Polyoxazoline-conjugated porcine serum albumin as an artificial plasma expander for dogs.

Veterinary medicine has made tremendous progress for domestic dogs, which are irreplaceable family members enriching human life. Nevertheless, no adequate supply system exists for their blood products. This study examined the synthesis, structure, safety, and efficacy of poly(2-ethyl-2-oxazoline)-conjugated porcine serum albumin (POx-PSA) as an artificial plasma expander for dogs. The aqueous POx-PSA solution showed moderately high colloid osmotic pressure and good blood cell compatibility. Actually, lyophilized powder stored for 1 year can regenerate into a homogeneous solution. The circulation half-life of POx-PSA in rats was 2.1-fold longer than that of naked PSA. Rats produced neither anti-PSA IgG antibody nor anti-POx IgG antibody, which suggests excellent immunological stealth properties of POx-PSA. Complete resuscitation of hemorrhagic shock in rats was achieved soon after injection of POx-PSA solution. Serum biochemistry tests and histopathological observations indicated no abnormality in the related organs. When POx-PSA was administered to dogs intravenously, (i) no serum biochemical or hematological alteration was observed, also (ii) no overt deterioration of animal health was observed. These results indicate that POx-PSA has potential as an artificial plasma expander for dogs.

Perioperative colloids: From theory to practice.

INTRODUCTION: Fluid administration is the cornerstone in hypovolemic patient's reanimation. Clinical guidelines restrict colloid administration favouring crystalloids. Currently, we don't know exactly which is the daily clinical practice during the perioperative period. The objective of this study is to describe perioperative use of colloids analysing possible reasons aiming to use them. MATERIAL AND METHODS: Prospective, cross-section, national, multicentre observational study. Fluid Day sub-study. We enrolled all patient's older than 18 years old who underwent surgery during the 24 h of the 2-days study (February, 2019, 18th and 20th). We registered demographic data, comorbidities, anaesthetic and surgical procedure data, fluids administered, perioperative bleeding and monitoring type used during the perioperative period. RESULTS: A total of 5928 cases were analysed and 542 patients (9.1%) received any type of colloids, being hydroxiethyl-starch the most frequently used (5.1%). Patients receiving colloids suffered more longing surgery (150 [90-255] vs. 75 [45-120] min), were urgently operated (13.7 vs. 7.5%) and were more frequent classified as high risk (22 vs. 4.8%). Their recovery was mostly in critical care units (45.1 vs.15.8%). Patients with bleeding less than 500 ml received colloids in a percentage of 5.9 versus 45.9% when this figure was overcome. Patients who received colloids were anaemic more frequently: 29.4 vs. 16.3%. Colloids administration had a higher risk for transfusion (OR 15.7). Advanced monitoring also increased the risk for receiving colloids (OR 9.43). CONCLUSIONS: In our environment with routine clinical practice, colloids administration is limited and close linked to perioperative bleeding.

Utility of 6% hydroxyethyl starch 130/0.4 in oral cancer surgeries with a duration of over 6 hours: A retrospective case-control study.

To evaluate the utility of 6% hydroxyethyl starch (HES) 130/0.4 in oral cancer surgeries with durations over 6 hours. Using a case-control study design, the investigators enrolled patients who underwent oral cancer surgery involving osteotomy or manipulation near the major blood vessels at the Department of Orofacial Surgery in our hospital between 2017 and 2020. The predictor variable was 6% HES130/0.4. Outcomes included in-out balance and other postoperative parameters pertaining to circulatory maintenance (blood loss, urine volume, infusion volume, blood transfusion volume, albumin dose, hemoglobin levels, blood albumin levels, and doses of vasopressors used to maintain blood pressure), as well as pre- and postoperative renal function, pH, bicarbonate levels, and base excess. Changes in renal function were evaluated by assessing blood urea nitrogen and creatinine levels before surgery and at 1 and 7 days postoperatively. The Mann-Whitney U test was used for between-group comparisons, and Student t test was used for intragroup comparisons. The statistical significance was set at P < .05. A total of 65 patients underwent oral cancer surgery with a duration over 6 hours during the study period. The administration of 6% HES130/0.4 at 22.1 ± 7.5 mL/kg/day did not increase blood loss or the blood transfusion volume. Moreover, patients who were administered 6% HES130/0.4 had a significantly larger mean urine volume and infusion volume than those who were not administered 6% HES130/0.4. The infusion therapy could maintain the urine volume and did not worsen renal function. The results of this study showed that administration of 6% HES130/0.4 at a dose lower than 25 mL/kg in patients undergoing oral cancer surgery over 6 hours was effective for circulation maintenance but did not increase the intraoperative blood loss or transfusion volume. This treatment did not cause any dilutional metabolic acidosis or renal dysfunction.

Manipulation of Nitric Oxide Levels via a Modified Hydroxyethyl Starch Molecule.

INTRODUCTION: Although the improving effect of nitric oxide (NO) donors has experimentally been demonstrated in shock, there are still no NO donor medications clinically available. Thiol-nitrosothiol-hydroxyethyl starch (S-NO-HES) is a novel molecule consisting of NO coupled to a thiolated derivative of hydroxyethyl starch (HES). It was aimed to assess the ability of S-NO-HES to serve as an NO donor under a variety of in vitro simulated physiologic conditions, which might be the first step to qualify this molecule as a novel type of NO donor-fluid. METHODS: We studied the effect of temperature on NO-releasing properties of S-NO-HES in blood, at 34°C, 37°C, and 41°C. Ascorbic acid (Asc) and amylase were also tested in a medium environment. In addition, we evaluated the activity of S-NO-HES in the isolated aortic ring and Langendorff-perfused heart setup. RESULTS: The NO release property of S-NO-HES was found at any temperature. Asc led to a significant increase in the production of NO compared to S-NO-HES incubation (P < 0.05). The addition of amylase together with Asc to the medium further increased the release of NO (P < 0.05). S-NO-HES exerted significant vasodilatory effects on phenylephrine precontracted aortic rings that were dose-dependent (P < 0.01). Furthermore, S-NO-HES significantly increased the heart rate and additionally reduced the duration of the cardiac action potential, as indicated by a reduction of QTc-B values (P < 0.01). CONCLUSIONS: We demonstrated for the first time that the S-NO-HES molecule exhibited its NO-releasing effects. The effectiveness of this new NO donor to substitute NO deficiency under septic conditions or in other indications needs to be studied.

Limiting calcium overload after cardiac arrest: The role of human albumin in controlled automated reperfusion of the whole body.

BACKGROUND: Regarding the overall inadequate results after cardiopulmonary resuscitation, the development of new treatment concepts is urgently needed. Controlled Automated Reperfusion of the whoLe body (CARL) represents a therapy bundle to control the conditions of reperfusion and the composition of the reperfusate after cardiac arrest (CA). The aim of this study was to investigate the plasma expander's role in the CARL priming solution and examine its mechanism of action. METHODS: Viscosity, osmolality, colloid osmotic pressure (COP), pH and calcium binding of different priming solutions were measured in vitro and compared to in vivo data. N = 16 pigs were allocated to receive CARL following 20 min of untreated CA with either human albumin 20% (HA, N = 8) or gelatin polysuccinate 4% (GP, N = 8). Blood gas analyses were performed during the first hour of reperfusion and catecholamine and fluid requirements were recorded. Neurological outcome was assessed by neurological deficit scoring (NDS) on the seventh day. RESULTS: In vitro, addition of HA to the CARL priming solution resulted in higher COP and higher calcium-binding than GP. In vivo, treatment with HA led to greater reduction of ionized calcium and higher extracorporeal flows within the first 30 min of reperfusion with no difference in catecholamine support and fluid requirement. Seven-day survival of 75% with no difference in NDS was observed in both groups. CONCLUSIONS: Our data show that the plasma expander in the CARL priming solution has a significant effect on the initial reperfusate and can potentially influence the course of resuscitation. However, seven-day survival and NDS did not differ between groups.

Impact of colloids or crystalloids in renal function assessed by NGAL and KIM-1 after hysterectomy: randomized controlled trial

Abstract Background Hydroxyethyl starches are colloids used in fluid therapy that may reduce volume infusion compared with crystalloids, but they can affect renal function in critical care patients. This study aims to assess renal effects of starches using renal biomarkers in the perioperative setting. Methods This prospective, controlled, randomized study compared Hydroxyethyl starch 6% (HES) with Ringer's lactate (RL) in hysterectomy. Each episode of mean arterial pressure (MAP) below 60 mmHg guided the fluid replacement protocol. The RL group received 300 mL bolus of RL solution while the HES group received 150 mL of HES solution. All patients received RL (2 mL.kg−1.h−1) intraoperatively to replace insensible losses. Blood and urine samples were collected at three time points (preoperatively, 24 hours, and 40 days postoperatively) to assess urinary NGAL and KIM-1, as primary outcome, and other markers of renal function. Results Seventy patients were randomized and 60 completed the study. The RL group received a higher crystalloid volume (1,277 ± 812.7 mL vs. 630.4 ± 310.2 mL; p= 0.0002) with a higher fluid balance (780 ± 720 mL vs. 430 ± 440 mL; p= 0.03) and fluid overload (11.7% ± 10.4% vs. 7.0% ± 6.3%; p= 0.04) compared to the HES group. NGAL and KIM-1 did not differ between groups at each time point, however both biomarkers increased 24 hours postoperatively and returned to preoperative levels after 40 days in both groups. Conclusion HES did not increase renal biomarkers following open hysterectomy compared to RL. Moreover, HES provided better hemodynamic parameters using less volume, and reduced postoperative fluid balance and fluid overload.

In vitro effect of hydroxyethyl starch on coagulation in dogs as assessed by dynamic viscoelastic coagulometry.

OBJECTIVE: To evaluate the effect of 6% hydroxyethyl starch (HES) 670/0.75 and 6% HES 130/0.4 dilution of canine whole blood on coagulation using dynamic viscoelastic coagulometry (DVC). ANIMALS: 56 healthy adult dogs. PROCEDURES: 2 blood samples were obtained from each dog and randomized to 1 of 7 groups-undiluted or 2 dilutions (1:3 or 1:10) of 3 different fluids: saline (0.9% NaCl) solution, 6% HES 670/0.75, or 6% HES 130/0.4. Dilutions were calculated to simulate approximately a 10- or 30-mL/kg body weight IV bolus of each fluid. DVC was performed on each sample. Coagulation parameters compared between groups included clot rate (CR), platelet function (PF), and activated clotting time. RESULTS: Dilution with saline solution did not significantly affect coagulation, while dilution with HES 670/0.75 and HES 130/0.4 caused a dose-dependent significant decrease in CR (1:3 HES 670/0.75, P = 0.007; 1:10 HES 670/0.75, P = 0.002; 1:3 HES130/0.4, P < 0.0001; and 1:10 HES 130/0.4, P = 0.0003) and PF (1:3 HES 670/0.75, P < 0.0001; 1:10 HES 670/0.75, P < 0.0001; 1:3 HES130/0.4, P < 0.0001; and 1:10 HES 130/0.4, P = 0.0015). CLINICAL RELEVANCE: Dilution of canine blood with HES 670/0.75 and HES 130/0.4, at clinically relevant doses (10 and 30 mL/kg), led to significant hypocoagulability beyond dilutional effect. This was, in part, due to impaired PF, which was significantly greater with HES 670/0.75. Further research using DVC to assess the effects of HES on coagulation in dogs, ideally with clinical conditions warranting HES administration, is needed.

Kinetics of 5% and 20% albumin: A controlled crossover trial in volunteers.

BACKGROUND: Albumin for intravenous infusion is marketed in two concentrations, 20% and 5%, but how they compare with regard to plasma volume expansion over time is unclear. METHODS: In a prospective crossover study, 12 volunteers received 3 ml kg-1 of 20% albumin and, on another occasion, 12 ml kg-1 of 5% albumin over 30 min. Hence, equivalent amounts of albumin were given. Blood was collected on 15 occasions over 6 h. Mass balance and volume kinetics were used to estimate the plasma volume expansion and the capillary leakage of albumin and fluid based on measurements of blood hemoglobin, plasma albumin, and the colloid osmotic pressure. RESULTS: The greatest plasma volume expansion was 16.0 ± 6.4% (mean ± SD) with 20% albumin and 19.0 ± 5.2% with 5% albumin (p < .03). The volume expansion with 20% albumin corresponded to twice the infused volume. One third of the 5% albumin volume quickly leaked out of the plasma, probably because of the higher colloid osmotic pressure of the volunteer plasma (mean, 24.5 mmHg) than the albumin solution (19.1 mmHg). At 6 h, the capillary leakage amounted to 42 ± 15% and 47 ± 11% of the administered albumin with the 20% and 5% preparations, respectively (p = .28). The corresponding urine outputs were 547 (316-780) ml and 687 (626-1080) ml (median and interquartile range; p = .24). CONCLUSION: The most important difference between the fluids was a dehydrating effect of 20% albumin when the same albumin mass was administered.

Modified fluid gelatin 4% for perioperative volume replacement in pediatric patients (GPS): Results of a European prospective noninterventional multicenter study.

INTRODUCTION: Modified fluid gelatin 4% is approved for use in children, but there is still a surprising lack of clinical studies including large numbers of pediatric patients. Therefore, we performed a European prospective noninterventional multicenter study to evaluate the use of a modified fluid gelatin 4% in saline (sal-GEL) or an acetate-containing balanced electrolyte solution (bal-GEL) in children undergoing major pediatric surgery. AIMS: The primary aim was to assess the indications and dosing of modified fluid gelatin, and the secondary aim was to assess the safety and efficacy, focusing, in particular, on routinely collected clinical parameters. METHODS: Children aged up to 12 years with ASA risk scores of I-III receiving sal-GEL or bal-GEL were followed perioperatively. Demographic data, surgical procedures performed, anesthesia, hemodynamic and laboratory data, adverse events, and adverse drug reactions were documented using a standardized case report form. RESULTS: 601 children that were investigated at 13 European pediatric centers from May 2015 to March 2020 (sal-GEL 20.1%, bal-GEL 79.9%; mean age 29.1 ± 38.6 (range 0-144) months; body weight 12.1 ± 10.5 (1.4-70) kg) were included in the analysis. The most frequent indications for GEL infusion were hemodynamic instability without bleeding (76.0%), crystalloids alone not being sufficient for hemodynamic stabilization (55.7%), replacement of preoperative deficit (26.0%), and significant bleeding (13.0%). Mean infused GEL volume was 13.0 ± 5.3 (2.4-37.5) ml kg-1 . The total dose was affected by age, with higher doses in younger patients. After gelatin infusion, mean arterial pressure increased (mean change 8.5 ± 7.3 [95% CI: 8 to 9.1] mmHg), and the hemoglobin concentrations decreased significantly (mean change -1.1 ± 1.8 [95% CI: -1.2 to -0.9] g·dL-1 ). Acid-base parameters were more stable with bal-GEL. No serious adverse drug reactions directly related to gelatin (i.e., anaphylactoid reaction, clotting disorders, and renal failure) were observed. CONCLUSION: Moderate doses up to 20 ml kg-1 of modified fluid gelatin were infused most frequently to improve hemodynamic stability in children undergoing major pediatric surgery. The acid-base balance was more stable when gelatin in a balanced electrolyte solution was used instead of saline. No serious adverse drug reactions associated with gelatin were observed.

Human albumin and 6% hydroxyethyl starches (130/0.4) in cardiac surgery: a meta-analysis revisited.

BACKGROUND: A meta-analysis of randomized controlled trials was recently published in BMC Surgery that compared the use of human albumin with 6% hydroxyethyl starches 130/0.4 for cardiopulmonary bypass prime and perioperative fluid management in pediatric and adult cardiac surgery patients. The two plasma expanding solutions are described as equivalent for efficacy and safety outcomes, and, on that basis, the preferential use of hydroxyethyl starches 130/0.4 was recommended for economic reasons because of the higher unit costs of human albumin solutions. RESULTS: In addition to the fact that trials were mostly small, single-center studies and the number of total participants was low, making the meta-analysis underpowered for several outcomes, selective reporting of data for ICU length of stay was identified. Re-calculation of statistics at higher precision showed that ICU length of stay of patients in the human albumin group was significantly shorter than that of patients in the 6% hydroxyethyl starches 130/0.4 group (standard mean difference - 0.181, 95% confidence interval - 0.361 to - 0.001, P = 0.049), which may offset any proposed economic advantage of using 6% hydroxyethyl starches 130/0.4. At the same time, the renal safety of 6% hydroxyethyl starches 130/0.4 in surgical patients is under regulatory review. CONCLUSIONS: Underpowered trials and selective reporting may impair the validity of the meta-analysis. A more cautious conclusion about the interchangeability between human albumin and 6% hydroxyethyl starches 130/0.4 in cardiac surgery should have been reached.

Prospective, randomized, controlled, double-blind, multi-center, multinational study on the safety and efficacy of 6% Hydroxyethyl starch (HES) sOlution versus an Electrolyte solutioN In patients undergoing eleCtive abdominal Surgery: study protocol for the PHOENICS study.

BACKGROUND: Hydroxyethyl starch (HES) solutions are used for volume therapy to treat hypovolemia due to acute blood loss and to maintain hemodynamic stability. This study was requested by the European Medicines Agency (EMA) to provide more evidence on the long-term safety and efficacy of HES solutions in the perioperative setting. METHODS: PHOENICS is a randomized, controlled, double-blind, multi-center, multinational phase IV (IIIb) study with two parallel groups to investigate non-inferiority regarding the safety of a 6% HES 130 solution (Volulyte 6%, Fresenius Kabi, Germany) compared with a crystalloid solution (Ionolyte, Fresenius Kabi, Germany) for infusion in patients with acute blood loss during elective abdominal surgery. A total of 2280 eligible patients (male and female patients willing to participate, with expected blood loss ≥ 500 ml, aged > 40 and ≤ 85 years, and ASA Physical status II-III) are randomly assigned to receive either HES or crystalloid solution for the treatment of hypovolemia due to surgery-induced acute blood loss in hospitals in up to 11 European countries. The dosing of investigational products (IP) is individualized to patients' volume needs and guided by a volume algorithm. Patients are treated with IP for maximally 24 h or until the maximum daily dose of 30 ml/kg body weight is reached. The primary endpoint is the treatment group mean difference in the change from the pre-operative baseline value in cystatin-C-based estimated glomerular filtration rate (eGFR), to the eGFR value calculated from the highest cystatin-C level measured during post-operative days 1-3. Further safety and efficacy parameters include, e.g., combined mortality/major post-operative complications until day 90, renal function, coagulation, inflammation, hemodynamic variables, hospital length of stay, major post-operative complications, and 28-day, 90-day, and 1-year mortality. DISCUSSION: The study will provide important information on the long-term safety and efficacy of HES 130/0.4 when administered according to the approved European product information. The results will be relevant for volume therapy of surgical patients. TRIAL REGISTRATION: EudraCT 2016-002162-30 . ClinicalTrials.gov NCT03278548.

Calculating and selecting fluid therapy and blood product replacements for horses with acute hemorrhage.

BACKGROUND: Blood products, crystalloids, and colloid fluids are used in the medical treatment of severe hemorrhage in horses with a goal of providing sufficient blood flow and oxygen delivery to vital organs. The fluid treatments for hemorrhage will vary depending upon severity and duration and whether hemorrhage is controlled or uncontrolled. DESCRIPTION: With acute and severe controlled hemorrhage, treatment is focused on rapidly increasing perfusion pressure and blood flow to vital organs. This can most easily be accomplished in field cases by the administration of hypertonic saline. If isotonic crystalloids are used for resuscitation, the volume administered should be at least as great as the estimated blood loss. Following crystalloid resuscitation, clinical signs, HCT, and laboratory evidence of tissue hypoxia may help determine the need for a whole blood transfusion. In uncontrolled hemorrhage, crystalloid resuscitation is often more conservative and is referred to as "permissive hypotension." The goal of "permissive hypotension" would be to provide enough perfusion pressure to vital organs such that function is maintained while keeping blood pressure below the normal range in the hope that clot formation will not be disrupted. Whole blood and fresh frozen plasma in addition to aminocaproic acid are indicated in most horses with severe uncontrolled hemorrhage. SUMMARY: Blood transfusion is a life-saving treatment for severe hemorrhage in horses. No precise HCT serves as a transfusion trigger; however, an HCT < 15%, lack of appropriate clinical response, or significant improvement in plasma lactate following crystalloid resuscitation and loss of 25% or more of blood volume is suggestive of the need for whole blood transfusion. Mathematical formulas may be used to estimate the amount of blood required for transfusion following severe but controlled hemorrhage, but these are not very accurate and, in practice, transfusion volume should be approximately 40% of estimated blood loss. KEY POINTS: Modest hemorrhage, <15% of blood volume (<12 mL/kg), can be fully compensated by physiological mechanisms and generally does not require fluid or blood product therapy. More severe hemorrhage, >25% of blood volume (> 20 mL/kg), often requires crystalloid or blood product replacement, while acute loss of greater than 30% (>24 mL/kg) of blood volume may result in hemorrhagic shock requiring resuscitation treatments Uncontrolled hemorrhage is a common occurrence in equine practice, and is most commonly associated with abdominal bleeding (eg, uterine artery rupture in mares). If the hemorrhage can be controlled such as by ligation of a bleeding vessel, then initial efforts to resuscitate the horse should focus on increasing perfusion pressure and blood flow to organs as quickly as possible with crystalloids or colloids while assessing need for whole blood transfusion. While fluid therapy is being administered every effort to physically control hemorrhage should be made using ligatures, application of compression, surgical methods, and local hemostatic agents like collagen-, gelatin-, and cellulose-based products, fibrin, yunnan baiyao (YB), and synthetic glues Although some synthetic colloids have been shown to be associated with acute kidney injury in people receiving resuscitation therapy,20 this undesirable effect in horses has not been reported.

Hemodynamic Responses to Crystalloid and Colloid Fluid Boluses during Noncardiac Surgery.

BACKGROUND: Colloids are thought to sustain blood pressure and cardiac index better than crystalloids. However, the relative effects of intraoperative hydroxyethyl starch and crystalloid administration on the cardiac index and blood pressure remain unclear. This study therefore tested in this subanalysis of a previously published large randomized trial the hypothesis that intraoperative goal-directed colloid administration increases the cardiac index more than goal-directed crystalloid administration. Further, the effects of crystalloid and colloid boluses on blood pressure were evaluated. METHODS: This planned subanalysis of a previous trial analyzed data from 973 patients, of whom 480 were randomized to colloids and 493 were randomized to crystalloids. Fluid administration was guided by esophageal Doppler. The primary outcome was the time-weighted average cardiac index during surgery between the colloid and crystalloid group. The secondary outcomes were the cardiac index just after bolus administration, time elapsed between boluses, and the average real variability during surgery. The study recorded cardiac index, corrected flow time, and blood pressure at 10-min intervals, as well as before and after each bolus. RESULTS: Time-weighted average of cardiac index over the duration of anesthesia was only slightly greater in patients given colloid than crystalloid, with the difference being just 0.20 l · min-1 · m-2 (95% CI, 0.11 to 0.29; P < 0.001). However, the hazard for needing additional boluses was lower after colloid administration (hazard ratio [95% CI], 0.60 [0.55 to 0.66]; P < 0.001) in a frailty time-to-event model accounting for within-subject correlation. The median [quartiles] number of boluses per patient was 4 [2, 6] for colloids and 6 [3, 8] for crystalloids, with a median difference (95% CI) of -1.5 (-2 to -1; P < 0.001). The average real mean arterial pressure variability did not differ significantly between the groups (difference in means [95% CI] of -0.03 (-0.07 to 0.02) mmHg, P = 0.229). CONCLUSIONS: There were not clinically meaningful differences in the cardiac index or mean pressure variability in patients given goal-directed colloid and crystalloids. As might be expected from longer intravascular dwell time, the interval between boluses was longer with colloids. However, on a case basis, the number of boluses differed only slightly. Colloids do not appear to provide substantial hemodynamic benefit.