blood volume (RBV). This may enable early detection of intravascular volume depletion prior to clinical sequelae. We aimed to investigate the feasibility of extended RBV monitoring and its epidemiology during usual CRRT management by clinicians unaware of RBV. Moreover, we studied the association between changes in RBV and net ultrafiltration (NUF) rates. Methods: In a cohort of adult intensive care unit patients receiving CRRT, we continuously monitored hematocrit and RBV using a pre-filter noninvasive optical sensor. We analyzed temporal changes in RBV and investigated the association between RBV change and NUF rates, using the classification of NUF rates into low, moderate, or high based on predefined cut-offs. Results: We obtained >60,000 minute-by-minute measurements in >1,000 CRRT hours in 36 patients. The median RBV change was negative (decrease) in 69% of patients and the median peak change in RBV was −9.3% (interquartile range: −3.9% to −14.3%). Moreover, the median RBV decreased from baseline by >5% in 40.2% of measurements and by >10% in 20.6% of measurements. Finally, RBV decreased significantly more when patients received a high NUF rate (>1.75 mL/kg/h) compared to low or moderate NUF rates (5.32% vs. 1.93% or 1.97%, p < 0.001). Conclusion: Continuous hematocrit and RBV monitoring during CRRT was feasible. RBV decreased significantly during CRRT, and decreases were greater with higher NUF rates. RBV monitoring may help optimize NUF management and prevent the occurrence of intravascular volume depletion.

Background Net ultrafiltration (NUF) rates correlate with outcomes in critically ill patients on continuous renal replacement therapy (CRRT), but optimal strategies for septic acute kidney injury (AKI) are unclear. This study evaluated early NUF rates and survival in septic AKI. Methods A retrospective cohort of 219 adults with septic AKI requiring CRRT at a tertiary ICU was analyzed. Early NUF (weight-adjusted fluid removal/hour during the first 48 h of CRRT) was stratified into low- (<1.22 mL/kg/h), moderate- (1.22–1.79 mL/kg/h), and high-intensity (>1.79 mL/kg/h) groups. The primary outcome was 28-day mortality. Associations were assessed using multivariable Cox regression and restricted cubic spline models, adjusted for demographics, severity scores, fluid balance, and biomarkers. Results The high-intensity group had the highest 28-day mortality (68.5% vs. 43.8% moderate vs. 45.2% low). High-intensity NUF was independently associated with increased mortality vs. moderate (adjusted HR = 1.88, 95% CI:1.19–2.97, p = 0.007) and low-intensity groups (adjusted HR = 2.01, 95% CI:1.25–3.22, p = 0.004). Nonlinear analysis demonstrated a nonlinear relationship, with risks escalating steeply at rates above 1.79 mL/kg/h. Conclusion High-intensity NUF during early CRRT was associated with higher mortality in patients with septic AKI mortality, particularly among those with high severity of illness. Moderate NUF had lowest mortality, suggesting that intermediate NUF rates may best balance the competing risks of worsening hemodynamic instability from excess NUF and persistent volume overload from inadequate NUF. However, future trials are needed to better define the optimal approach to NUF in patients with septic AKI.

Background: An early net ultrafiltration (NUF) rate may be associated with prognosis in patients receiving continuous kidney replacement therapy (CKRT). In this study, we tested whether high or low early NUF rates in patients treated with CKRT were associated with increased mortality.Methods: We conducted a retrospective, observational study among all patients in the Medical Information Mart for Intensive Care IV database who received CKRT for more than 24 h within 14 days after intensive care unit admission. We defined the early (initial 48 h) NUF rate as the amount of fluid removal per hour adjusted by the patients' weight and took it as a classified variable (low rate: <1.6, moderate rate: 1.6–3.1 and high rate: > 3.1 ml/kg/h). The association between 28-day mortality and the NUF rate was analyzed by logistic regression and mediation analyses.Results: A total of 911 patients were included in our study. The median NUF rate was 2.71 (interquartile range 1.90–3.86) ml/kg/h and the 28-day mortality was 40.1%. Compared with the moderate NUF rate, the low NUF rate (adjusted odds ratio 1.56, 95% CI 1.04–2.35, p = 0.032) and high NUF rate (adjusted odds ratio 1.43, 95% CI 1.02–2.01, p = 0.040) were associated with higher 28-day mortality. The putative effect of high or low NUF rates on 28 day mortality was not direct [adjusted average direct effects (ADE) for a low NUF rate = 0.92, p = 0.064; adjusted ADE for a high NUF rate = 1.03, p = 0.096], but mediated by effects of the NUF rate on fluid balance during the same period [adjusted average causal mediation effects (ACME) 0.96, p = 0.010 for a low NUF rate; adjusted ACME 0.99, p = 0.042 for a high NUF rate]. Moreover, we found an increase trend in the NUF rate corresponding to the lowest mortality when fluid input increased.Conclusion: Compared with NUF rates between 1.6–3.1 ml/kg/h in the first 48 h of CKRT, NUF rates > 3.1 and <1.6 ml/kg/h were associated with higher mortality.

Background: An early net ultrafiltration (NUF) rate may be associated with prognosis in patients receiving continuous kidney replacement therapy (CKRT). In this study, we tested whether high or low early NUF rates in patients treated with CKRT were associated with increased mortality. Methods: We conducted a retrospective, observational study among all patients in the Medical Information Mart for Intensive Care IV database who received CKRT for more than 24 hours within 14 days after intensive care unit admission. We defined the early (initial 48 hours) NUF rate as the amount of fluid removal per hour adjusted by the patients’ weight and took it as a classified variable (low rate: 3.1 mL/kg/h). The association between 28-day mortality and the NUF rate was analyzed by logistic regression and mediation analyses. Results: A total of 911 patients were included in our study. The median NUF rate was 2.71 (interquartile range 1.90–3.86) mL/kg/h and the 28-day mortality was 40.1%. Compared with the moderate NUF rate, the low NUF rate (adjusted odds ratio 1.56, 95% CI 1.04–2.35, p = 0.032) and high NUF rate (adjusted odds ratio 1.43, 95% CI 1.02–2.01, p = 0.040) were associated with higher 28-day mortality. The putative effect of high or low NUF rates on 28 day mortality was not direct [adjusted average direct effects (ADE) for a low NUF rate = 0.92, p = 0.064; adjusted ADE for a high NUF rate = 1.03, p = 0.096], but mediated by effects of the NUF rate on fluid balance during the same period [adjusted average causal mediation effects (ACME) 0.96, p = 0.010 for a low NUF rate; adjusted ACME 0.99, p = 0.042 for a high NUF rate]. Moreover, we found an increase trend in the NUF rate corresponding to the lowest mortality when fluid input increased. Conclusion: Compared with NUF rates between 1.6–3.1 mL/kg/h in the first 48 hours of CKRT, NUF rates > 3.1 mL/kg/h and < 1.6 mL/kg/h were associated with higher mortality.

In patients treated with continuous renal replacement therapy (CRRT), early net ultrafiltration (NUF) rates may be associated with differential outcomes. We tested whether higher early NUF rates are associated with increased mortality in CRRT patients. We performed a retrospective, observational study of all patients treated with CRRT within 14 days of intensive care unit admission. We defined the early (first 48 h) NUF rate as the volume of fluid removed per hour adjusted for patient body weight and analysed as a categorical variable (>1.75, 1.01-1.75 and <1.01 mL/kg/h). The primary outcome was 28-day mortality. To deal with competing risk, we also compared different time epochs. We studied 347 patients {median age 64 [interquartile range (IQR) 53-71] years and Acute Physiology and Chronic Health Evaluation III score 73 [IQR 54-90]}. Compared with NUF rates <1.01 mL/kg/h, NUF rates >1.75 mL/kg/h were associated with greater mortality rates in each epoch: Days 0-5, adjusted hazard ratio (aHR) 1.27 [95% confidence interval (CI) 1.21-1.33]; Days 6-10, aHR 1.62 (95% CI 1.55-1.68); Days 11-15, aHR 1.87 (95% CI 1.79-1.94); Days 16-26, aHR 1.92 (95% CI 1.84-2.01) and Days 27-28, aHR 4.18 (95% CI 3.98-4.40). For every 0.5 mL/kg/h NUF rate increase, mortality similarly increased during these epochs. Compared with early NUF rates <1.01 mL/kg/h, NUF rates >1.75 mL/kg/h are associated with increased mortality. These observations provide the rationale for clinical trials to confirm or refute these findings.

Introduction: Higher net ultrafiltration (UF_NET) rates are associated with mortality among critically ill patients with acute kidney injury (AKI) and treated with continuous renal replacement therapy (CRRT). Objective: The aim of the study was to discover whether UF_NET rates are associated with renal recovery and independence from renal replacement therapy (RRT). Methods: Retrospective cohort study using data from the Randomized Evaluation of Normal versus Augmented Level of Renal Replacement Therapy trial that enrolled 1,433 critically ill patients with AKI and treated with CRRT between December 2005 and November 2008 across 35 intensive care units in Australia and New Zealand. We examined the association between UF_NET rate and time to independence from RRT by day 90 using competing risk regression after accounting for mortality. The UF_NET rate was defined as the volume of fluid removed per hour adjusted for patient body weight. Results and Conclusions: Median age was 67.3 (interquartile range [IQR], 57–76.3) years, 64.4% were male, median Acute Physiology and Chronic Health Evaluation-III score was 100 (IQR, 84–118), and 634 (44.2%) died by day 90. Kidney recovery occurred in 755 patients (52.7%). Using tertiles of UF_NET rates, 3 groups were defined: high, >1.75; middle, 1.01–1.75; and low, <1.01 mL/kg/h. Proportion of patients alive and independent of RRT among the groups were 47.8 versus 57.2 versus 53.0%; p = 0.01. Using competing risk regression, higher UF_NET rate tertile compared with middle (cause-specific hazard ratio [csHR], 0.79, 95% CI, 0.66–0.95; subdistribution hazard ratio [sHR], 0.80, 95% CI, 0.67–0.97) and lower (csHR, 0.69, 95% CI, 0.56–0.85; sHR, 0.78, 95% CI 0.64–0.95) tertiles were associated with a longer time to independence from RRT. Every 1.0 mL/kg/h increase in rate was associated with a lower probability of kidney recovery (csHR, 0.81, 95% CI, 0.74–0.89; and sHR, 0.87, 95% CI, 0.80–0.95). Using the joint model, longitudinal increases in UF_NET rates were also associated with a lower renal recovery (β = −0.29, p < 0.001). UF_NET rates >1.75 mL/kg/h compared with rates 1.01–1.75 and <1.01 mL/kg/h were associated with a longer duration of dependence on RRT. Randomized clinical trials are required to confirm this UF_NET rate-outcome relationship.

BackgroundFluid overload, a critical consequence of acute kidney injury (AKI), is associated with worse outcomes. The optimal fluid removal rate per day during continuous renal replacement therapy (CRRT) is unknown. The purpose of this study is to evaluate the impact of the ultrafiltration rate on mortality in critically ill patients with AKI receiving CRRT.MethodsThis was a retrospective cohort study where we reviewed 1398 patients with AKI who received CRRT between December 2006 and November 2015 at the Mayo Clinic, Rochester, MN, USA. The net ultrafiltration rate (UFNET) was categorized into low- and high-intensity groups (<35 and ≥35 mL/kg/day, respectively). The impact of different UFNET intensities on 30-day mortality was assessed using logistic regression after adjusting for age, sex, body mass index, fluid balance from intensive care unit (ICU) admission to CRRT initiation, Acute Physiologic Assessment and Chronic Health Evaluation III and sequential organ failure assessment scores, baseline serum creatinine, ICU day at CRRT initiation, Charlson comorbidity index, CRRT duration and need of mechanical ventilation.ResultsThe mean ± SD age was 62 ± 15 years, and 827 (59%) were male. There were 696 patients (49.7%) in the low- and 702 (50.2%) in the high-intensity group. Thirty-day mortality was 755 (54%). There were 420 (60%) deaths in the low-, and 335 (48%) in the high-intensity group (P < 0.001). UFNET ≥35 mL/kg/day remained independently associated with lower 30-day mortality (adjusted odds ratio = 0.47, 95% confidence interval 0.37–0.59; P < 0.001) compared with <35 mL/kg/day.ConclusionsMore intensive fluid removal, UFNET ≥35 mL/kg/day, among AKI patients receiving CRRT is associated with lower mortality. Future prospective studies are required to confirm this finding.

Introduction: In continuous renal replacement therapy (CRRT)-treated patients, a net ultrafiltration (NUF) rate >1.75 mL/kg/h has been associated with increased mortality. However, there may be heterogeneity of effect of NUF rate on mortality, according to patient characteristics. Methods: To investigate the presence and impact of heterogeneity of effect, we performed a secondary analysis of the “Randomized Evaluation of Normal versus Augmented Level of Renal Replacement Therapy” (RENAL) trial. Exposure was NUF rate (weight-adjusted fluid volume removed per hour) stratified into tertiles (<1.01 mL/kg/h; 1.01–1.75 mL/kg/h; or >1.75 mL/kg/h). Primary outcome was 90-day mortality. Patients were clustered according to baseline characteristics. Heterogeneity of effect was assessed according to clusters and baseline edema and related to the additional impact of baseline cardiovascular Sequential Organ Failure Assessment (SOFA) score. We excluded patients with missing values for baseline weight and/or treatment duration. Results: We identified 2 clusters. The largest (cluster 1; n = 941) included more severely ill patients, with more sepsis, more edema, and more vasopressor therapy (all p < 0.001). Compared to the middle tertile, the probability of harm was greater with the high tertile of NUF rate in patients in cluster 1 and in patients with baseline edema (probability of harm, cluster 1: 99.9%; edema: 99.1%). Moreover, higher baseline cardiovascular SOFA score also increased mortality risk with both high and low compared to middle NUF rates in cluster 1 patients and in patients with edema. Conclusions: In CRRT patients, both high and low NUF rates may be harmful, especially in those with edema, sepsis, and greater illness severity. Cardiovascular SOFA scores modulate this association. Additional studies are needed to test these hypotheses, and targeted trials of NUF rates based on risk stratification appear justified. Trial Registration: ClinicalTrials.gov identifier: NCT00221013.

Background and Aims During continuous renal replacement therapy (CRRT), a high net ultrafiltration (NUF) rate is associated with increased mortality. However, it is unknown what might mediate its putative effect on mortality. This study aims to investigate whether the relationship between early (first 48h) NUF and mortality is mediated by fluid balance (FB), hemodynamic instability or low potassium or phosphate blood levels. Method We performed a retrospective, observational study in patients treated with CRRT within 14 days of ICU admission who survived &amp;gt;48 hours. The primary outcome was hospital mortality. We applied multiple mediation analysis to identify possible mediators of NUF’s putative impact on mortality. Results We studied 347 patients [median (interquartile range) age: 64 (53–71) years and Acute Physiology and Chronic Health Evaluation (APACHE) III score: 73 (54–90)]. After adjustment for confounders, compared with a NUF&amp;lt;1.01 ml/kg/h, a NUF rate &amp;gt; 1.75 mL/kg/h was associated with significantly greater mortality (adjusted odds ratio [aOR], 1.15 [95%CI, 1.03 to 1.29]; p = 0.011). Adjusted univariable mediation analysis found no suggestion of a causal mediation effect for blood pressure, vasopressor therapy, or potassium levels, but identified a possible effect for FB (average causal mediation effect (ACME), 0.95 [95%CI, 0.90 to 0.99]; p = 0.062) and percentage of phosphate measurements with hypophosphatemia (ACME, 0.96 [95%CI, 0.92 to 1.00]; p = 0.055). However, on multiple mediator analysis, such variables lost any suggestion of a significant effect. In contrast, NUF rate remained associated with mortality even in their presence (average direct effect, 1.24 [95%CI, 1.11 to 1.40]; p &amp;lt; 0.001). Conclusion An early NUF greater than 1.75 mL/kg/h was independently associated with increased hospital mortality. Its putative effect was not mediated by FB, low blood pressure, vasopressor use, hypokalemia or hypophosphatemia.

Clinical practice guidelines for the provision of renal service in Hong Kong: General Nephrology.

Introduction: In patients with cirrhosis, non-recovery from acute kidney injury (AKI) is associated with major adverse kidney events (MAKE). However, in patients with AKI recovery, little is known about how the timing of recovery affects the risk of MAKE. Thus, we aimed to examine the association between timing of recovery and risk of MAKE in patients with AKI recovery. Methods: Hospitalized patients with cirrhosis and AKI in the Cerner Health Facts database from 1/2009-09/2017 were assessed for AKI recovery and were followed for 180 days for outcomes. The timing of AKI recovery [return of serum creatinine (sCr) < 0.3mg/dL of baseline] from AKI onset was grouped into 0-2, 3-7, 8-14, and >14 days. The primary outcome was MAKE at 90-180 days. Per consensus definition, MAKE was defined as the composite outcome of >25% decline in estimated glomerular filtration rate (eGFR) compared with baseline with CKD stage >3 or progression of CKD (defined as >50% reduction in eGFR compared with baseline) or new hemodialysis. Competing risk multivariable modeling (death/transplant as competing risk) was performed to determine the independent association between timing of recovery and risk of MAKE. Results: Out of 6,250 eligible patients, 4,655 (75%) achieved AKI recovery. The median age was 60 years [interquartile range (IQR) 25, 70], 71% White and 60% male. The most common etiologies of cirrhosis were non-alcoholic steatohepatitis (38%), alcohol (27%), and hepatitis C (17%), and the median (IQR) MELD-Na score was 23 (16, 28). 60% had ascites and the median baseline sCr was 1.00 (0.70, 1.44) mg/dL. The characteristics of patients who recovered 0-2 (n=2,791, 60%), 3-7 (n=1,455, 31%), , 8-14 (n=255, 5%), and >14 days (n=184, 4%) after AKI are shown in Table. The incidence of MAKE was 12%, 16%, 22%, and 25% for 0-2, 3-7, 8-14, and >14 days recovery groups, respectively. On adjusted multivariable competing risk analysis, compared to 0-2 days, recovery at 3-7, 8-14, and >14 days was independently associated with an increased risk for MAKE: sHR 1.48 (95% CI 1.03-2.14, p=0.036), sHR 2.92 (95% CI 1.11-4.31, p=0.023), and sHR 2.60 (95% CI 1.37-4.96, p=0.004), respectively. Conclusion: In patients with cirrhosis who recover from AKI, longer time to recovery is associated with an increased risk of major adverse kidney events. Interventions to hasten recovery from AKI should be considered in patients with cirrhosis who develop AKI. Table 1. - Comparison of Patient and Clinical Demographics Between AKI Recovery Groups Variable 0-2 Days N=2,791 3-8 Days N=1,455 8-14 days N=225 >14 days N=184 P-value Age 60 (52, 69) 62 (53, 71) 62 (55, 71) 60 (50, 68) < 0.001 Race, white 71 71 68 68 0.069 Sex, male 61 59 60 59 0.925 Etiology of cirrhosis Hepatitis C Alcohol NASH Other Unknown etiology 17 29 37 5 12 18 24 40 6 12 17 19 47 6 11 21 27 34 6 12 0.635 0.001 0.006 0.518 0.966 Ascites 56 66 68 73 < 0.001 Hepatic encephalopathy 25 27 31 32 0.054 Diabetes 50 55 64 54 < 0.001 Hypertension 57 60 63 9 0.044 Baseline creatinine, mg/dL 0.94 (0.70, 1.44) 1.00 (0.74, 1.42) 1.10 (0.80, 1.74) 1.07 (0.76, 1.82) < 0.001 MELD-Na at time of AKI 20 (14, 26) 24 (19, 29) 26 (21, 30) 26 (23, 31) < 0.001 Stage of AKI at diagnosis 1/2/3 87/10/3 69/20/11 61/21/18 63/14/13 < 0.001 Peak AKI stage 1/2/3 75/13/12 48/27/25 20/31/49 16/21/63 < 0.001 Infection 25 30 41 35 < 0.001 Required ICU care 24 28 37 33 < 0.001 Mechanical ventilation use 12 14 24 12 < 0.001 Vasopressor use 14 17 24 23 < 0.001 Continuous variables shown as median interquartile range (IQR); categorical variables presented as %.

Introduction: Hypotension is common during intermittent hemodialysis (IHD) and may be due to a decreased cardiac index (CI). However, no study has simultaneously and continuously measured CI and mean arterial pressure (MAP) to understand the prevalence, severity, and duration of CI decreases or relate them to MAP, blood volume (BV), and net ultrafiltration (NUF) rate. Methods: In a prospective, pilot and feasibility investigation, we studied 10 chronic IHD patients. We used the ClearSight System™ to continuously monitor CI and MAP; the CRIT-LINE®IV monitor to detect BV changes and collected data on NUF rate. Results: Device tolerance and compliance were 100%. All patients experienced at least ≥1 episode of severe CI decrease (>25% from baseline), with a median duration of 24 min (IQR 6–87) and of 68 min [14–106] for moderate decreases (>15% but ≤25% from baseline). Eight patients experienced a low CI state (<2.2 L/min/m2). The lowest CI was 0.9 L/min/m2 with a concomitant MAP of 94 mm Hg. When the fall in CI was severe, MAP increased in 58% of cases and remained stable in 28%. Overall, CI decreased by −0.55 L/min/m2 when BV decrease was moderate versus mild (p < 0.001) and by −0.8 L/min/m2 when NUF rate was high versus low (p < 0.001). Conclusion: Continuous CI monitoring is feasible in IHD and shows frequent moderate-severe CI decreases, sometimes to low CI state levels. Such decreases are typically associated with markers of decreased intravascular volume status but not with a decrease in MAP, implying marked vasoconstriction.

Continuous renal replacement therapy (CRRT) plays a crucial role in the volume management for critically ill patients. Net ultrafiltration (NUF) rate, as an important therapeutic parameter of CRRT, has received widespread attention for its individualized prescription and functionin volume management of critically ill patients. The aim of this article is to identify the relationship between NUF rate settings and the prognosis of critically ill patients in the clinical practice of CRRT, determine the optimal therapeutic range of NUF rate, and thus improve the effect of CRRT volume management, and provide insights into to future NUF rate studies.

Background: Historically IV and enteral fluids given during acute kidney injury (AKI) were restricted before the introduction of continuous renal replacement therapies (CRRTs) when more liberal fluids improved nutrition for the critically ill. However, fluid accumulation can occur when higher volumes each day are not considered in the fluid balance prescribing and the NET ultrafiltration (NUF) volume target. Key Messages: The delivered hours of CRRT each day are vital for achievement of fluid balance and time off therapy makes the task more challenging. Clinicians inexperienced with CRRT make this aspect of AKI management a focus of rounding with senior oversight, clear communication, and “precision” a clinical target. Sepsis-associated AKI can be a complex patient where resuscitation and admission days are with a positive fluid load and replacement mind set. Subsequent days in ICU requires fluid regulation, removal, with a comprehensive multilayered assessment before prescribing the daily fluid balance target and the required hourly NET plasma water removal rate (NUF rate). Future machines may include advanced software, new alarms – display metrics, messages and association with machine learning and “AKI models” for setting, monitoring, and guaranteeing fluid removal. This could also link to current hardware such as on-line blood volume assessment with continuous haematocrit measurement. Summary: Fluid balance in the acutely ill is a challenge where forecasting and prediction are necessary. NUF rate and volume each hour should be tracked and adjusted to achieve the daily target. This requires human and machine connections.

Net ultrafiltration (NUF) is frequently used to treat fluid overload among critically ill patients, but whether the rate of NUF affects outcomes is unclear. To examine the association of NUF with survival among critically ill patients with acute kidney injury being treated with continuous venovenous hemodiafiltration. The Randomized Evaluation of Normal vs Augmented Level (RENAL) of Renal Replacement Therapy trial was conducted between December 30, 2005, and November 28, 2008, at 35 intensive care units in Australia and New Zealand among critically ill adults with acute kidney injury who were being treated with continuous venovenous hemodiafiltration. This secondary analysis began in May 2018 and concluded in January 2019. Net ultrafiltration rate, defined as the volume of fluid removed per hour adjusted for patient body weight. Risk-adjusted 90-day survival. Of 1434 patients, the median (interquartile range) age was 67.3 (56.9-76.3) years; 924 participants (64.4%) were male; median (interquartile range) Acute Physiology and Chronic Health Evaluation III score was 100 (84-118); and 634 patients (44.2%) died. Using tertiles, 3 groups were defined: high, NUF rate greater than 1.75 mL/kg/h; middle, NUF rate from 1.01 to 1.75 mL/kg/h; and low, NUF rate less than 1.01 mL/kg/h. The high-tertile group compared with the low-tertile group was not associated with death from day 0 to 6. However, death occurred in 51 patients (14.7%) in the high-tertile group vs 30 patients (8.6%) in the low-tertile group from day 7 to 12 (adjusted hazard ratio [aHR], 1.51; 95% CI, 1.13-2.02); 45 patients (15.3%) in the high-tertile group vs 25 patients (7.9%) in the low-tertile group from day 13 to 26 (aHR, 1.52; 95% CI, 1.11-2.07); and 48 patients (19.2%) in the high-tertile group vs 29 patients (9.9%) in the low-tertile group from day 27 to 90 (aHR, 1.66; 95% CI, 1.16-2.39). Every 0.5-mL/kg/h increase in NUF rate was associated with increased mortality (3-6 days: aHR, 1.05; 95% CI, 1.00-1.11; 7-12 days: aHR, 1.08; 95% CI, 1.02-1.15; 13-26 days: aHR, 1.11; 95% CI, 1.04-1.18; 27-90 days: aHR, 1.13; 95% CI, 1.05-1.22). Using longitudinal analyses, increase in NUF rate was associated with lower survival (β = .056; P < .001). Hypophosphatemia was more frequent among patients in the high-tertile group compared with patients in the middle-tertile group and patients in the low-tertile group (high: 308 of 477 patients at risk [64.6%]; middle: 293 of 472 patients at risk [62.1%]; low: 247 of 466 patients at risk [53.0%]; P < .001). Cardiac arrhythmias requiring treatment occurred among all groups: high, 176 patients (36.8%); middle: 175 patients (36.5%); and low: 147 patients (30.8%) (P = .08). Among critically ill patients, NUF rates greater than 1.75 mL/kg/h compared with NUF rates less than 1.01 mL/kg/h were associated with lower survival. Residual confounding may be present from unmeasured risk factors, and randomized clinical trials are required to confirm these findings. ClinicalTrials.gov identifier: NCT00221013.