Efficacy of renal replacement therapy in critically ill patients: a propensity analysis

Introduction

Although renal replacement therapy (RRT) is a common procedure in critically ill patients with acute kidney injury (AKI), its efficacy remains uncertain. Patients who receive RRT usually have higher mortality rates than those who do not. However, many differences exist in severity patterns between patients with and those without RRT and available results are further confounded by treatment selection bias since no consensus on indications for RRT has been reached so far. Our aim was to account for these biases to accurately assess RRT efficacy, with special attention to RRT timing.

Methods

We performed a propensity analysis using data of the French longitudinal prospective multicenter Outcomerea database. Two propensity scores for RRT were built to match patients who received RRT to controls who did not despite having a close probability of receiving the procedure. AKI was defined according to RIFLE criteria. The association between RRT and hospital mortality was examined through multivariate conditional logistic regression analyses to control for residual confounding. Sensitivity analyses were conducted to examine the impact of RRT timing.

Results

Among the 2846 study patients, 545 (19%) received RRT. Crude mortality rates were higher in patients with than in those without RRT (38% vs 17.5%, P < 0.001). After matching and adjustment, RRT was not associated with a reduced hospital mortality. The two propensity models yielded concordant results.

Conclusions

In our study population, RRT failed to reduce hospital mortality. This result emphasizes the need for randomized studies comparing RRT to conservative management in selected ICU patients, with special focus on RRT timing.     

Sustained Low-Efficiency Daily Diafiltration for Diabetic Nephropathy Patients with Acute Kidney Injury

Objective

To investigate the efficacy, safety and cost of treating patients with acute kidney injury (AKI) and diabetic nephropathy (DN) with continuous renal replacement therapy (CRRT) or sustained low-efficiency daily diafiltration with hemofiltration (SLEDD-f).

Subjects and Methods

Medical records of patients with AKI/DN from January 2006 to December 2012 were reviewed. Fifty-five patients who received CRRT and 52 who received SLEDD-f were included in the study. CRRT and SLEDD-f were performed for 20-72 h per session and 8-10 h per session, respectively. Mortality and renal function recovery rates were evaluated 30 days after the initiation of renal replacement therapy (RRT) and APACHE-II and SOFA scores, anticoagulant dose, inflammatory indices and cost were calculated at baseline and at the end of RRT.

Results

Of the 55 patients treated with CRRT, 49 (89.1%) had a 30-day survival rate and 30 (54.5%) had a 30-day renal recovery rate. Of the 52 patients with SLEDD-f, these rates were 92.3% (n = 48) and 61.5% (n = 32), respectively. The dosage of low-molecular-weight heparin in the CRRT and SLEDD-f groups was 15,230 ± 1,460 and 6,320 ± 490 U/day, respectively. The cost of hemopurification and the total cost for patients treated with CRRT was CNY 28,628 ± 5,576 (USD 4,210 ± 820) and CNY 38,828 ± 6,324 (USD 5,710 ± 930), respectively. These were higher than those for patients treated with SLEDD-f at CNY 13,260 ± 1,564 (USD 1,950 ± 230) and CNY 19,720 ± 2,652 (USD 2,900 ± 390), respectively.

Conclusions

SLEDD-f offered a similar chance of renal recovery and also had further advantages such as a lower heparin dosage, a shorter therapy time and lower hospitalization costs for patients than CRRT. Studies with larger, randomized sample sizes are needed to confirm these findings.Key Words: Acute kidney injury, Diabetic nephropathy, Continuous renal replacement treatment, Sustained low-efficiency daily diafiltration     

The effect of continuous versus intermittent renal replacement therapy on the outcome of critically ill patients with acute renal failure (CONVINT): a prospective randomized controlled trial

Introduction

Acute renal failure (ARF) requiring renal replacement therapy (RRT) occurs frequently in ICU patients and significantly affects mortality rates. Previously, few large clinical trials investigated the impact of RRT modalities on patient outcomes. Here we investigated the effect of two major RRT strategies (intermittent hemodialysis (IHD) and continuous veno-venous hemofiltration (CVVH)) on mortality and renal-related outcome measures.

Methods

This single-center prospective randomized controlled trial (“CONVINT”) included 252 critically ill patients (159 male; mean age, 61.5 ± 13.9 years; Acute Physiology and Chronic Health Evaluation (APACHE) II score, 28.6 ± 8.8) with dialysis-dependent ARF treated in the ICUs of a tertiary care academic center. Patients were randomized to receive either daily IHD or CVVH. The primary outcome measure was survival at 14 days after the end of RRT. Secondary outcome measures included 30-day-, intensive care unit-, and intrahospital mortality, as well as course of disease severity/biomarkers and need for organ-support therapy.

Results

At baseline, no differences in disease severity, distributions of age and gender, or suspected reasons for acute renal failure were observed. Survival rates at 14 days after RRT were 39.5% (IHD) versus 43.9% (CVVH) (odds ratio (OR), 0.84; 95% confidence interval (CI), 0.49 to 1.41; P = 0.50). 14-day-, 30-day, and all-cause intrahospital mortality rates were not different between the two groups (all P > 0.5). No differences were observed in days on RRT, vasopressor days, days on ventilator, or ICU-/intrahospital length of stay.

Conclusions

In a monocentric RCT, we observed no statistically significant differences between the investigated treatment modalities regarding mortality, renal-related outcome measures, or survival at 14 days after RRT. Our findings add to mounting data demonstrating that intermittent and continuous RRTs may be considered equivalent approaches for critically ill patients with dialysis-dependent acute renal failure.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT01228123","term_id":"NCT01228123"}}NCT01228123, clinicaltrials.gov     

Fluid balance,intradialytic hypotension,and outcomes in critically ill patients undergoing renal replacement therapy: a cohort study

Introduction

In this cohort study, we explored the relationship between fluid balance, intradialytic hypotension and outcomes in critically ill patients with acute kidney injury (AKI) who received renal replacement therapy (RRT).

Methods

We analysed prospectively collected registry data on patients older than 16 years who received RRT for at least two days in an intensive care unit at two university-affiliated hospitals. We used multivariable logistic regression to determine the relationship between mean daily fluid balance and intradialytic hypotension, both over seven days following RRT initiation, and the outcomes of hospital mortality and RRT dependence in survivors.

Results

In total, 492 patients were included (299 male (60.8%), mean (standard deviation (SD)) age 62.9 (16.3) years); 251 (51.0%) died in hospital. Independent risk factors for mortality were mean daily fluid balance (odds ratio (OR) 1.36 per 1000 mL positive (95% confidence interval (CI) 1.18 to 1.57), intradialytic hypotension (OR 1.14 per 10% increase in days with intradialytic hypotension (95% CI 1.06 to 1.23)), age (OR 1.15 per five-year increase (95% CI 1.07 to 1.25)), maximum sequential organ failure assessment score on days 1 to 7 (OR 1.21 (95% CI 1.13 to 1.29)), and Charlson comorbidity index (OR 1.28 (95% CI 1.14 to 1.44)); higher baseline creatinine (OR 0.98 per 10 μmol/L (95% CI 0.97 to 0.996)) was associated with lower risk of death. Of 241 hospital survivors, 61 (25.3%) were RRT dependent at discharge. The only independent risk factor for RRT dependence was pre-existing heart failure (OR 3.13 (95% CI 1.46 to 6.74)). Neither mean daily fluid balance nor intradialytic hypotension was associated with RRT dependence in survivors. Associations between these exposures and mortality were similar in sensitivity analyses accounting for immortal time bias and dichotomising mean daily fluid balance as positive or negative. In the subgroup of patients with data on pre-RRT fluid balance, fluid overload at RRT initiation did not modify the association of mean daily fluid balance with mortality.

Conclusions

In this cohort of patients with AKI requiring RRT, a more positive mean daily fluid balance and intradialytic hypotension were associated with hospital mortality but not with RRT dependence at hospital discharge in survivors.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0624-8) contains supplementary material, which is available to authorized users.     

Timing of renal replacement therapy initiation by AKIN classification system

Introduction

Previous studies using Acute Kidney Injury Network (AKIN)/RIFLE criteria to classify early initiation of renal replacement therapy (RRT) have defined it as the therapy started in less severe AKIN/RIFLE stages. Generally, these studies failed in demonstrating measurable benefits.

Methods

We compared RRT initiation in critically ill patients and defined early or late RRT in reference to timing after stage 3 AKIN was met: patients beginning RRT within 24 hours after acute kidney injury (AKI) stage 3 were considered early starters. AKIN criteria were evaluated by both urine output (UO) and serum creatinine (sCr) and patients with acute-on-chronic kidney disease were excluded. A propensity score methodology was used to control variables.

Results

A total of 358 critically ill patients were submitted to RRT. Only 150 patients with pure AKI at stage 3 were analyzed. Mortality was lower in the early RRT group (51.5 vs. 77.9%, P = 0.001). After achieving balance between the groups using a propensity score, there was a significant 30.5 (95% confidence interval [CI] 14.4 to 45.2%, P = 0.002) relative decrease of mortality in the early RRT group. Moreover, patients on the early RRT group had lower duration of mechanical ventilation, time on RRT and a trend to lower intensive care unit (ICU) length of stay.

Conclusions

For the first time, AKIN was used with UO criterion to evaluate early and late RRT. Using a time-based approach could be a better parameter to access the association between RRT initiation and outcomes in patients with AKI.     

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Introduction

Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.

Methods

We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.

Results

Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G₁ cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.

Conclusions

Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.

Trial registration

ClinicalTrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT01209169","term_id":"NCT01209169"}}NCT01209169.     

Introducing intravascular microdialysis for continuous lactate monitoring in patients undergoing cardiac surgery: a prospective observational study

Introduction

Lactate is a marker of hypoperfusion and may be used for risk assessment in critically ill patients. Although evidence suggests that repeated lactate measurements are of clinical interest, how and when lactate should be analyzed is controversial. Intravascular microdialysis provides a novel method for the continuous monitoring of lactate, which may be clinically beneficial in critically ill patients.

Methods

Circulating lactate levels were continuously monitored in 80 patients undergoing cardiac surgery using either a separate single-lumen microdialysis catheter or a triple-lumen central venous catheter with an integrated microdialysis function. The catheter was placed with the tip positioned in the superior vena cava. Arterial blood gas samples were taken every hour to obtain reference values, and the lactate levels were analyzed in a blood gas analyzer.

Results

A total of 1,601 paired microdialysis–arterial blood gas lactate samples were obtained. Bland-Altman analysis showed a bias (mean difference) ± limits of agreement (±1.96 SD) of 0.02 ± 0.42 mmol/L. The regression coefficient was 0.98 (P = 0.0001).

Conclusions

Central venous microdialysis is an accurate and reliable method for continuous blood lactate monitoring in patients undergoing cardiac surgery. The system may be useful for early lactate-guided therapy in critically ill patients.     

Development and Standardization of a Furosemide Stress Test to Predict the Severity of Acute Kidney Injury

Introduction

In the setting of early acute kidney injury (AKI), no test has been shown to definitively predict the progression to more severe stages.

Methods

We investigated the ability of a furosemide stress test (FST) (one-time dose of 1.0 or 1.5 mg/kg depending on prior furosemide-exposure) to predict the development of AKIN Stage-III in 2 cohorts of critically ill subjects with early AKI. Cohort 1 was a retrospective cohort who received a FST in the setting of AKI in critically ill patients as part of Southern AKI Network. Cohort 2 was a prospective multicenter group of critically ill patients who received their FST in the setting of early AKI.

Results

We studied 77 subjects; 23 from cohort 1 and 54 from cohort 2; 25 (32.4%) met the primary endpoint of progression to AKIN-III. Subjects with progressive AKI had significantly lower urine output following FST in each of the first 6 hours (p<0.001). The area under the receiver operator characteristic curves for the total urine output over the first 2 hours following FST to predict progression to AKIN-III was 0.87 (p = 0.001). The ideal-cutoff for predicting AKI progression during the first 2 hours following FST was a urine volume of less than 200mls(100ml/hr) with a sensitivity of 87.1% and specificity 84.1%.

Conclusions

The FST in subjects with early AKI serves as a novel assessment of tubular function with robust predictive capacity to identify those patients with severe and progressive AKI. Future studies to validate these findings are warranted.     

Fluid balance and urine volume are independent predictors of mortality in acute kidney injury

Introduction

In ICUs, both fluid overload and oliguria are common complications associated with increased mortality among critically ill patients, particularly in acute kidney injury (AKI). Although fluid overload is an expected complication of oliguria, it remains unclear whether their effects on mortality are independent of each other. The aim of this study is to evaluate the impact of both fluid balance and urine volume on outcomes and determine whether they behave as independent predictors of mortality in adult ICU patients with AKI.

Methods

We performed a secondary analysis of data from a multicenter, prospective cohort study in 10 Italian ICUs. AKI was defined by renal sequential organ failure assessment (SOFA) score (creatinine >3.5 mg/dL or urine output (UO) <500 mL/d). Oliguria was defined as a UO <500 mL/d. Mean fluid balance (MFB) and mean urine volume (MUV) were calculated as the arithmetic mean of all daily values. Use of diuretics was noted daily. To assess the impact of MFB and MUV on mortality of AKI patients, multivariate analysis was performed by Cox regression.

Results

Of the 601 included patients, 132 had AKI during their ICU stay and the mortality in this group was 50%. Non-surviving AKI patients had higher MFB (1.31 ± 1.24 versus 0.17 ± 0.72 L/day; P <0.001) and lower MUV (1.28 ± 0.90 versus 2.35 ± 0.98 L/day; P <0.001) as compared to survivors. In the multivariate analysis, MFB (adjusted hazard ratio (HR) 1.67 per L/day, 95%CI 1.33 to 2.09; <0.001) and MUV (adjusted HR 0.47 per L/day, 95%CI 0.33 to 0.67; <0.001) remained independent risk factors for 28-day mortality after adjustment for age, gender, diabetes, hypertension, diuretic use, non-renal SOFA and sepsis. Diuretic use was associated with better survival in this population (adjusted HR 0.25, 95%CI 0.12 to 0.52; <0.001).

Conclusions

In this multicenter ICU study, a higher fluid balance and a lower urine volume were both important factors associated with 28-day mortality of AKI patients.     

Postoperative intubation time is associated with acute kidney injury in cardiac surgical patients

Introduction

Acute kidney injury (AKI) is a frequent complication after cardiac surgery and is associated with a poor prognosis. Mechanical ventilation is an important risk factor for developing AKI in critically ill patients. Ventilation with high tidal volumes has been associated with postoperative organ dysfunction in cardiac surgical patients. No data are available about the effects of the duration of postoperative respiratory support in the immediate postoperative period on the incidence of AKI in patients after cardiac surgery.

Method

We performed a secondary analysis of 584 elective cardiac surgical patients enrolled in an observational trial on the association between preoperative cerebral oxygen saturation and postoperative organ dysfunction and analyzed the incidence of AKI in patients with different times to extubation. The latter variable was graded in 4 h intervals (if below 16 h) or equal to or greater than 16 h. AKI was staged according to the AKI Network criteria.

Results

Overall, 165 (28.3%) patients developed AKI (any stage), 43 (7.4%) patients needed renal replacement therapy. Patients developing AKI had a significantly (P <0.001) lower renal perfusion pressure (RPP) in the first 8 hours after surgery (57.4 mmHg (95% CI: 56.0 to 59.0 mmHg)) than patients with a postoperatively preserved renal function (60.5 mmHg ((95% CI: 59.9 to 61.4 mmHg). The rate of AKI increased from 17.0% in patients extubated within 4 h postoperatively to 62.3% in patients ventilated for more than 16 h (P <0.001). Multivariate logistic regression analysis of variables significantly associated with AKI in the univariate analysis revealed that the time to the first extubation (OR: 1.024/hour, 95% CI: 1.011 to 1.044/hour; P <0.001) and RPP (OR: 0.963/mmHg; 95% CI: 0.934 to 0.992; P <0.001) were independently associated with AKI.

Conclusion

Without taking into account potentially unmeasured confounders, these findings are suggestive that the duration of postoperative positive pressure ventilation is an important and previously unrecognized risk factor for AKI in cardiac surgical patients, independent from low RPP as an established AKI trigger, and that even a moderate delay of extubation increases AKI risk. If replicated independently, these findings may have relevant implications for clinical care and for further studies aiming at the prevention of cardiac surgery associated AKI.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0547-4) contains supplementary material, which is available to authorized users.     

Whole body protein kinetics during hypocaloric and normocaloric feeding in critically ill patients

Introduction

Optimal feeding of critically ill patients in the ICU is controversial. Existing guidelines rest on rather weak evidence. Whole body protein kinetics may be an attractive technique for assessing optimal protein intake. In this study, critically ill patients were investigated during hypocaloric and normocaloric IV nutrition.

Methods

Neurosurgical patients on mechanical ventilation (n = 16) were studied during a 48-hour period. In random order 50% and 100% of measured energy expenditure was given as IV nutrition during 24 hours, corresponding to hypocaloric and normocaloric nutrition, respectively. At the end of each period, whole body protein turnover was measured using d5-phenylalanine and 13C-leucine tracers.

Results

The phenylalanine tracer indicated that whole-body protein synthesis was lower during hypocaloric feeding, while whole-body protein degradation and amino acid oxidation were unaltered, which resulted in a more negative protein balance, namely −1.9 ± 2.1 versus −0.7 ± 1.3 mg phenylalanine/kg/h (P = 0.014). The leucine tracer indicated that whole body protein synthesis and degradation and amino acid oxidation were unaltered, but the protein balance was negative during hypocaloric feeding, namely −0.3 ± 0.5 versus 0.6 ± 0.5 mg leucine/kg/h (P < 0.001).

Conclusion

In the patient group studied, hypocaloric feeding was associated with a more negative protein balance, but the amino acid oxidation was not different. The protein kinetics measurements and the study’s investigational protocol were useful for assessing the efficacy of nutrition support on protein metabolism in critically ill patients.     

Urinary angiotensinogen predicts adverse outcomes among acute kidney injury patients in the intensive care unit

Introduction

Acute kidney injury (AKI) is commonly observed in the intensive care unit (ICU), where it can be caused by a variety of factors. The objective of this study was to evaluate the prognostic value of urinary angiotensinogen, a candidate prognostic AKI biomarker identified in post-cardiac surgery patients, in this heterogeneous population.

Methods

Urinary angiotensinogen was measured by ELISA and corrected for urine creatinine in 45 patients who developed AKI in the ICU. Patients were grouped by AKI etiology, and the angiotensinogen-to-creatinine ratio (uAnCR) was compared among the groups using the Kruskal-Wallis test. The ability of uAnCR to predict the following endpoints was tested using the area under the ROC curve (AUC): the need for renal replacement therapy (RRT) or death, increased length of stay (defined as hospital discharge > 7 days or death ≤ 7 days from sample collection), and worsening AKI (defined as an increase in serum creatinine > 0.3 mg/dL after sample collection or RRT).

Results

uAnCR was significantly elevated in patients who met the composite outcome RRT or death (89.4 vs 25.4 ng/mg; P = 0.01), and it was a strong predictor of this outcome (AUC = 0.73). Patients with uAnCR values above the median for the cohort (55.21 ng/mg) had increased length of stay compared to patients with uAnCR ≤ 55.21 ng/mg (22 days vs 7 days after sample collection; P = 0.01). uAnCR was predictive of the outcome increased length of stay (AUC = 0.77). uAnCR was also a strong predictor of worsening of AKI (AUC = 0.77). The uAnCR of patients with pre-renal AKI was lower compared to patients with AKI of other causes (median uAnCR 11.3 vs 80.2 ng/mg; P = 0.02).

Conclusions

Elevated urinary angiotensinogen is associated with adverse events in AKI patients in the ICU. It could be used to identify high risk patients who would benefit from timely intervention that could improve their outcomes.     

Combining creatinine and volume kinetics identifies missed cases of acute kidney injury following cardiac arrest

Introduction

Fluid resuscitation in the critically ill often results in a positive fluid balance, potentially diluting the serum creatinine concentration and delaying diagnosis of acute kidney injury (AKI).

Methods

Dilution during AKI was quantified by combining creatinine and volume kinetics to account for fluid type, and rates of fluid infusion and urine output. The model was refined using simulated patients receiving crystalloids or colloids under four glomerular filtration rate (GFR) change scenarios and then applied to a cohort of critically ill patients following cardiac arrest.

Results

The creatinine concentration decreased during six hours of fluid infusion at 1 litre-per-hour in simulated patients, irrespective of fluid type or extent of change in GFR (from 0% to 67% reduction). This delayed diagnosis of AKI by 2 to 9 hours. Crystalloids reduced creatinine concentration by 11 to 19% whereas colloids reduced concentration by 36 to 43%. The greatest reduction was at the end of the infusion period. Fluid dilution alone could not explain the rapid reduction of plasma creatinine concentration observed in 39 of 49 patients after cardiac arrest. Additional loss of creatinine production could account for those changes. AKI was suggested in six patients demonstrating little change in creatinine, since a 52 ± 13% reduction in GFR was required after accounting for fluid dilution and reduced creatinine production. Increased injury biomarkers within a few hours of cardiac arrest, including urinary cystatin C and plasma and urinary Neutrophil-Gelatinase-Associated-Lipocalin (biomarker-positive, creatinine-negative patients) also indicated AKI in these patients.

Conclusions

Creatinine and volume kinetics combined to quantify GFR loss, even in the absence of an increase in creatinine. The model improved disease severity estimation, and demonstrated that diagnostic delays due to dilution are minimally affected by fluid type. Creatinine sampling should be delayed at least one hour following a large fluid bolus to avoid dilution. Unchanged plasma creatinine post cardiac arrest signifies renal injury and loss of function.

Trial registration

Australian and New Zealand Clinical Trials Registry ACTRN12610001012066.     

The clinical utility window for acute kidney injury biomarkers in the critically ill

Introduction

Acute Kidney Injury (AKI) biomarker utility depends on sample timing after the onset of renal injury. We compared biomarker performance on arrival in the emergency department (ED) with subsequent performance in the intensive care unit (ICU).

Methods

Urinary and plasma Neutrophil Gelatinase-Associated Lipocalin (NGAL), and urinary Cystatin C (CysC), alkaline phosphatase, γ-Glutamyl Transpeptidase (GGT), α- and π-Glutathione S-Transferase (GST), and albumin were measured on ED presentation, and at 0, 4, 8, and 16 hours, and days 2, 4 and 7 in the ICU in patients after cardiac arrest, sustained or profound hypotension or ruptured abdominal aortic aneurysm. AKI was defined as plasma creatinine increase ≥26.5 μmol/l within 48 hours or ≥50% within 7 days.

Results

In total, 45 of 77 patients developed AKI. Most AKI patients had elevated urinary NGAL, and plasma NGAL and CysC in the period 6 to 24 hours post presentation. Biomarker performance in the ICU was similar or better than when measured earlier in the ED. Plasma NGAL diagnosed AKI at all sampling times, urinary NGAL, plasma and urinary CysC up to 48 hours, GGT 4 to 12 hours, and π-GST 8 to 12 hours post insult. Thirty-one patients died or required dialysis. Peak 24-hour urinary NGAL and albumin independently predicted 30-day mortality and dialysis; odds ratios 2.87 (1.32 to 6.26), and 2.72 (1.14 to 6.48), respectively. Urinary NGAL improved risk prediction by 11% (IDI_event of 0.06 (0.002 to 0.19) and IDI_non-event of 0.04 (0.002 to 0.12)).

Conclusion

Early measurement in the ED has utility, but not better AKI diagnostic performance than later ICU measurement. Plasma NGAL diagnosed AKI at all time points. Urinary NGAL best predicted mortality or dialysis compared to other biomarkers.

Trial registration

Australian and New Zealand Clinical Trials Registry ACTRN12610001012066. Registered 12 February 2010     

Inflammation biomarkers and delirium in critically ill patients

Introduction

Delirium is a common occurrence in critically ill patients and is associated with an increase in morbidity and mortality. Septic patients with delirium may differ from a general critically ill population. The aim of this investigation was to study the relationship between systemic inflammation and the development of delirium in septic and non-septic critically ill patients.

Methods

We performed a prospective cohort study in a 20-bed mixed intensive care unit (ICU) including 78 (delirium = 31; non-delirium = 47) consecutive patients admitted for more than 24 hours. At enrollment, patients were allocated to septic or non-septic groups according to internationally agreed criteria. Delirium was diagnosed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) during the first 72 hours of ICU admission. Blood samples were collected within 12 hours of enrollment for determination of tumor necrosis factor (TNF)-α, soluble TNF Receptor (STNFR)-1 and -2, interleukin (IL)-1β, IL-6, IL-10 and adiponectin.

Results

Out of all analyzed biomarkers, only STNFR1 (P = 0.003), STNFR2 (P = 0.005), adiponectin (P = 0.005) and IL-1β (P < 0.001) levels were higher in delirium patients. Adjusting for sepsis and sedation, these biomarkers were also independently associated with delirium occurrence. However, none of them were significant influenced by sepsis.

Conclusions

STNFR1, STNFR2, adiponectin and IL-1β were associated with delirium. Sepsis did not modify the relationship between the biomarkers and delirium occurrence.     

Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury - true GFR versus urinary creatinine clearance and estimating equations

Introduction

Estimation of kidney function in critically ill patients with acute kidney injury (AKI), is important for appropriate dosing of drugs and adjustment of therapeutic strategies, but challenging due to fluctuations in kidney function, creatinine metabolism and fluid balance. Data on the agreement between estimating and gold standard methods to assess glomerular filtration rate (GFR) in early AKI are lacking. We evaluated the agreement of urinary creatinine clearance (CrCl) and three commonly used estimating equations, the Cockcroft Gault (CG), the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, in comparison to GFR measured by the infusion clearance of chromium-ethylenediaminetetraacetic acid (⁵¹Cr-EDTA), in critically ill patients with early AKI after complicated cardiac surgery.

Methods

Thirty patients with early AKI were studied in the intensive care unit, 2 to 12 days after complicated cardiac surgery. The infusion clearance for ⁵¹Cr-EDTA obtained as a measure of GFR (GFR_51Cr-EDTA) was calculated from the formula: GFR (mL/min/1.73m²) = (⁵¹Cr-EDTA infusion rate × 1.73)/(arterial ⁵¹Cr-EDTA × body surface area) and compared with the urinary CrCl and the estimated GFR (eGFR) from the three estimating equations. Urine was collected in two 30-minute periods to measure urine flow and urine creatinine. Urinary CrCl was calculated from the formula: CrCl (mL/min/1.73m²) = (urine volume × urine creatinine × 1.73)/(serum creatinine × 30 min × body surface area).

Results

The within-group error was lower for GFR_51Cr-EDTA than the urinary CrCl method, 7.2% versus 55.0%. The between-method bias was 2.6, 11.6, 11.1 and 7.39 ml/min for eGFR_CrCl, eGFR_MDRD, eGFR_CKD-EPI and eGFR_CG, respectively, when compared to GFR_51Cr-EDTA. The error was 103%, 68.7%, 67.7% and 68.0% for eGFR_CrCl, eGFR_MDRD, eGFR_CKD-EPI and eGFR_CG, respectively, when compared to GFR_51Cr-EDTA.

Conclusions

The study demonstrated poor precision of the commonly utilized urinary CrCl method for assessment of GFR in critically ill patients with early AKI, suggesting that this should not be used as a reference method when validating new methods for assessing kidney function in this patient population. The commonly used estimating equations perform poorly when estimating GFR, with high biases and unacceptably high errors.     

Elevated plasma thrombomodulin and angiopoietin-2 predict the development of acute kidney injury in patients with acute myocardial infarction

Introduction

Acute kidney injury (AKI) following acute myocardial infarction (AMI) is associated with unfavorable prognosis. Endothelial activation and injury were found to play a critical role in the development of both AKI and AMI. This pilot study aimed to determine whether the plasma markers of endothelial injury and activation could serve as independent predictors for AKI in patients with AMI.

Methods

This prospective study was conducted from March 2010 to July 2012 and enrolled consecutive 132 patients with AMI receiving percutaneous coronary intervention (PCI). Plasma levels of thrombomodulin (TM), von Willebrand factor (vWF), angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) were measured on day 1 of AMI. AKI was defined as elevation of serum creatinine of more than 0.3 mg/dL within 48 hours.

Results

In total, 13 out of 132 (9.8%) patients with AMI developed AKI within 48 hours. Compared with patients without AKI, patients with AKI had increased plasma levels of Ang-2 (6338.28 ± 5862.77 versus 2412.03 ± 1256.58 pg/mL, P = 0.033) and sTM (7.6 ± 2.26 versus 5.34 ± 2.0 ng/mL, P < 0.001), and lower estimated glomerular filtration rate (eGFR) (46.5 ± 20.2 versus 92.5 ± 25.5 mL/min/1.73 m², P < 0.001). Furthermore, the areas under the receiver operating curves demonstrated that plasma thrombomodulin (TM) and Ang-2 levels on day 1 of AMI had modest discriminative powers for predicting AKI development following AMI (0.796, P <0.001; 0.833, P <0.001; respectively).

Conclusions

Endothelial activation, quantified by plasma levels of TM and Ang-2 may play an important role in development of AKI in patients with AMI.     

Early treatment with IgM-enriched intravenous immunoglobulin does not mitigate critical illness polyneuropathy and/or myopathy in patients with multiple organ failure and SIRS/sepsis: a prospective,randomized, placebo-controlled,double-blinded trial

Introduction

Critical illness polyneuropathy and/or myopathy (CIPNM) is a severe complication of critical illness. Retrospective data suggest that early application of IgM-enriched intravenous immunoglobulin (IVIG) may prevent or mitigate CIPNM. Therefore, the primary objective was to assess the effect of early IgM-enriched IVIG versus placebo to mitigate CIPNM in a prospective setting.

Methods

In this prospective, randomized, double-blinded and placebo-controlled trial, 38 critically ill patients with multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS)/sepsis, and early clinical signs of CIPNM were included. Patients were randomly assigned to be treated either with IgM-enriched IVIG or placebo over a period of three days. CIPNM was measured by the CIPNM severity sum score based on electrophysiological stimulation of the median, ulnar, and tibial nerves on days 0, 4, 7, 14 and on the histological evaluation of muscle biopsies on days 0 and 14 and ranged from 0 (no CIPNM) to 8 (very severe CIPNM).

Results

A total of 38 critically ill patients were included and randomized to receive either IgM-enriched IVIG (n = 19) or placebo (n = 19). Baseline characteristics were similar between the two groups. CIPNM could not be improved by IVIG treatment, represented by similar CIPNM severity sum scores on day 14 (IVIG vs. placebo: 4.8 ± 2.0 vs. 4.5 ± 1.8; P = 0.70). CIPNM severity sum score significantly increased from baseline to day 14 (3.5 ± 1.6 vs. 4.6 ± 1.9; P = 0.002). After an interim analysis the study was terminated early due to futility in reaching the primary endpoint.

Conclusions

Early treatment with IVIG did not mitigate CIPNM in critically ill patients with MOF and SIRS/sepsis.

Trial registration

Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01867645","term_id":"NCT01867645"}}NCT01867645     

Calorie intake and patient outcomes in severe acute kidney injury: findings from The Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study trial

Introduction

Current practice in the delivery of caloric intake (DCI) in patients with severe acute kidney injury (AKI) receiving renal replacement therapy (RRT) is unknown. We aimed to describe calorie administration in patients enrolled in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy (RENAL) study and to assess the association between DCI and clinical outcomes.

Methods

We performed a secondary analysis in 1456 patients from the RENAL trial. We measured the dose and evolution of DCI during treatment and analyzed its association with major clinical outcomes using multivariable logistic regression, Cox proportional hazards models, and time adjusted models.

Results

Overall, mean DCI during treatment in ICU was low at only 10.9 ± 9 Kcal/kg/day for non-survivors and 11 ± 9 Kcal/kg/day for survivors. Among patients with a lower DCI (below the median) 334 of 729 (45.8%) had died at 90-days after randomization compared with 316 of 727 (43.3%) patients with a higher DCI (above the median) (P = 0.34). On multivariable logistic regression analysis, mean DCI carried an odds ratio of 0.95 (95% confidence interval (CI): 0.91-1.00; P = 0.06) per 100 Kcal increase for 90-day mortality. DCI was not associated with significant differences in renal replacement (RRT) free days, mechanical ventilation free days, ICU free days and hospital free days. These findings remained essentially unaltered after time adjusted analysis and Cox proportional hazards modeling.

Conclusions

In the RENAL study, mean DCI was low. Within the limits of such low caloric intake, greater DCI was not associated with improved clinical outcomes.

Trial registration

ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT00221013","term_id":"NCT00221013"}}NCT00221013