Anaesthesiol Intensive Ther. Article Google Scholar. Effect of albumin on diuretic response to furosemide in patients with hypoalbuminemia. Am J Crit Care.
The influence of moderate hypoalbuminaemia on the renal metabolism and dynamics of furosemide in the rabbit. Br J Pharmacol. Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients. Kidney Int. Asare K. Management of loop diuretic resistance in the intensive care unit. Am J Health-Syst Pharm. Comparison of loop diuretics in patients with chronic renal insufficiency.
Adverse reactions to human serum albumin. Ann Pharmacother. Albumin and furosemide combination for management of edema in nephrotic syndrome: a review of clinical studies. Diuretic effect of frusemide in patients with nephrotic syndrome: is it potentiated by intravenous albumin?
Albumin in the nephrotic syndrome. Pharmacokinetics and effects of frusemide in patients with the nephrotic syndrome. Eur J Clin Pharmacol. Information from the National Library of Medicine To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Please refer to this study by its ClinicalTrials.
More Information. Publications automatically indexed to this study by ClinicalTrials. Furosemide and albumin for diuresis of edema FADE : a study protocol for a randomized controlled trial. Edema Hypoproteinemia Albumin Diuresis Critical illness.
National Library of Medicine U. National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Edema Hypoproteinemia. Drug: Intravenous albumin Drug: Normal saline. Phase 3. Study Type :. In contrast, others failed to demonstrate this effect [ 17 , 18 ].
In studies of hypoalbuminemic cirrhotic patients, one study has shown the benefit of the combination [ 19 ] while others have shown no significant differences in water and sodium excretion between furosemide alone and the combination of furosemide plus albumin [ 20 , 21 ]. Although there is a common usage of the combination of furosemide and albumin in hypoalbuminemic patients in clinical practice, whether there is any significant benefit of this combination for the treatment of edema in hypoalbuminemic patients especially in patients with chronic kidney disease is still unknown.
Due to the high price of albumin and allergic reactions which can occur to it [ 22 , 23 ], we conducted a randomized controlled crossover study to compare the efficacy of diuresis between furosemide alone and the combination of furosemide plus albumin for the treatment of edema in stable hypoalbuminemic chronic kidney disease patients by measuring urine output and urine sodium.
Written informed consent was obtained from each patient. Patient characteristics were documented. Their dosage was kept unchanged throughout the study. Patients were randomly assigned first to have furosemide alone or the combination of furosemide plus albumin.
The body weight, height, and blood pressure were recorded. Blood samples were initially collected from each patient for determination of electrolytes, albumin, blood urea nitrogen and creatinine at time 0 and then at 6, 24, 30, and 48 hours. Urine was collected to determine the volume and electrolytes at 6 and 24 hours before and after the intervention. Patients were advised to take oral fluids as much as their urine output.
After they had completed the first part, they were assigned to have the second part at least two weeks apart Figure 1. The increment of urine output after treatment at each period 6 or 24 hours was calculated by using post-treatment urine output minus pre-treatment urine output at each corresponding period. Also, the increment of urine sodium was calculated by using the same method.
This scheme shows the steps of the experiment. A Shows diagram of cross over study. B Shows timeline for blood and urine collections before and after intervention. Statistical analysis was performed using SPSS version The calculation revealed 20 patients. For baseline hour urine protein data, they did not show a normal distribution, so we used median and interquartile range for the calculation.
A nonparametric test was used to evaluate significant differences between groups. Twenty-four stable chronic kidney patients with hypoalbuminemia were included in this study.
There were 11 male and 13 female patients. The average GFR in this study was The other baseline characteristics before intervention have been summarized in Table 1. After the intervention, there were no significant differences in blood pressure and calculated GFR between both groups Table 3.
As expected, there were significant differences in serum albumin at 6 hours 2. There were significant increases in urine output in post-treatment compared to pre-treatment in both interventions at 6 hours 0. Also, there were significant increases in urine sodium in post-treatment compared to pre-treatment in both interventions at 6 hours Comparison of urine volume between pre- and post-treatment with furosemide alone or the combination of furosemide plus albumin in all chronic kidney disease patients.
Comparison of urine sodium between pre- and post-treatment with furosemide alone or the combination of furosemide plus albumin in all chronic kidney disease patients. Comparison of the increment of urine volume after treatment with furosemide alone or with the combination of furosemide plus albumin at 6 and 24 hours in all chronic kidney disease patients. Comparison of the increment of urine sodium between after treatment with furosemide alone or with the combination of furosemide plus albumin at 6 and 24 hours in all chronic kidney disease patients.
After the intervention, there were also significant differences in urine potassium at 6 hours In this study, we focused to compare the efficacy of diuretics between furosemide alone and the combination of furosemide plus albumin in stable hypoalbuminemic chronic kidney disease patients with clinical edema and without nephrotic range proteinuria.
The results of our study show the short-term beneficial effect at 6 hours of the combination of furosemide plus albumin over furosemide alone in natriuresis and diuresis in these patients. This may imply that, in the situation of diuretic resistance, CKD patients with low serum albumin and fluid overload may receive more benefits from this combination regimen.
At 24 hours after treatment, the results of the study did not show the beneficial effect of the combination treatment over furosemide alone. These data are similar to the results studied by Fliser et al. They found that the superior effect of one single dose of the combination of furosemide plus albumin over furosemide alone is found in only the first 8 hours after treatment. This has also been noted in other studies [ 24 ].
This could possibly be due to the short duration of action of furosemide. Furosemide is a short half-life diuretic 1—2 hours [ 25 , 26 ]. A significant natriuresis and free water clearance is noted during the 6-hour period that the diuretic is acting. However, sodium excretion gradually falls down during the remaining 18 hours of the day, because the associated volume depletion leads to the activation of the sodium-retaining mechanism [ 27 ].
Our findings suggest that combination treatment increases the natriuretic potency of furosemide at least at submaximal doses, but does not directly address the issue of whether the same is still true at maximal does of furosemide. Thus, one single dose of the combination of furosemide plus albumin might not be adequate to show the beneficial effect over furosemide alone at 24 hours.
Multiple administrations or an increased dose of diuretic may be required to maximize its potency. This entails that a strictly diuretic strategy in this category of patients with moderate proteinuria and edema in the absence of oliguria is encumbered by the risk of inducing a further fall in renal supply and glomerular filtration rate during the action of diuretics.
Since we did not have a third study arm with albumin infusion alone, the issue of whether the simple adjunct of intravenous albumin alone is able to induce an increase in diuresis, compared to basal urine volume, in this group of patients cannot be answered. It should be noted that the rise of serum albumin after human albumin administration in this study is greater than that observed in other studies Table 3.
This could possibly be due to the degree of severity of nephrotic syndrome in most other studies. Allocation of patients to the study group will be carried out by the transfusion medicine service, who will contact a web-based randomization system set up by the statistics team. The transfusion medicine personnel responsible for assignment are distinct from the study personnel enrolling subjects in the study in the ICUs. The transfusion medicine service will keep an electronic list of patient names, study ID numbers, and treatment allocation.
Study investigators will not have access to this list and will have to contact the transfusion medicine service to unblind patients for any reason, for example, suspected adverse reaction to a study treatment. Trial participants, care providers, data collectors, and outcome assessors will be blinded to treatment assignment. The placebos will then be stored in the transfusion medicine department for use in the study.
Once a patient has been randomized and assigned to a treatment group, the transfusion medicine service will cover the assigned treatment bottles with an opaque plastic sleeve and dispense them to the ICU, along with opaque intravenous tubing. Fluids will be infused into direct intravenous ports rather than distal intravenous tubing so that all study treatments will be administered directly from the covered bottles and opaque tubing without intervening clear intravenous tubing, which may threaten blinding.
The opaque sleeves and intravenous tubing will allow bedside nurses to infuse the fluids without compromising blinding of themselves or the caregiving physicians. To further reduce bias of reporting, the majority of the outcomes of interest in the study are objective that is, laboratory values, physiologic measurements , rather than subjective outcomes requiring adjudication.
To ensure the safety of study participants, a protocol for emergency unblinding exists. In the event of an adverse reaction that could be attributed to the study treatment for example, anaphylactic reaction or transfusion-related reaction , the study coordinators will be notified and will unmask group assignment by communicating with the third party personnel in the blood bank responsible for group allocation.
Code breaks will occur only under exceptional circumstances. All code breaks with justification will be reported on the relevant case report forms. The treatment and data collection protocol is outlined in Figure 2. The placebo will be ml of normal 0. This volume is negligible compared with the total fluid intake of critically ill patients for feeds, medications, and so on , and unlikely to adversely affect study or patient outcomes, but will still provide adequate blinding of caregivers and study personnel.
Clinicians will be encouraged to prescribe furosemide twice daily so as to facilitate the timely administration of study treatment prior to furosemide administration. In the event of new or worsening acute kidney injury, hypotension requiring further boluses of intravenous fluids or vasopressor agents, or if the caregiving team decides that further diuresis is unnecessary, study treatment will be held as long as the caregiving team also holds the furosemide.
If the participant develops a suspected adverse reaction to either the albumin, placebo, or furosemide, or the patient leaves the ICU is transferred to the ward, another institution, or dies study treatment will be discontinued.
No further administration of colloid intravenous fluids albumin or starch will be permitted while the patient is receiving study treatment. In the event that blood product transfusion is required for low serum hemoglobin levels as opposed to active bleeding with hemodynamic instability , one dose of the study treatment may be held and the prescribed furosemide may be given after the blood transfusion is completed, at the discretion of the caregiving team.
Nursing staff will be provided with a bedside schedule to ensure that the study drug is administered in a timely fashion and that necessary measurements are performed and blood samples collected. The short duration of treatment and the ease of study drug administration will facilitate adherence across both ICUs. Outcome measures are detailed in Table 2.
If all five criteria are met, feasibility will have been determined. Likewise, if the majority more than three of five of the criteria are met, and the unmet criteria could potentially be addressed with reasonable changes to the study protocol, feasibility will have been determined. If the unmet criteria cannot be addressed with changes to study protocol, or only a minority one or two of five of criteria are met, then non-feasibility will have been determined.
We will also collect clinical and physiologic outcome data, in anticipation of conducting a larger follow-up trial, should this study determine feasibility. The primary outcome for that trial will be the number of ventilator-free days from time of randomization. Ventilator-free days are defined over a day period, with a patient receiving one ventilator-free day for each 24 hour period spent without the need for mechanical ventilation.
Patients who die during the 28 days will automatically be assigned 0 ventilator-free days[ 20 ]. This is a commonly used outcome in critical care trials, as it incorporates patient-important outcomes of duration of mechanical ventilation and mortality, both of which have been associated with volume overload in observational studies.
The secondary clinical outcomes that we will collect data for include: 1 duration of mechanical ventilation, measured from time of randomization until extubation that is successful for 24 hours or more, recorded in days; 2 number of episodes of interrupting treatment with furosemide for example, hypotensive episodes, renal failure, contraction alkalosis ; 3 proportion of patients receiving dialysis; 4 length of ICU stay from randomization; 5 ICU mortality; and 6 30 day mortality.
We determined that the greatest threat to the feasibility is the ability to administer the first dose of study treatment in a timely fashion, within two hours of the first administration of furosemide. As such, it was selected as the outcome used to determine our sample size. Assuming an actual adherence of Other important feasibility outcomes include the administration of 72 hours of study treatment to each patient, and the absence of hyperoncotic albumin administration in the control arm.
Estimated sample sizes required to show those outcomes with the desired level of precision are shown in Table 3. Data to be collected are listed in Table 4. Demographic information, prior medical conditions, and reason for admission to ICU will be recorded.
The administration and doses of intravenous fluids, blood products, and diuretics will also be recorded. Data related to rationale for diuresis will also be collected peripheral edema, pulmonary edema on chest X-ray, low urine output, elevated central venous pressures or left atrial pressures.
Blood samples, to determine standard and extended electrolyte levels, renal profile, complete blood count with differential, serum albumin and total protein levels, and blood gas data, are routinely collected in patients undergoing diuresis and will be collected at least daily.
Colloid osmotic pressure and serum total protein will also be assessed at baseline, day 3 and day 5. Study data will be collected from the time of ICU admission to hospital discharge or 30 days after enrollment.
All of these data are measured routinely in the ICU and subject to minimal interobserver variation. Subject data will be collected daily through examination of the patient chart, including electronic ICU charting and the Meditech laboratory reporting system. Standardized electronic case report forms will be used to collect patient and study data. Data recording will be performed using standardized case report forms in duplicate to ensure minimal human error.
Data from case report forms will be entered into an electronic database on a secure computer server. Given the short time of study treatment 3 days and intensive follow-up to 5 days, retention of study subjects is not anticipated to pose a problem. Similarly, longer-term follow-up data for our outcomes of interest transfer from ICU, ventilator-free days, and death are easily retrieved from hospital records.
Data will be entered using electronic case report forms into a computerized database stored on a secure server in the Department of Epidemiology and Biostatistics at McMaster University. All data will be analyzed using statistical software on an intention-to-treat basis. All randomized participants, regardless of protocol adherence, will be included in the main analysis.
Data regarding our primary and secondary clinical outcomes will also be collected during this pilot study for future analysis; however, no analysis of clinical outcomes will be made for this pilot study, as the main purpose is to inform the definitive trial.
Data collected from this pilot study will remain blinded and eventually incorporated into the dataset for the definitive trial, with the following pre-specified analyses.
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