A Randomized Trial of Albumin Infusion to Prevent Intradialytic Hypotension in Hypoalbuminemic Patients

Background: Intradialytic hypotension (IDH) is a frequent complication of intermittent hemodialysis (IHD), occurring from 15 to 50% of ambulatory sessions, and is more frequent among hospitalized patients with hypoalbuminemia 1 . IDH limits adequate uid removal and increases the risk for vascular access thrombosis, early hemodialysis (HD) termination, and mortality. Albumin infusion before and during therapy has been used for treating IDH with varying results. We evaluated the ecacy of albumin infusion in preventing IDH during IHD in hypoalbuminemic inpatients. Methods: A randomized, crossover trial was performed in 65 AKI or ESRD patients with hypoalbuminemia (albumin<3g/dl) who required HD during hospitalization. Patients were randomized to receive 100ml of either 0.9%sodium chloride or 25% albumin intravenously at the initiation of each dialysis. These two solutions were alternated for up to 6 sessions. Patients’ vital signs and ultraltration removal rate were recorded every 15 to 30 minutes during dialysis. IDH was assessed by different denitions reported in the literature. All symptoms associated with a noted hypotensive event as well as interventions during the dialysis were recorded. Results: 65 patients were submitted to 249 sessions; mean age was 58 (+/-12), 46 (70%) were male with a mean weight of 76 (+/-18) kg. Presence of IDH was lower during albumin sessions based on all denitions. The risk of hypotension was signicantly decreased based on the Kidney Disease Outcomes Quality Initiative (KDOQI) denition; (15% with NS vs. 7% with albumin, p=0.002). Lowest intradialytic SBP was signicantly worse in patients that received 0.9% sodium chloride in comparison to albumin (NS 83 vs. Albumin 90 mmHg,p = 0.035). Overall ultraltration rate was signicantly higher in the albumin therapies (NS -8.25 ml/kg/h (-11.18 -5.80) vs. 8.27ml/kg/h (-12.22 - 5.53) with albumin, p =0.011). Conclusion: In hypoalbuminemic patients who need HD, administration of albumin before dialysis results in fewer episodes of hypotension and improves uid removal. Albumin infusion may be of benet to improve safety of HD and achievement of uid balance in these high-risk patients. patients undergoing standard of care dialysis. We provide a pragmatic approach for reducing the inherent risk for IDH with albumin infusions administered at the start of dialysis without any changes in the dialysis prescription. In comparison to previously published studies, we show that uid removal can be enhanced and ecacy parameter met with albumin infusions. These procedures are simple to apply and are applicable for general adaptation. Our study is limited to being a single-center study and a crossover design with albumin levels measured only at the initial dialysis session. Our results could be inuenced by changes in albumin levels during the hospitalization course and subsequent dialysis sessions following the albumin replacement. However, our data provide support for further evaluations as has been proposed for a new study evaluating albumin infusions for slow low-eciency dialysis 27 .


Introduction
Despite the use of diuretics, uid overload (> 10% change in body weight from admission) is commonly encountered in hospitalized patients. The amount and duration of uid overload is a major independent risk factor for adverse outcomes including mortality, reduced renal recovery, and resource utilization2-6.
Avoidance of uid accumulation and early mobilization of uid are now the main therapeutic goals for these patients and often portend a need for dialysis initiation. Unfortunately, uid mobilization and removal with intermittent hemodialysis (IHD) are often di cult, particularly in patients with severe AKI/ESRD and multi-organ failure due to the development of intradialytic hypotension (IDH). IDH complicates 17-70% of acute hemodialysis (HD) sessions in the ICU 7-11, and in as much as 50% in the inpatient setting12. It decreases the e cacy of renal replacement therapy, delays function recovery, and organ failures reversal 13,14. During ultra ltration, the plasma-re lling rate is dependent on colloid osmotic pressure and consequently, volume expanders, including mannitol, albumin, hypertonic and 0.9% sodium chloride, dextran and hydroxyethyl starch have been used in the management of IDH in chronic outpatient HD with varying results. In hypoalbumenic patients, infusion of albumin would be expected to increase colloid osmotic pressure and thus enhance plasma re lling to improve uid mobilization and reduce IDH. In this study, we evaluated the e cacy of albumin infusion in preventing intradialytic hypotension during HD in hospitalized patients. We hypothesized that the concurrent use of intravenous albumin during dialysis would result in higher quantities of uid removal per unit time and would be associated with a reduced incidence of IDH.

Methods
In this prospective randomized controlled trial, we enrolled hospitalized adult patients (> 18 ys) with AKI, AKI on CKD, and ESRD who required uid removal with dialysis and had a serum albumin level < 3 g/dl at initiation of dialysis. Patients with a renal transplant and those not expected to be on dialysis for more than 24 hrs were excluded. The study was a crossover design where standard care dialysis was supplemented with the addition of a single dose of 25 g albumin (100 ml of Grifols 25%) or 100 ml of 0.9% sodium chloride (normal saline (NS)) given intravenously at the start of IHD. Patients were randomized to start dialysis with albumin or 0.9% sodium chloride and subsequently alternated with the other solution for a maximum of 6 sessions for each patient. Vital signs and ultra ltration removal rate were recorded every 15 to 30 minutes during dialysis. The dialysis nurse recorded in a standartized case report form, all symptoms associated with hypotension as well as interventions during the dialysis. We utilized 7 different classi cations to determine hypotensive episodes (Table 1). Hypotension was de ned based on lowest systolic blood pressure, changes in systolic blood pressure, symptoms, and need for intervention during each dialysis session to determine whether the subject experienced any hypotensive episodes during the dialysis session.

Dialysis Procedures
Standard IHD was prescribed according to the prevailing standard of care according to the nephrology attending physician, with the exception of albumin or 0.9% sodium chloride infusion before the initiation of the procedure. Dialysis prescriptions were individualized for each patient (blood and dialysate ow rates, dialysate composition) to achieve a minimum urea reduction ratio of 65% and achieve target dry weights. Ultra ltration (UF) rates per hour were determined by the attending nephrologist to achieve desired uid balance for each session. Standard unit protocols were followed for managing symptoms and hypotension in each session (UF changes, 0.9% sodium chloride boluses, Trendelenburg position, dialysate temperature adjustments).
There was no difference in the prescribed or delivered time in sessions with albumin and 0.9% sodium chloride (Table 3). Ultra ltration rate expressed by ml/kg/hour was signi cantly higher in albumin sessions (p = 0.011).
The study considered co-primary outcomes of e cacy and safety. The e cacy outcome was the achieved uid removal expressed as ml/kg/hour. The safety outcome included the number and duration of cardiovascular complications, including hypotensive episodes with or without symptoms; symptoms alone without hypotension (nausea, headache, vomiting, altered sensorium, fatigue) and arrhythmias. Secondary outcomes included urea reduction ratios and Kt/V per session, time to correct uid overload and volume of 0.9% sodium chloride administered during therapy.

Statistical Analysis
Continuous variables and categorical variables were reported as mean (SD) and count (percentage).
Generalized estimating equations (GEE) was used to compare the effect of albumin and 0.9% sodium chloride on IHD parameters. We compared the presence of hypotension based on various de nitions in Table 1. We used the presence of symptomatic hypotension recorded by nurse as our gold standard for hypotension. Urea reduction ratios (URR) value was calculated based on pre and post blood urea nitrogen value. Kt/V values were recorded from the dialysis machine. GEE was used to compare the effect of the solution on URR and Kt/V. For all of the analysis, an exchangeable working correlation was used for the generalized estimating equation.  Presence of a hypotensive episode during a session of HD varied from 12 (4.9%) to 111 (44%) according to the de nition of IDH applied (Table 1). There was varying recognition by the dialysis nurse of hypotensive episodes and subsequent interventions. The Nadir < 100, Fall 20 and Fall 30 de nitions based on changes in SBP were encountered 45%, 43% and 28% of the time respectively, however, were recorded 64%, 25% and 24% of the time by the nurse and intervention occurred in 32%, 17%, and 14%. The Hemodialysis Study (HEMO) de nition, considering hypotension when an intervention results from an unspeci c fall in BP occurred 33% more frequently than the KDOQI de nition. Of the sessions with an absolute intradialytic nadir of SBP < 90 mmHg, 23 (43%) were not followed by any intervention. Symptomatic hypotension, the KDOQI de nition, was infrequently encountered and was intervened on 64% and recorded almost always when occurred, in 92% of the cases.
Infusion of albumin at initiation of therapy was signi cantly associated with less hypotensive episodes de ned by SBP decline of 20 mmHg (p = 0.026), 30 mmHg (p = 0.041), the composite de nition of decline of 20 mmHg in SBP and minimal SBP of 90 mmHg (p = 0.016), and based on KDOQI de nition (p = 0.002).
We used the presence of symptomatic hypotension, recorded by the dialysis nurse, as our gold standard for hypotension. It occurred in 35 patients during 85 dialysis sessions (Table 3). Meantime to the rst hypotensive episode was 57 min. Lowest systolic blood pressure was signi cantly lower in 0.9% sodium chloride sessions; NS 83 vs. albumin 90 mmHg, p < 0.035. Most episodes were not severe enough to require discontinuation of ultra ltration, however, UF was more frequently discontinued during NS sessions v. albumin and the total duration for which UF was on hold during HD was signi cantly higher in NS sessions v. albumin (Table 4 or Fig. 1). When 0.9% sodium chloride infusion was necessary to reverse hypotension, the mean volume administered was 177 ml, with no difference between volume given during albumin or 0.9% sodium chloride sessions (Table 4).  Data are mean (SD). UF: ultra ltration *Generalized estimating equations was used to analyze the effect of albumin on hypotension outcome.

Discussion
Fluid accumulation is common in hospitalized patients, particularly those in the ICU and is attributed to the need for resuscitation and hemodynamic stabilization. It is now recognized that the duration and degree of uid overload contribute to the risk of adverse outcomes and correction of uid overload can reduce this risk. Dialysis is often utilized to remove uids and restore homeostasis; however, uid mobilization is often limited by the development of IDH. Several different de nitions continue to be used in the literature and clinical practice, preventing the appreciation of the effects of IDH and patient outcomes. Our study con rms the varying frequency of IDH, ranging from 4.9-44% of the dialysis sessions depending on the de nition applied and re ects the vast variation in which recognition of hypotension and interventions to correct it occur. Recently, a large epidemiologic study has shown that an absolute nadir of SBP < 90 mmHg was the most potently associated with mortality 15 . In our study, we found that of the sessions with an absolute intradialytic nadir of SBP < 90 mmHg, 30 (56%) were not followed by any intervention.
The pathogenesis of IDH includes a multitude of factors related to the dialysis prescription, process of care, such as sedation, patient comorbidities, and severity of illness. During the therapy of ultra ltration, plasma volume decreases and oncotic pressure rises 16 . Plasma re lling, which is the shift of uid from the interstitial and intracellular compartments to the intravascular compartment, is favored by the resulting rise in oncotic pressure. When the ultra ltration rate surpasses re lling rate, reduction in pre-load induces a fall in stroke volume that predisposes to hemodynamic instability 17,18 , 19−22 .
While interventions to prevent IDH have been extensively studied in chronic HD, few studies have evaluated the role of albumin infusions and treating hypotension. A previous protocol in patients at inpatient dialysis units and ICU settings the use of NS, mannitol, and albumin were compared in a stepwise approach for intradialytic hypotension treatment. 23 . However, with this protocol, albumin was administered in only 6% of the 2,559 HD treatments as most hypotensive episodes were reversed with NS. The protocol was designed to evaluate cases of established IDH, and nal ultra ltration volume achieved was not an outcome. In a randomized clinical trial, Jardin et al. 24 showed that albumin infusions given at the start of dialysis resulted in greater ultra ltration and hemodynamic stability for patients with sepsisinduced acute renal failure. A systematic review on IV albumin for IDH in chronic HD patients yielded a single study, which showed that the frequency of IDH was similar between 0.9% sodium chloride and 5% albumin 25,26 . It is important to mention that the studies mentioned above did not evaluate hypoalbuminemic patients separately with mean albumin levels of 3.8 g/dL.
In our study, the patient population consisted of only hypoalbumenic patients and mostly with AKI. We found that albumin infusions reduced IDH events across multiple de nitions. Based on the Fall20Nadir90 de nition, a patient receiving albumin at the beginning of the dialysis session is 74.2% less likely to experience a hypotensive event. Additionally, in albumin sessions, UF was discontinued less frequently, less NS was required to restore SBP, and the time off UF was almost half of the NS sessions. The reduction in IDH episodes was accompanied by an increase in uid removal rates to achieve the target weight.
Our study characterizes the variation in recognition of and interventions applied to manage IDH in hospitalized hypoalbuminemic patients undergoing standard of care dialysis. We provide a pragmatic approach for reducing the inherent risk for IDH with albumin infusions administered at the start of dialysis without any changes in the dialysis prescription. In comparison to previously published studies, we show that uid removal can be enhanced and e cacy parameter met with albumin infusions. These procedures are simple to apply and are applicable for general adaptation. Our study is limited to being a single-center study and a crossover design with albumin levels measured only at the initial dialysis session. Our results could be in uenced by changes in albumin levels during the hospitalization course and subsequent dialysis sessions following the albumin replacement. However, our data provide support for further evaluations as has been proposed for a new study evaluating albumin infusions for slow lowe ciency dialysis 27 .

Conclusion
In hypoalbuminemic patients who need IHD, administration of albumin before dialysis results in fewer episodes of hypotension and improves uid removal rates. Albumin infusions may be of bene t to improve the safety and e cacy of HD in these high-risk patients. Authors' contributions RM designed the study and was a major contributor in writing the manuscript. EM, BK and RM analyzed and interpreted the patient data. EL performed the statistical analysis. All authors read and approved the nal manuscript. Figure 1 Frequency of complication associated with intradialytic hypotension in albumin and 0.9% sodium chloride sessions. Data are n (%), or mean (SD). SBP: systolic blood pressure; UF: ultra ltration; NS:

Figures
normal saline (0.9% sodium chloride). P values are based on GEE analysis.