A Narrative Literature Review of the Established Safety of Human Serum Albumin Use as a Stabilizer in Aesthetic Botulinum Toxin Formulations Compared to Alternatives.

Despite more than 80 years of use in a number of conditions, including in critically ill patients, comments have recently arisen regarding the safety and efficacy of human serum albumin (HSA) as a therapeutic product and stabilizer/excipient in botulinum neurotoxins. This review summarizes the literature on the safety of HSA. Beyond decades of safe use, the largest clinical dataset of HSA safety is a large meta-analysis of HSA supplier data, which found only an extremely remote risk of serious adverse events across millions of doses of therapeutic concentrations of HSA. There is a paucity of literature identifying HSA-specific adverse events when used as a stabilizer/excipient; however, studies of HSA-containing botulinum neurotoxins (BoNTs) suggest that adverse events are not related to HSA. Polysorbates, which are synthetically produced and not physiologically inert, are contained in pending or new-to-market BoNT formulations. In contrast to HSA, evidence exists to suggest that polysorbates (particularly PS20/PS80) can cause serious adverse events (e.g., hypersensitivity, anaphylaxis, and immunogenicity).

Effect of 6% Hydroxyethyl Starch 130/0.4 on Inflammatory Response and Pulmonary Function in Patients Having Cardiac Surgery: A Randomized Clinical Trial.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass induces a profound inflammatory response that, when severe, can lead to multiorgan system dysfunction. Preliminary data suggest that administration of hydroxyethyl starch (HES) solutions may mitigate an inflammatory response and improve pulmonary function. Our goal was to examine the effect of 6% HES 130/0.4 versus 5% human albumin given for intravascular plasma volume replacement on the perioperative inflammatory response and pulmonary function in patients undergoing cardiac surgery. METHODS: This was a subinvestigation of a blinded, parallel-group, randomized clinical trial of patients undergoing elective aortic valve replacement surgery at the Cleveland Clinic main campus, titled "Effect of 6% Hydroxyethyl Starch 130/0.4 on Kidney and Haemostatic Function in Cardiac Surgical Patients." Of 141 patients who were randomized to receive either 6% HES 130/0.4 or 5% human albumin for intraoperative plasma volume replacement, 135 patients were included in the data analysis (HES n = 66, albumin n = 69). We assessed the cardiopulmonary bypass-induced inflammatory response end points by comparing the 2 groups' serum concentrations of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and macrophage migration inhibitory factor (MIF), measured at baseline and at 1 and 24 hours after surgery. We also compared the 2 groups' postoperative pulmonary function end points, including the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2:Fio2 ratio), dynamic lung compliance, oxygenation index (OI), and ventilation index (VI) at baseline, within 1 hour of arrival to the intensive care unit, and before tracheal extubation. The differences in the postoperative levels of inflammatory response and pulmonary function between the HES and albumin groups were assessed individually in linear mixed models. RESULTS: Serum concentrations of the inflammatory markers (TNF-α, IL-6, MIF) were not significantly different (P ≥ .05) between patients who received 6% HES 130/0.4 or 5% albumin, and there was no significant heterogeneity of the estimated treatment effect over time (P ≥ .15). The results of pulmonary function parameters (Pao2:Fio2 ratio, dynamic compliance, OI, VI) were not significantly different (P ≥ .05) between groups, and there was no significant heterogeneity of the estimated treatment effect over time (P ≥ .15). CONCLUSIONS: Our investigation found no significant difference in the concentrations of inflammatory markers and measures of pulmonary function between cardiac surgical patients who received 6% HES 130/0.4 versus 5% albumin.

Safety verification for polysorbate 20, pharmaceutical excipient for intramuscular administration, in Sprague-Dawley rats and New Zealand White rabbits.

Human serum albumin (HSA) has been widely used as a pharmaceutical excipient in Botulinum toxin serotype A (BoNT/A) products that are indicated for use in therapeutics and cosmetics. However, HSA as a human-derived material has some concerns, such as the potential risk of transmission of infectious agents, an insufficient supply, and difficulty in maintaining a certain quality. For those reasons, newly developed BoNT/A products (CORETOX®, Medytox, Inc., Republic of Korea) contained polysorbate 20, a non-human-derived excipient, to replace the HSA. However, most safety studies of polysorbate 20 have been conducted with non-invasive routes of administration, and thus there are a few studies on the safety of polysorbate 20 when administered intramuscularly. To secure the in vivo safety profile of polysorbate 20, a four-week repeated intramuscular dose toxicity study (0.02, 0.1, and 0.4 mg/kg, one injection every two weeks for a total of three injections) was conducted in 66 Sprague-Dawley (SD) rats. An intradermal irritation study was further conducted with 18 New Zealand White (NZW) rabbits. The toxicological evaluation of HSA (0.06 and 0.12 mg/kg) was also carried out as a comparative substance. Systemic and local toxicities were not observed in any of the SD rats or NZW rabbits based on clinical signs, body weight, hematology, clinical biochemistry, macroscopic findings on necropsy, histopathology of the injection site, and allergic reactions. The current study suggested that intramuscular administration of polysorbate 20 was considered to be safe at a level similar to that of HSA, which has an in vivo safety profile accumulated over the years. This provided the basis for the in vivo safety profile of polysorbate 20 administered intramuscularly and the scientific reliability of the use of polysorbate 20 as an alternative to HSA, which is used as an excipient for various pharmaceuticals in terms of its safety.

Albumin in Advanced Liver Diseases: The Good and Bad of a Drug!

Human serum albumin is the most abundant plasma protein, and it regulates diverse body functions. In patients with advanced and decompensated cirrhosis, serum albumin levels are low because of a reduction in the hepatocyte mass due to disease per se and multiple therapeutic interventions. Because of their oncotic and nononcotic properties, administration of human albumin solutions (HAS) have been found to be beneficial in patients undergoing large-volume paracentesis or who have hepatorenal syndrome or spontaneous bacterial peritonitis. Albumin also improves the functionality of the immune cells and mitigates the severity and risk of infections in advanced cirrhosis. Its long-term administration can modify the course of decompensated cirrhosis patients by reducing the onset of new complications, improving the quality of life, and probably providing survival benefits. There is, however, a need to rationalize the dose, duration, and frequency of albumin therapy in different liver diseases and stages of cirrhosis. In patients with acute-on-chronic liver failure, potentially toxic oxidized isoforms of albumin increase substantially, especially human nonmercaptalbumin and 2, and nitrosoalbumin. The role of administration of HAS in such patients is unclear. Determining whether removal of the pathological and dysfunctional albumin forms in these patients by "albumin dialysis" is helpful, requires additional studies. Use of albumin is not without adverse events. These mainly include allergic and transfusion reactions, volume overload, antibody formation and coagulation derangements. Considering their cost, limited availability, need for a health care setting for their administration, and potential adverse effects, judicious use of HAS in liver diseases is advocated. There is a need for new albumin molecules and economic alternatives in hepatologic practice.

Delayed type III hypersensitivity reaction with acute kidney injury in two dogs following administration of concentrated human albumin during treatment for hypoalbuminemia secondary to septic peritonitis.

OBJECTIVE: To describe 2 dogs with acute kidney injury secondary to type III hypersensitivity reaction to 25% human serum albumin (HSA). CASE SERIES SUMMARY: Two dogs were presented with evidence of septic peritonitis. The dogs were hospitalized following definitive surgical correction of a jejunal laceration following routine ovariohysterectomy, and removal of a jejunal foreign body. In the postoperative period, both dogs developed hypoalbuminemia and received 25% HSA. At the time of initial discharge, both dogs were doing well clinically and had normal renal parameters. Eleven and 18 days after HSA infusion, respectively, both dogs were re-presented with clinical signs of inappetence, vomiting, and lameness that progressed to urticaria, peripheral and angioedema, and petechiae, consistent with a delayed type III hypersensitivity reaction. Treatment for the type III hypersensitivity reaction to HSA included administration of diphenhydramine and glucocorticoids. Despite partial resolution of edema and joint swelling, both dogs developed progressive azotemia together with hypoalbuminemia and proteinuria. One dog developed an anuric acute kidney injury (AKI). Both dogs were humanely euthanized. Histopathology of the kidneys of both dogs was consistent with immune complex deposition and vasculitis. NEW OR UNIQUE INFORMATION: Severe type III hypersensitivity reactions have been documented in healthy dogs and clinical patients following the administration of HSA. This report describes the first documented delayed type III hypersensitivity reaction in 2 dogs with septic peritonitis that resulted in AKI, glomerulonephritis, and oligo- to anuria in clinical patients following administration of 25% HSA.

Congenital nephrotic syndrome: is early aggressive treatment needed?-No.

The management of infants with congenital nephrotic syndrome (CNS) is very challenging as they are prone to severe complications such as hemodynamic disturbances, infections, thromboses, and impaired growth, and most will develop end-stage kidney disease (ESKD) within a few years. Since the seventies, an "aggressive" approach, including daily albumin infusions, early nephrectomies, dialysis, and transplantation, has dramatically improved survival and morbidity. More recent case-note reviews have reported successful conservative treatment (using optimized nutrition, complication prophylaxis, and delayed renal replacement therapy), which led to similarly good outcomes and low complication rates. This questions the indications for early preemptive bilateral nephrectomy and dialysis given the mortality and morbidity rates in dialysis in infants and their life-long management with possible repeated transplantations. Two large series provide the most recent evidences supporting the conservative management: firstly, at least 55% children with CNS are not spontaneously in ESKD at the age of 2 years; secondly, albumin tapering/discontinuation and hospital discharge are possible before nephrectomy; and lastly, CNS complication rates are similar in case of preemptive nephrectomies or conservative care. Until now, no clear genotype-phenotype correlation has been identified to guide clinical management. Taken together, these data support the safety of conservative care until ESKD in a subset of patients with CNS.

Effect of postoperative hypoalbuminemia and supplement of human serum albumin on the development of surgical site infection following spinal fusion surgery: a retrospective study.

PURPOSE: To determine the association between postoperative hypoalbuminemia and the development of surgical site infection (SSI) and evaluate whether the supplement of exogenous human serum albumin (HSA) in patients following spinal surgery would decrease the rate of postoperative SSI. METHODS: We performed a retrospective review of all patients who underwent lumbar spinal fusion surgery in our institution between January 2014 and December 2018. Patients with postoperative SSI were identified. We reviewed the demographic and clinical records of the patients and performed multiple logistic regression models to clarify the relevance between postoperative hypoalbuminemia, the supplement of HSA and SSI. Statistical adjustment for the potential confounders was also performed to exclude possible variation. RESULTS: Twenty-four of 602 patients developed SSI after lumbar spinal fusion surgery. No statistical significance was found between postoperative hypoalbuminemia and SSI rate (OR 0.74; 95% CI 0.22-2.48; P = 0.6199). However, the supplement of exogenous HSA was significantly associated with increased postoperative SSI rate (OR 1.21; 95% CI 1.05-1.41; P = 0.0094). Interestingly, stratified analyses showed supplement of HSA in patients without postoperative hypoalbuminemia increased the risk of SSI (OR 2.55; 95% CI 1.01-6.45; P = 0.0475), compared with patients with postoperative hypoalbuminemia (OR 1.17; 95% CI 1.00-1.36; P = 0.0434). CONCLUSIONS: The present study suggests that postoperative hypoalbuminemia is not associated with the development of SSI after spinal surgery. However, the supplement of HSA following spinal surgery will increase the rate of SSI. These slides can be retrieved under Electronic Supplementary Material.

Pharmacokinetics and pharmacodynamics of a recombinant fusion protein linking activated coagulation factor VII with human albumin (rVIIa-FP) in patients with congenital FVII deficiency.

Objectives: Recombinant fusion protein linking activated factor VIIa to human albumin (rVIIa-FP) is a therapeutic option designed to prevent and treat bleeding events in patients with congenital FVII deficiency with reduced infusion frequency compared to current FVII treatments. This study characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of rVIIa-FP.Methods: A phase I multicenter, randomized, open-label, parallel-arm, single-dose study (NCT02470871) was conducted in nine patients with severe congenital FVII deficiency. Patients received their routine FVII product (30 IU/kg plasma-derived FVII [pdFVII] or 25 µg/kg recombinant activated FVII (rFVIIa) [eptacog alfa]), and were then randomly assigned to receive 100 or 300 µg/kg of rVIIa-FP. Blood samples for PK and PD assessments were drawn up to 48 hr after administration. FVIIa activity was determined using a one-stage clotting assay. PD parameters were derived from thrombin generation testing, using the Nijmegen hemostasis assay.Results: rVIIa-FP showed improved PK compared to rFVIIa, with 2- to 3-fold longer t1/2 and 4- to 8-fold lower clearance. Analysis of PD data showed a sustained suppression of lag time below 4.5 min (upper limit of healthy people) for rVIIa-FP compared to rFVIIa. AUEC and ECmax were similar across the two dose groups of rVIIa-FP and rFVIIa.Discussion: rVIIa-FP was well tolerated in patients with congenital FVII deficiency, showed a longer half-life and lower clearance compared to rFVIIa, and lag time remaining within healthy ranges for ≥8 hr.Conclusion: These results warrant further investigation into the efficacy of rVIIa-FP to control and prevent bleeding in patients with FVII deficiency.

Prospective Review of Clinical Hypersensitivity Reactions After Administration of 5% Human Serum Albumin in 40 Critically Ill Cats.

This prospective study assesses the presence of immediate and delayed clinical hypersensitivity reactions in 40 hypoalbuminemic critically ill cats during and after an intravenous administration of 5% human serum albumin (HSA). Twenty hypoalbuminemic critically ill cats with no known exposure to HSA (control group) were also checked in order to highlight any clinical signs related to the underlying disease which could mimic hypersensitivity reactions. The administration of 10-20 mL/kg of 5% HSA at 2 mL/kg/h in critically ill cats did not lead to clinical signs of types I and III hypersensitivity reactions at days 0, 7, 14, 21, and 28, unlike previous findings with 25% HSA in this species.

Tailored NEOadjuvant epirubicin, cyclophosphamide and Nanoparticle Albumin-Bound paclitaxel for breast cancer: The phase II NEONAB trial-Clinical outcomes and molecular determinants of response.

BACKGROUND: This study evaluated the feasibility of achieving high response rates in stage II or III breast cancer by tailoring neoadjuvant therapy using clinical and histopathological features and the Oncotype DX Breast Recurrence Score. Genomic determinants of response and resistance were also explored. PATIENTS AND OUTCOME MEASURES: Fifty-one patients were enrolled. The primary cohort comprised 40 patients: 15 human epidermal growth factor receptor type 2 (HER2)-amplified; 15 triple-negative (TNBC); and ten hormone receptor (HR)-positive, HER2-non-amplified tumours; with recurrence scores ≥25. Patients were treated with epirubicin and cyclophosphamide, followed by nab-paclitaxel, with the addition of trastuzumab if HER2-amplified. The primary endpoint was pathological complete response (pCR) in the breast. Pre- and post-treatment tumour samples underwent variant burden, gene and gene pathway, mutational signature profile and clonal evolution analyses. RESULTS: The pCR rates were: overall 55% (n = 22), HER2-amplified 80% (n = 12), triple-negative 46% (n = 7) and HR-positive, HER2-non-amplified 30% (n = 3). Grade 3 or 4 adverse events included febrile neutropenia (8%), neutropenia (18%), sensory neuropathy (5%), deranged transaminases (5%), fatigue (2%), diarrhoea (2%), and pneumothorax (2%). Molecular analyses demonstrated strong similarities between residual disease and matched primary tumour. ATM signalling pathway alterations and the presence of a COSMIC Signature 3 implied the majority of tumours contained some form of homologous repair deficiency. ATM pathway alterations were identified in the subset of TNBC patients who did not achieve pCR; Signature 3 was present in both pCR and non-pCR subgroups. Clonal evolution analyses demonstrated both persistence and emergence of chemoresistant clones. CONCLUSIONS: This treatment regime resulted in a high rate of pCR, demonstrating that tailored neoadjuvant therapy using a genomic recurrence score is feasible and warrants further investigation. Molecular analysis revealed few commonalities between patients. For TNBC future clinical gains will require precision medicine, potentially using DNA sequencing to identify specific targets for individuals with resistant disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT01830244.

Vitamin D attenuates human gingival fibroblast inflammatory cytokine production following advanced glycation end product interaction with receptors for AGE.

BACKGROUND AND OBJECTIVES: Vitamin D [1,25(OH)2 D3 or 1,25D3] is critical in musculoskeletal health, inflammation, immune response, and glucose metabolism. Patients with vitamin D deficiency may be at higher risk of diabetes and periodontitis. Diabetic patients exhibit exacerbated inflammation and more periodontal destruction. Advanced glycation end products (AGEs), formed during diabetic hyperglycemia, activate inflammatory pathways in periodontitis. Human gingival fibroblasts (HGFs) express receptors for AGEs (RAGEs) and can contribute to inflammation. OBJECTIVES: Determine whether glycated human serum albumin (G-HSA) augments HGF IL-6 and IL-8 production, and whether treatment with 1,25D3 attenuates cytokine production following stimulation with G-HSA + IL-1ß and/or IL-17. MATERIAL AND METHODS: HGFs were incubated ±G-HSA or normal human serum albumin (HSA), ±IL-1ß and/or IL-17, ±1,25D3. Cytokines were measured by ELISA. Neutralizing anti-RAGE was used to assess AGE-RAGE interaction. Endotoxin was measured using the ToxinSensor™ System. Data were expressed as mean ± standard deviation and analyzed using a one-way analysis of variance (ANOVA) and Scheffe's F procedure for post hoc comparisons. RESULTS: G-HSA or IL-1ß, but not HSA, significantly stimulated IL-6 and IL-8 production. G-HSA or HSA when combined with IL-1ß or IL-1ß + IL-17 synergistically stimulated IL-6 and IL-8. Neutralizing anti-RAGE inhibited IL-6 and IL-8 produced by cells stimulated with IL-1ß + G-HSA but not (+HSA). Synergism caused by HSA did not appear to be mediated by endotoxin since its levels in G-HSA and HSA were not sufficient to stimulate fibroblasts. Vitamin D inhibited IL-6 and IL-8 production stimulated by G-HSA or HSA + IL-1ß or IL-1ß + IL-17. CONCLUSIONS: Results suggest that the "perioprotective" effects of vitamin D are related to its ability to regulate inflammatory cytokine production by HGFs following AGE-RAGE interaction.

Con: The Unclear Benefit of Albumin.

Many studies have shown that 20% human albumin solution infusions improve circulatory function in patients with advanced liver disease, and this treatment is widely recommended and used by all hepatologists. However, it is more expensive than other crystalloids or colloids, and several countries suffer shortages of supply. This article examines whether other fluids might be considered for these patients.

The Safety and Efficacy of Regional Citrate Anticoagulation in Albumin-Assisted Liver Dialysis for Extracorporeal Liver Support in Pediatric Patients.

AIMS: To establish the safety and efficacy of regional citrate anticoagulation (RCA) for pediatric liver failure (LF) patients receiving extracorporeal liver support (ELS) with albumin-assisted dialysis. METHODS: Retrospective review of pediatric LF patients receiving ELS from April 2014 to December 2016 at a tertiary children's hospital pediatric intensive care unit. Demographic and ELS data collected by chart review. Citrate accumulation (CA) was defined as total calcium (mmol/L): ionized calcium (mmol/L) > 2.5 (tCa:iCa). Efficacy was assessed by treatment duration. Safety was assessed by adverse events: bleeding, hemodynamic instability, arrhythmias, unplanned treatment discontinuation. RESULTS: Fifteen patients (median age 3 [interquartile range (IQR) 0.7-8.0]) received 108 ELS treatments (median 5 [IQR 4-7.5]). Sixty-eight episodes of CA were identified. Of those, 6 coincided with intervention and 1 coincided with ELS discontinuation. There were no deaths attributed to ELS or RCA. CONCLUSION: RCA provides safe and effective anticoagulation for pediatric LF patients requiring ELS.

Acid/base alterations during major abdominal surgery: 6% hydroxyethyl starch infusion versus 5% albumin.

BACKGROUND: To compare the effects of intraoperative infusions of balanced electrolyte solution (BES)-based hydroxyethyl starch (HES) and saline-based albumin on metabolic acidosis and acid/base changes during major abdominal surgery conducted using Stewart's approach. METHODS: Forty patients, aged 20-65 years, undergoing major abdominal surgery, were randomly assigned to the HES group (n = 20; received 500 ml of BES-based 6% HES 130/0.4) or the albumin group (n = 20; received 500 ml of normal saline-based 5% albumin). Acid-base parameters were measured and calculated using results obtained from arterial blood samples taken after anesthesia induction (T1), 2 hours after surgery commencement (T2), immediately after surgery (T3), and 1 hour after arriving at a postanesthetic care unit (T4). RESULTS: Arterial pH in the HES group was significantly higher than that in the albumin group at T3 (7.40 ± 0.04 vs. 7.38 ± 0.04, P = 0.043), and pH values exhibited significant intergroup difference over time (P = 0.002). Arterial pH was significantly lower at T3 and T4 in the HES group and at T2, T3, and T4 in the albumin group than at T1. Apparent strong ion difference (SIDa) was significantly lower at T2, T3, and T4 than at T1 in both groups. Total plasma weak nonvolatile acid (ATOT) was significantly lower in the HES group than in the albumin group at T2, T3 and T4 and exhibited a significant intergroup difference over time (P < 0.001). CONCLUSIONS: BES-based 6% HES infusion was associated with lower arterial pH values at the end of surgery than saline-based 5% albumin infusion, but neither colloid caused clinically significant metabolic acidosis (defined as an arterial pH < 7.35).

The use of human albumin in patients with cirrhosis: a European survey.

BACKGROUND: The administration of human albumin (HA) in patients with decompensated cirrhosis is still debated. The European Foundation for the Study of Chronic Liver Failure (EF-CLIF) promoted an online survey to assess its use across Europe. METHODS: Hepatologists were invited to participate to an electronic questionnaire based on multiple-choice questions divided in 6 different areas. A descriptive statistical analysis was performed to analyze the responses. RESULTS: One hundred-one hepatologists (36% non-EF-CLIF member), belonging to 86 centers (25% non-academic hospitals) completed the survey. The vast majority of participants prescribe HA for the evidence-based indications supported by international guidelines, while a proportion of them consider HA administration useful for other complications currently not supported by solid scientific evidence. Participants show a good level of knowledge about the non-oncotic properties of the molecule, while HA prescription does not appear to be restricted by health authorities in most centers, at least for the evidence-based indications. CONCLUSIONS: The present survey indicates that hepatologists across Europe present adherence to international guidelines and highlights the areas where solid scientific data are awaited to achieve a more appropriate HA prescription in patients with decompensated cirrhosis.

Amphotericin B-albumin conjugates: Synthesis, toxicity and anti-fungal activity.

Amphotericin B (AmB), a hydrophobic drug with negligible aqueous solubility was conjugated to bovine serum albumin (BSA) via amide bond coupling to give 6 to 8 wt% drug payload. The resulting conjugate was characterized using SDS-PAGE and UV-visible, FTIR and CD spectroscopy. The conjugate was water-soluble to the extent of 150 mg/ml, was non-toxic to HEK 293 T cells at a concentration of 500 µg/ml (equivalent to ~30 µg AmB) and showed hemolysis of <5% at 200 µg/ml (equivalent to ~12 µg AmB) against human erythrocytes in vitro. In vitro release studies at 37 °C demonstrated steady release of AmB up to 20% from the conjugate with little burst effect in phosphate buffered saline whereas thrice the amount was released in human plasma in 72 h. AmBisome® used as a reference showed a very similar release profile in plasma. The conjugate exhibited potential anti-fungal activity against yeast strains such as C. albicans, C. neoformans and C. parapsilosis with the minimum inhibitory concentration (MIC) equivalent to AmB ranging from 0.7 to 1.1 µg/ml while AmBisome® and AmB alone showed the MIC between 0.78 and 1.5 and 0.53-0.78 µg/ml respectively. Although AmB has been conjugated to various natural and synthetic polymers to improve its solubility and reduce its toxicity, the results obtained in this study using the model protein BSA as a carrier point to the possibility of taking this pro-drug approach to human clinical use using human serum albumin (HSA) as the carrier, since HSA has emerged as a versatile drug carrier for treating diabetes and cancer and improving the pharmacokinetic profile of many drugs with US FDA approving HSA as a drug carrier for the anti-cancer drug paclitaxel (Abraxane®) for human use.

No Differences in Renal Function between Balanced 6% Hydroxyethyl Starch (130/0.4) and 5% Albumin for Volume Replacement Therapy in Patients Undergoing Cystectomy: A Randomized Controlled Trial.

BACKGROUND: The use of artificial colloids has declined in critical care, whereas they are still used in perioperative medicine. Little is known about the nephrotoxic potential in noncritically ill patients during routine surgery. The objective of this trial was to evaluate the influences of albumin 5% and balanced hydroxyethyl starch 6% (130/0.4) on renal function and kidney injury. METHODS: One hundred urologic patients undergoing elective cystectomy were randomly assigned for this prospective, single-blinded, controlled study with two parallel groups to receive either albumin 5% or balanced hydroxyethyl starch 6% (130/0.4) as the only perioperative colloid. The primary endpoint was the ratio of serum cystatin C between the last visit at day 90 and the first preoperative visit. Secondary endpoints were estimated glomerular filtration rate and serum neutrophil gelatinase-associated lipocalin until the third postoperative day and risk, injury, failure, loss, and end-stage renal disease criteria at postoperative days 3 and 90. RESULTS: The median cystatin C ratio was 1.11 (interquartile range, 1.01 to 1.23) in the albumin and 1.08 (interquartile range, 1.00 to 1.20) in the hydroxyethyl starch group (median difference = 0.03; 95% CI, -0.09 to 0.08; P = 0.165). Also, there were no significant differences concerning serum cystatin C concentrations; estimated glomerular filtration rate; risk, injury, failure, loss, and end-stage renal disease criteria; and neutrophil gelatinase-associated lipocalin. Infusion requirements, transfusion rates, and perioperative hemodynamics were similar in both groups. CONCLUSIONS: With respect to renal function and kidney injury, this study indicates that albumin 5% and balanced hydroxyethyl starch 6% have comparable safety profiles in noncritically ill patients undergoing major surgery.

An evaluation of four modes of low-dose anticoagulation during intermittent haemodialysis.

INTRODUCTION: Intensive care participants that need dialysis frequently suffer from increased risk of bleeding. Standard intermittent haemodialysis (SHD) includes anticoagulation to avoid clotting of the dialysis system. The aim of this study was to clarify which of four different low-dose anticoagulant modes was preferable in reducing the exposure to i.v. unfractionated heparin (heparin) and maintaining patency of the dialysis circuit. METHODS: Twenty-three patients on SHD were included to perform haemodialysis with four modes of low-dose anticoagulation. For comparative analyses, patients served as their own control. Haemodialysis with a single bolus of tinzaparin at the start was compared to haemodialysis initiated without i.v. heparin but priming with (1) heparin in saline (H), (2) heparin and albumin in saline (HA), (3) heparin and albumin in combination with a citrate-containing dialysate (HAC), (4) saline and usinga heparin-coated filters (Evodial®). The priming fluid was discarded before dialysis started. Blood samples were collected at 0, 30 and 180 min during haemodialysis. Smaller bolus doses of heparin (500 Units/dose) were allowed during the modes to avoid interruption by clotting. FINDINGS: The mean activated partial thromboplastin (APTT) time as well as the doses of anticoagulation administered was highest with SHD and least with HAC and Evodial®. Mode H versus SHD had the highest rate of prematurely interrupted dialyses (33%, p = 0.008). The urea reduction rate was less with Evodial® vs. SHD (p < 0.01). One hypersensitivity reaction occurred with Evodial®. Changes in blood cell concentrations and triglycerides differed between the modes. DISCUSSION: If intermittent haemodialysis is necessary in patients at risk of bleeding, anticoagulation using HAC and Evodial® appeared most preferable with least administration of heparin, lowest APTT increase and lowest risk for prematurely clotted dialyzers in contrast to the least plausible H mode.