Non-interventional follow-up versus fluid bolus in RESPONSE to oliguria in hemodynamically stable critically ill patients: a randomized controlled pilot trial.

BACKGROUND: Fluid bolus therapy is a common intervention to improve urine output. Data concerning the effect of a fluid bolus on oliguria originate mainly from observational studies and remain controversial regarding the actual benefit of such therapy. We compared the effect of a follow-up approach without fluid bolus to a 500 mL fluid bolus on urine output in hemodynamically stable critically ill patients with oliguria at least for 2 h (urine output < 0.5 mL/kg/h) in randomized setting. METHODS: We randomized 130 patients in 1:1 fashion to receive either (1) non-interventional follow-up (FU) for 2 h or (2) 500 mL crystalloid fluid bolus (FB) administered over 30 min. The primary outcome was the proportion of patients who doubled their urine output, defined as 2-h urine output post-randomization divided by urine output 2 h pre-randomization. The outcomes were adjusted for the stratification variables (presence of sepsis or AKI) using two-tailed regression. Obtained odds ratios were converted to risk ratios (RR) with 95% confidence intervals (CI). The between-group difference in the continuous variables was compared using mean or median regression and expressed with 95% CIs. RESULTS: Altogether 10 (15.9%) of 63 patients in the FU group and 22 (32.8%) of 67 patients in FB group doubled their urine output during the 2-h period, RR (95% CI) 0.49 (0.23-0.71), P = 0.026. Median [IQR] change in individual urine output 2 h post-randomization compared to 2 h pre-randomization was - 7 [- 19 to 17] mL in the FU group and 19[0-53] mL in the FB group, median difference (95% CI) - 23 (- 36 to - 10) mL, P = 0.001. Median [IQR] duration of oliguria in the FU group was 4 [2-8] h and in the FB group 2 [0-6] h, median difference (95%CI) 2 (0-4) h, P = 0.038. Median [IQR] cumulative fluid balance on study day was lower in the FU group compared to FB group, 678 [518-1029] mL versus 1071 [822-1505] mL, respectively, median difference (95%CI) - 387 (- 635 to - 213) mL, P < 0.001. CONCLUSIONS: Follow-up approach to oliguria compared to administering a fluid bolus of 500 mL crystalloid in oliguric patients improved urine output less frequently but lead to lower cumulative fluid balance. Trial registration clinical. TRIALS: gov, NCT02860572. Registered 9 August 2016.

Fluid management in acute kidney injury: from evaluating fluid responsiveness towards assessment of fluid tolerance.

Despite the widespread use of intravenous fluids in acute kidney injury (AKI), solid evidence is lacking. Intravenous fluids mainly improve AKI due to true hypovolaemia, which is difficult to discern at the bedside unless it is very pronounced. Empiric fluid resuscitation triggered only by elevated serum creatinine levels or oliguria is frequently misguided, especially in the presence of fluid intolerance syndromes such as increased extravascular lung water, capillary leak, intra-abdominal hypertension, and systemic venous congestion. While fluid responsiveness tests clearly identify patients who will not benefit from fluid administration (i.e. those without an increase in cardiac output), the presence of fluid responsiveness does not guarantee that fluid therapy is indicated or even safe. This review calls for more attention to the concept of fluid tolerance, incorporating it into a practical algorithm with systematic venous Doppler ultrasonography assessment to use at the bedside, thereby lowering the risk of detrimental kidney congestion in AKI.

Assessment of glomerular and tubular function to guide fluid management in a pre-eclamptic critical patient with oliguria and volume overload: case report.

Oliguria in the setting of critically ill patients is usually treated by admini-stering fluids and furosemide [1]. Invasive therapies, namely renal replacement therapies (RRT), are reserved for patients in whom less invasive measures have failed [2], especially if acute pulmonary oedema complicates the clinical picture [1]. Intravascular volume depletion elicits a kidney response consisting of augmented sodium retention at Henle's loop and water at the collecting tubules. In such conditions, loop diuretics such as furosemide would be less effective to improve diuresis and water loss than osmotic diuretics such as mannitol [3, 4]. This case report aims to highlight the utility of the assessment of the glomerular and tubular functions to identify an ineffective diuretic strategy and to select a successful one, which prevented the use of invasive RRT. A 33-year-old female patient suffering from preeclampsia (gestational age was 35 + 6 weeks) was admitted to our Post-surgical Intensive Care Unit (PICU) after an urgent caesarean section performed under spinal anaesthesia, without further incidents.

COVID-19 patients in intensive care develop predominantly oliguric acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a syndrome of reduced glomerular filtration rate and/or reduced urine flow associated with mortality in corona virus disease 2019 (COVID-19). AKI is often associated with renal tissue damage, which may lead to chronic kidney disease. Biomarkers of tissue damage may identify patients of particular risk. METHODS: In a prospective observational study of 57 patients admitted to intensive care, AKI incidence and characteristics was evaluated according to KDIGO criteria and related to days after admission. Urinary albumin, Neutrophil Gelatinase-Associated Lipocalin (NGAL), Kidney Injury Molecule 1 (KIM-1) and Plasma Tissue Inhibitor of MetalloProteinase 2 (TIMP-2) were analysed in 52 patients at admission. The majority (n = 51, 89%) of patients developed AKI, and 27 (47%) patients had predominantly oliguric AKI where oliguria was more severe than plasma Creatinine increase. Severe oliguria within first 2 days after admission was common (n = 37, 65%), whereas stage 2 and 3 AKI due to Creatinine occurred later than day 2 in 67% (12/18) of cases. Renal replacement therapy was started in 9 (16%) patients, and 30-day mortality was 28%. Urinary biomarkers were increased in a majority of patients, but did not robustly predict KDIGO stage. Most patients had microalbuminuria, and severe albuminuria (albumin Creatinine ratio > 30 mg/mmol) was found in n = 9 (17%) patients. CONCLUSIONS: A majority of patients with COVID-19 admitted to the ICU develop AKI. The functional deficit is often low urinary volume, and initial levels of biomarkers are generally increased without clear relation to final AKI stage.

Pacientes oligúricos hemodinamicamente estáveis geralmente não respondem ao desafio hídrico / Hemodynamically stable oliguric patients usually do not respond to fluid challenge

RESUMO Objetivo: Avaliar a responsividade renal após desafio hídrico em pacientes oligúricos na unidade de terapia intensiva. Método: Conduzimos um estudo observacional prospectivo em uma unidade de terapia intensiva universitária. Pacientes com débito urinário inferior a 0,5mL/kg/hora por 3 horas, com pressão arterial média acima de 60mmHg receberam um desafio hídrico. Examinamos a responsividade renal aos fluidos (definida como débito urinário acima de 0,5mL/kg/hora por 3 horas) após o desafio hídrico. Resultados: Avaliaram-se 42 pacientes (idade 67 ± 13 anos; APACHE II 16 ± 6). As características dos pacientes foram similares entre os respondedores e os não respondedores renais. Treze pacientes (31%) foram respondedores renais. Antes do desafio hídrico, os parâmetros hemodinâmicos e de perfusão não foram diferentes entre os pacientes que apresentaram aumento do débito urinário e os que não apresentaram. Calcularam-se as áreas sob a curva receiver operating characteristic para os níveis pré-desafio hídrico de pressão arterial média, frequência cardíaca, creatinina, ureia, depuração de creatinina, proporção ureia/creatinina e lactato. Nenhum desses parâmetros foi sensível ou suficientemente específico para predizer a reversão da oligúria. Conclusão: Após obtenção de estabilidade hemodinâmica, os pacientes oligúricos não alcançaram aumento do débito urinário em resposta ao desafio hídrico. Os parâmetros de hemodinâmica sistêmica, perfusão ou renais foram preditores fracos de responsividade urinária. Nossos resultados sugerem que a reposição de volume com objetivo de corrigir oligúria em pacientes sem hipovolemia óbvia deve ser realizada com cautela.

ABSTRACT Objective: To evaluate renal responsiveness in oliguric critically ill patients after a fluid challenge. Methods: We conducted a prospective observational study in one university intensive care unit. Patients with urine output < 0.5mL/kg/h for 3 hours with a mean arterial pressure > 60mmHg received a fluid challenge. We examined renal fluid responsiveness (defined as urine output > 0.5mL/kg/h for 3 hours) after fluid challenge. Results: Forty-two patients (age 67 ± 13 years; APACHE II score 16 ± 6) were evaluated. Patient characteristics were similar between renal responders and renal nonresponders. Thirteen patients (31%) were renal responders. Hemodynamic or perfusion parameters were not different between those who did and those who did not increase urine output before the fluid challenge. The areas under the receiver operating characteristic curves were calculated for mean arterial pressure, heart rate, creatinine, urea, creatinine clearance, urea/creatinine ratio and lactate before the fluid challenge. None of these parameters were sensitive or specific enough to predict reversal of oliguria. Conclusion: After achieving hemodynamic stability, oliguric patients did not increase urine output after a fluid challenge. Systemic hemodynamic, perfusion or renal parameters were weak predictors of urine responsiveness. Our results suggest that volume replacement to correct oliguria in patients without obvious hypovolemia should be done with caution.

Noninterventional follow-up vs fluid bolus in RESPONSE to oliguria-The RESPONSE trial protocol and statistical analysis plan.

BACKGROUND: Oliguria is a frequent trigger for administering a fluid bolus, but the effect of fluid bolus in improving urine output is inadequately demonstrated. Here, we summarize the protocol and detailed statistical analysis plan of the randomized, controlled RESPONSE trial comparing follow-up as the experimental group and a 500 mL crystalloid fluid bolus as the control group for oliguria in critically ill oliguric patients. METHODS: Our trial is an investigator-initiated, randomized, controlled, pilot trial conducted in three ICUs in two centers. We aim to randomize 1:1 altogether 130 hemodynamically stable oliguric patients either to a 2-hour follow-up without interventions or to receive a crystalloid bolus of 500 mL over 30 minutes. The primary outcome is the change in individual urine output during the 2-hour period compared to 2 hours preceding randomization. Doubling of the urine output is considered clinically significant. Additionally, we record the duration of oliguria, physiological and biochemical variables, adverse events, and the incidences of acute kidney injury and renal replacement therapy. CONCLUSIONS: Oliguria is a frequent trigger for potentially harmful fluid loading. Therefore, the RESPONSE trial will give information of the potential effect of fluid bolus on oliguria in critically ill patients. TRIAL REGISTRATION: clinical.trials.gov, NCT02860572.

Hemodynamically stable oliguric patients usually do not respond to fluid challenge. / Pacientes oligúricos hemodinamicamente estáveis geralmente não respondem ao desafio hídrico.

OBJECTIVE: To evaluate renal responsiveness in oliguric critically ill patients after a fluid challenge. METHODS: We conducted a prospective observational study in one university intensive care unit. Patients with urine output < 0.5mL/kg/h for 3 hours with a mean arterial pressure > 60mmHg received a fluid challenge. We examined renal fluid responsiveness (defined as urine output > 0.5mL/kg/h for 3 hours) after fluid challenge. RESULTS: Forty-two patients (age 67 ± 13 years; APACHE II score 16 ± 6) were evaluated. Patient characteristics were similar between renal responders and renal nonresponders. Thirteen patients (31%) were renal responders. Hemodynamic or perfusion parameters were not different between those who did and those who did not increase urine output before the fluid challenge. The areas under the receiver operating characteristic curves were calculated for mean arterial pressure, heart rate, creatinine, urea, creatinine clearance, urea/creatinine ratio and lactate before the fluid challenge. None of these parameters were sensitive or specific enough to predict reversal of oliguria. CONCLUSION: After achieving hemodynamic stability, oliguric patients did not increase urine output after a fluid challenge. Systemic hemodynamic, perfusion or renal parameters were weak predictors of urine responsiveness. Our results suggest that volume replacement to correct oliguria in patients without obvious hypovolemia should be done with caution.

OBJETIVO: Avaliar a responsividade renal após desafio hídrico em pacientes oligúricos na unidade de terapia intensiva. MÉTODO: Conduzimos um estudo observacional prospectivo em uma unidade de terapia intensiva universitária. Pacientes com débito urinário inferior a 0,5mL/kg/hora por 3 horas, com pressão arterial média acima de 60mmHg receberam um desafio hídrico. Examinamos a responsividade renal aos fluidos (definida como débito urinário acima de 0,5mL/kg/hora por 3 horas) após o desafio hídrico. RESULTADOS: Avaliaram-se 42 pacientes (idade 67 ± 13 anos; APACHE II 16 ± 6). As características dos pacientes foram similares entre os respondedores e os não respondedores renais. Treze pacientes (31%) foram respondedores renais. Antes do desafio hídrico, os parâmetros hemodinâmicos e de perfusão não foram diferentes entre os pacientes que apresentaram aumento do débito urinário e os que não apresentaram. Calcularam-se as áreas sob a curva receiver operating characteristic para os níveis pré-desafio hídrico de pressão arterial média, frequência cardíaca, creatinina, ureia, depuração de creatinina, proporção ureia/creatinina e lactato. Nenhum desses parâmetros foi sensível ou suficientemente específico para predizer a reversão da oligúria. CONCLUSÃO: Após obtenção de estabilidade hemodinâmica, os pacientes oligúricos não alcançaram aumento do débito urinário em resposta ao desafio hídrico. Os parâmetros de hemodinâmica sistêmica, perfusão ou renais foram preditores fracos de responsividade urinária. Nossos resultados sugerem que a reposição de volume com objetivo de corrigir oligúria em pacientes sem hipovolemia óbvia deve ser realizada com cautela.

Importance of intraoperative oliguria during major abdominal surgery: findings of the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery trial.

BACKGROUND: The association between intraoperative oliguria during major abdominal surgery and the subsequent development of postoperative acute kidney injury (AKI) remains poorly defined. We hypothesised that, in such patients, intraoperative oliguria would be an independent predictor of subsequent AKI. METHODS: We performed a post hoc analysis of data from the Restrictive versus Liberal Fluid Therapy in Major Abdominal Surgery (RELIEF) trial of conservative vs liberal fluid therapy during and after major abdominal surgery. We used χ2, logistic regression, and fractional polynomials to study the association between intraoperative oliguria defined as a urinary output <0.5 ml kg-1 h-1 and the development of postoperative AKI defined by the Kidney Disease Improving Global Outcomes consensus criteria. RESULTS: We included 2444 of 2983 patients from the RELIEF trial in this study. A total of 889 patients (36%) met oliguric criteria intraoperatively. Oliguria occurred in 35% of those without AKI, and 44%, 48%, and 45% of those who developed postoperative AKI Stages 1-3, respectively (P<0.001 for trend). Intraoperative oliguria was associated with an increased risk of AKI, risk ratio: 1.38 (95% confidence interval: 1.14-1.44; P<0.001), but greater intensity of oliguria (urine output <0.3 ml kg-1 h-1) did not increase this risk further. Most patients with oliguria did not develop AKI; the positive predictive value of oliguria was 25.5%, and the negative predictive value was 81.6%. CONCLUSIONS: Intraoperative oliguria, defined as urine output <0.5 ml kg-1 h-1, was relatively common and was associated with postoperative AKI. However, the predictive utility of oliguria for AKI was low, whilst its absence had a good predictive value for an AKI-free postoperative course. CLINICAL TRIAL REGISTRATION: NCT01424150.

Oliguria in critically ill patients: a narrative review.

Oliguria is often observed in critically ill patients. However, different thresholds in urine output (UO) have raised discussion as to the clinical importance of a transiently reduced UO of less than 0.5 ml/kg/h lasting for at least 6 h. While some studies have demonstrated that isolated oliguria without a concomitant increase in serum creatinine is associated with higher mortality rates, different underlying pathophysiological mechanisms suggest varied clinical importance of reduced UO, as some episodes of oliguria may be fully reversible. We aim to explore the clinical relevance of oliguria in critically ill patients and propose a clinical pathway for the diagnostic and therapeutic management of an oliguric, critically ill patient.

Urine volume as a predicting factor for furosemide clearance during continuous infusion in AKI septic shock patients on hemodiafiltration.

BACKGROUND: This study assessed the contribution of intracorporeal (IC) and extracorporeal clearance (EC) of furosemide in patients with septic acute kidney injury (AKI), and the relationship between plasma concentrations and urine volume. METHODS: Prospective cohort observational study of 15 patients with septic AKI undergoing continuous veno-venous hemodiafiltration (CVVHDF) divided according to urine volume (< 500 ml/12 h, Oliguria group, n = 5; > 500 ml/12 h, Diuresis group, n = 10) during continuous infusion of furosemide (120 mg/12 h) at steady-state condition. Plasma and effluent furosemide concentrations were determined by high-performance liquid chromatography (HPLC)-mass spectrometry every 12 h for 48 h. RESULTS: Furosemide plasma concentrations and total body clearance (TBC) were 6.14 mg/l and 22.1 ml/min for the Oliguria group, and 2.63 mg/l and 54.4 ml/min for the Diuresis group, respectively (p < 0.05). When urine volume was < 500 ml/24 h, the furosemide plasma concentrations peaked at the potentially toxic value of 13.0 mg/l. Furosemide EC was not relevant for the Diuresis group, but it represented 18% of TBC for the Oliguria group. Furosemide plasma concentrations correlated positively with dose infusion for both groups (r = 0.728 and 0.685, p < 0.05), and negatively with urine volume only for the Diuresis (r = - 0.578, p < 0.01) but not for the Oliguria group (r = - 0.089, p = 0.715). CONCLUSIONS: For patients with urine volume > 500 ml/12 h continuous infusion of furosemide up to 480 mg/24 h leads to increasing urine volume, which can predict furosemide plasma levels within its safety range. When the urine volume is lower, the furosemide plasma levels are increased beyond any further diuretic efficacy.

Factors affecting serum concentration of vancomycin in critically ill oliguric pediatric patients receiving continuous venovenous hemodiafiltration.

Vancomycin is known to be unintentionally eliminated by continuous renal replacement therapy, and the protein bound fraction of vancomycin is also known to be different in adults and children. However, there are only a few studies investigating the relationship between the dose of continuous venovenous hemodiafiltration (CVVHDF) parameters and serum concentration of vancomycin in pediatric patients. The aim of this study was to determine clinical and demographic parameters that significantly affect serum vancomycin concentrations. This retrospective cohort study was conducted at a pediatric intensive care unit in a tertiary university children's hospital. Data from oliguric patients who underwent CVVHDF and vancomycin therapeutic drug monitoring were collected. The correlation between factors affecting serum concentration of vancomycin was analyzed using mixed effect model. A total of 177 serum samples undergoing vancomycin therapeutic drug monitoring were analyzed. The median age of study participants was 2.23 (interquartile range, 0.3-11.84) years, and 126 (71.19%) were male patients. Serum concentration of vancomycin decreased significantly as the effluent flow rate (EFR; P < 0.001), dialysate flow rate (DFR; P = 0.009), replacement fluid flow rate (RFFR; P = 0.008), the proportion of RFFR in the sum of DFR and RFFR (P = 0.025), and residual urine output increased. The adjusted R2 of the multivariate regression model was 0.874 (P < 0.001) and the equation was as follows: Vancomycin trough level (mg/L) = (0.283 × daily dose of vancomycin [mg/kg/d]) + (365.139 / EFR [mL/h/kg])-(15.842 × residual urine output [mL/h/kg]). This study demonstrated that the serum concentration of vancomycin was associated with EFR, DFR, RFFR, the proportion of RFFR, and residual urine output in oliguric pediatric patients receiving CVVHDF.

[Preliminary study of the arm equilibrium pressure to predict the effect of fluid challenge on urine output in oliguric intensive care unit patients].

Objective: To evaluate whether arm equilibrium pressure (Parm) is helpful to predict the effect of fluid load in improving oliguria in intensive care unit(ICU) patients. Methods: Hemodynamically stable patients [mean artery pressure (MAP)>65 mmHg (1 mmHg=0.133 kPa), heart rate (HR)<120 beats/min, lactic acid<2 mmol/L] with urine output (UO)<0.5 ml·kg(-1)·h(-1) for 3 consecutive hours were enrolled. The fluid loading was performed by infusion of ringer's lactate 500 ml within 30 minute after baseline hemodynamic data were recorded. The positive renal response was defined as UO increased more than 0.5 ml·kg(-1)·h(-1) 1 hour after fluid challenge, otherwise was negative. Results: A total of 30 oliguric ICU patients were enrolled including 17 males and 13 females with median age (54.2±16.3) years. After fluid load, patients' HR decreased[(84±13)beat/min vs. (80±10) beat/min, P<0.01], central venous pressure (CVP) increased[(7.0±2.4)mmHg vs. (8.8±2.6) mmHg, P<0.01], 30s Parm [(33.4±5.3) mmHg vs. (35.4±5.8) mmHg, P<0.01] and 60s Parm [(26.9±4.5) mmHg vs. (28.7±5.0) mmHg, P<0.01] increased, and UO [(18.5±8.8)ml/h vs. (64.1±38.3)ml/h, P<0.01] increased significantly, while MAP and lactic acid did not change (P>0.05). There were eighteen renal responders and 12 patients did not response. In responding group, MAP[(78.1±10.7) mmHg vs. (91.2±11.7) mmHg, P<0.01], 30s Parm[(30.4±3.8) mmHg vs. (38.0±3.7) mmHg, P<0.01] and 60s Parm [(24.3±2.5) mmHg vs. (30.8±4.0) mmHg, P<0.01] before fluid load were lower than those in negative group. HR, CVP, lactic acid, age and body weight were comparable between two groups (P>0.05). After volume loading, MAP, 30s and 60s Parm in positive group were still lower than those in negative group (P<0.05), while HR, CVP and lactic acid were similar (P>0.05). Correlation analysis showed that baseline 30s Parm (r=-0.75, P<0.01), 60s Parm (r=-0.69, P<0.01), and MAP (r=-0.46, P<0.05) were negatively correlated with 1 h UO after fluid load, but HR and CVP were not (P>0.05). The receiver operating curve (ROC) showed that 30s Parm had the largest area under curve (AUC) of 0.94 (95% CI 0.84-1.05, P<0.01), which 35.5 mmHg was the best threshold with sensitivity 94.4% and specificity 91.7%(likelihood ratio 11.37). Conclusion: In hemodynamically stable oliguric ICU patients, if Parm is lower than normal reference value, volume expansion is more likely to increase UO. Thus Parm can be used to predict the effect of fluid loadon UO.

Influenza-associated thrombotic microangiopathies.

Thrombotic microangiopathy (TMA) refers to phenotypically similar disorders, including hemolytic uremic syndromes (HUS) and thrombotic thrombocytopenic purpura (TTP). This review explores the role of the influenza virus as trigger of HUS or TTP. We conducted a literature survey in PubMed and Google Scholar using HUS, TTP, TMA, and influenza as keywords, and extracted and analyzed reported epidemiological and clinical data. We identified 25 cases of influenza-associated TMA. Five additional cases were linked to influenza vaccination and analyzed separately. Influenza A was found in 83%, 10 out of 25 during the 2009 A(H1N1) pandemic. Two patients had bona fide TTP with ADAMTS13 activity <10%. Median age was 15 years (range 0.5-68 years), two thirds were male. Oligoanuria was documented in 81% and neurological involvement in 40% of patients. Serum C3 was reduced in 5 out of 14 patients (36%); Coombs test was negative in 7 out of 7 and elevated fibrin/fibrinogen degradation products were documented in 6 out of 8 patients. Pathogenic complement gene mutations were found in 7 out of 8 patients tested (C3, MCP, or MCP combined with CFB or clusterin). Twenty out of 24 patients recovered completely, but 3 died (12%). Ten of the surviving patients underwent plasma exchange (PLEX) therapy, 5 plasma infusions. Influenza-mediated HUS or TTP is rare. A sizable proportion of tested patients demonstrated mutations associated with alternative pathway of complement dysregulation that was uncovered by this infection. Further research is warranted targeting the roles of viral neuraminidase, enhanced virus-induced complement activation and/or ADAMTS13 antibodies, and rational treatment approaches.