Fluid Therapy With Gelatin May Have Deleterious Effects on Kidney Function: An Observational Trial.

OBJECTIVE: To explore the effects of fluid therapy with the synthetic colloids hydroxyethyl starch (HES) and gelatin (GEL) on the incidence of acute kidney injury (AKI) and need for renal replacement therapy (RRT) in patients undergoing cardiac surgery. DESIGN: Secondary analysis of a prospective observational study in cardiac surgical patients. DESIGN: University hospital. PARTICIPANTS: The study included 584 elective patients (excluding patients on preoperative dialysis). MEASUREMENTS AND MAIN RESULTS: Anamnestic and surgical core data, hemodynamics, and hemodynamic treatments were recorded intraoperatively and postoperatively. Postoperative kidney dysfunction was graded according to the Acute Kidney Injury Network criteria from perioperative changes in plasma creatinine and urine flow. Statistical analyses were performed descriptively, by logistic and probit regression, omitting inotropic and vasoactive medications as established renal risk factors. The incidence of AKI and new renal replacement therapy was 28.6% and 7.5%, respectively. Patients with AKI were older, had a higher additive Euroscore, lower preoperative glomerular filtration rates and hemoglobin level, and presented with a longer duration of cardiopulmonary bypass and surgery and higher postoperative drainage loss. HES (1 [0-2] units of 500 mL) and GEL (3 [2-5] units of 500 mL) were used in 317 and 563 patients, respectively. Crystalloids were used in all patients (4,560 [4,080-5,042] mL). Patients presenting with AKI or new RRT were treated with significantly higher amounts of GEL. The use of HES and crystalloids did not differ between these groups. Probit regression showed significant dose-response relationships between the amount of infused gelatin and the probability of AKI and new RRT. Probit regression showed significant (p = 0.0001 and 0.0003, respectively) dose-response relationships between the total units of gelatin polysuccinate infused and the probability of AKI and new RRT (Fig 1). Logistic regression revealed a statistically significant odds ratio (OR) of 1.9741 (95% CI: 1.3104-2.9740; p = 0.0011) for an association between the number of gelatin units infused and AKI (grade 1-3) but no direct association between the number of gelatin units administered and new RRT. No association between a decrease in kidney function and the application of HES was observed. CONCLUSIONS: Taking into account the limitations of the small sample size and a low event rate, the nonconsideration of established renal risk factors such as inotropes and vasopressors, and potentially unmeasured confounders, these findings suggested that gelatin solutions may have deleterious effects on renal function in cardiac surgical patients. The adverse clinical effects of HES on kidney function observed in other studies may have been blunted by the restrictive use of this synthetic colloid.

Assessment of Hydroxyethyl Starch (6% HES 130/0.4) Kidney Storage in Critically Ill Dogs: A Post-mortem Prospective Study.

Objective: Intravenous hydroxyethyl starch (HES) solutions are potentially nephrotoxic due to rapid renal tissue uptake, subsequent osmotic nephrosis, and long-lasting intracellular storage. This study aimed to investigate the severity of intracellular storage of HES in renal tissue samples from critically ill dogs receiving 6% HES 130/0.4. Materials and Methods: Fresh, post-mortem (<2 h after death) renal tissue samples were analyzed through histology, immunohistochemistry (HES 130/0.4-specific antibodies), and electron microscopy for the severity of renal tubular vacuolization (VAC), intravacuolar HES accumulation (ACC), and ultra-structure impairment. Moreover, we investigated the relationship between VAC or ACC grade and HES dose (mL/kg), duration of HES administration (h), and pre-HES plasma creatinine concentrations. Results: Histology revealed that 2/20 dogs (10%) had no, 11/20 dogs (55%) had mild, 5/20 dogs (25%) had moderate, and 2/20 dogs (10%) had severe VAC. Immunohistochemistry revealed that 5/20 dogs (25%) had no, 6/20 dogs (30%) had mild, 7/20 dogs (35%) had moderate, and 2/20 dogs (10%) had severe ACC. Both changes were predominantly found in the distal tubular epithelium of mild and moderate cases, and all tubular segments were affected in severe cases. Seven of 20 dogs (35%) had osmotic nephrosis (ON). On electron microscopy, large granules with an electron-dense content were repeatedly detected in individual cells, mainly in the distal tubules. No correlation was found between cumulative HES dose or duration of HES administration and VAC grade, ACC grade, or presence/absence of ON. Conclusion: A high percentage of dogs had renal tubular HES storage and one-third of dogs showed HES-induced ON. Short-term HES administration caused VAC and ACC, regardless of the dose or duration of administration. In contrast to previous studies, HES 130/0.4 deposits were mainly located in the renal distal tubule.

A prospective randomized open-label trial on the comparative effects of 6% hydroxyethyl starch 130/0.4 versus polyionic isotonic crystalloids on coagulation parameters in dogs with spontaneous hemoperitoneum.

OBJECTIVE: To evaluate the effects of 6% hydroxyethyl starch 130/0.4 (HES) and a polyionic isotonic crystalloid (CRYS) on standard coagulation tests and rotational thromboelastometry (ROTEM) in dogs with spontaneous hemoperitoneum (SHP). DESIGN: Prospective randomized open-label clinical study. SETTING: University teaching hospital. ANIMALS: Forty-two client-owned dogs presented with SHP. INTERVENTIONS: Dogs diagnosed with SHP and hypovolemic shock were randomly allocated to receive HES (10 mL/kg, n = 22) or CRYS (30 mL/kg, n = 20) intravenously over 20 minutes for hemodynamic stabilization. MEASUREMENTS AND MAIN RESULTS: Parameters measured before (T0 ) and after (T1 ) treatment were HCT, platelet counts, prothrombin time, activated partial thromboplastin time, fibrinogen concentrations, and extrinsic activated (EXTEM), intrinsic activated (INTEM), and extrinsic activated with platelet inhibition ROTEM assays. Data were analyzed as absolute values and as the percentage change from T0 to T1 . No significant differences between groups were detected in any variable at T0 , and for HCT, platelet counts, prothrombin time, activated thromboplastin time, and fibrinogen concentrations at T1 . Clot formation time in EXTEM was significantly prolonged (P = 0.037), and maximum clot firmness was significantly decreased (P = 0.038) in the HES group compared to the CRYS group at T1 . The percentage change in EXTEM clotting time (P = 0.012) and INTEM clot formation time (P = 0.031) was greater after HES than CRYS. Lysis indices remained at 100% for all ROTEM assays in both groups. CONCLUSION: Compared to a 3-fold volume of CRYS, administration of HES was associated with impairment in ROTEM parameters in dogs with SHP, but no evidence of hyperfibrinolysis was detected.

Blood acid-base, haematological and haemostatic effects of hydroxyethyl starch (130/0.4) compared to succinylated gelatin colloid infusions in normovolaemic dogs.

Synthetic colloids are commonly administered to dogs to treat absolute or relative hypovolaemia. Voluven® (tetrastarch 130/0.4) and Gelofusine® (succinylated gelatin) are available to veterinarians in South Africa. In humans, use of these products has caused acid-base derangements, changes in haematology and impaired haemostasis. We aimed to investigate these effects in healthy normovolaemic dogs. Eight healthy adult beagle dogs underwent a cross-over study, receiving Voluven® or Gelofusine® (10 mL/kg/h for 120 min) once each with a 14-day washout between treatments. Dogs were premedicated with dexmedetomidine (10 µg/kg intramuscularly). Anaesthesia was induced with propofol and the dogs were maintained with isoflurane-in-oxygen. The anaesthetised dogs were connected to a multi-parameter monitor to monitor physiological parameters throughout. Catheters placed in a jugular vein and dorsal metatarsal artery allowed sampling of venous and arterial blood. Blood was collected immediately prior to commencement of colloid infusion, after 60 min infusion and at the end of infusion (120 min) to allow for arterial blood gas analysis, haematology and coagulation testing (activated partial thromboplastin time [aPTT], prothrombin time [PT] and thromboelastography [TEG]). There was no effect, between treatments or over time, on blood pH. The haemoglobin concentration, erythrocyte count and haematocrit decreased significantly over time (all p 0.01), with no differences between treatments, and remained within normal clinical ranges. There were no differences between treatments or over time for the TEG, aPTT and PT tests of haemostasis. At the dose studied, Voluven® and Gelofusine® had comparably negligible effects on blood acid-base balance and coagulation in normovolaemic dogs.

Evaluation of biomarkers of kidney injury following 4% succinylated gelatin and 6% hydroxyethyl starch 130/0.4 administration in a canine hemorrhagic shock model.

OBJECTIVE: To investigate the association between synthetic colloids and biomarkers of acute kidney injury (AKI) in dogs with hemorrhagic shock. DESIGN: Experimental interventional study. SETTING: University. ANIMALS: Twenty-four healthy ex-racing Greyhounds. INTERVENTIONS: Anesthetized Greyhounds subjected to hemorrhage for 60 min were resuscitated with 20 mL/kg of fresh whole blood (FWB), 6% hydroxyethyl starch (HES) 130/0.4, 4% succinylated gelatin (GELO), or 80 mL/kg of isotonic crystalloid (CRYST) over 20 min (n = 6 per treatment). Concentrations of biomarkers of AKI were measured at baseline, end of hemorrhage, and at 40 (T60), 100 (T120), and 160 (T180) min after fluid bolus. Biomarkers included neutrophil gelatinase-associated lipocalin in urine and serum (uNGAL; sNGAL), and urine cystatin C (uCYSC), kidney injury molecule-1 (uKIM), clusterin (uCLUST), osteopontin, gamma-glutamyl transferase, monocyte chemoattractant protein-1 (uMCP), interleukin-6, interleukin-8, protein (uPROT), hyaluronan, and F2 -isoprostanes. Renal histology was scored for tubular injury and microvesiculation. Biomarker fold-change from baseline was compared between groups using mixed effects models (Bonferroni-Holm corrected P<0.05). Frequencies of histology scores were compared by Fisher's exact test. MEASUREMENTS AND MAIN RESULTS: In dogs treated with GELO, uNGAL fold-change was markedly greater compared with all other groups at T60, T120, and T180 (all P<0.001), and uCYSC was greater at T60 compared with CRYST (P<0.001), and at T120 and T180 compared with all other groups (all P<0.001). Smaller, albeit significant, between-group differences in uKIM, uCLUST, uMCP, and urine protein concentration were observed across the FWB, GELO, and HES groups, compared with CRYST. The GELO group more frequently had marked tubular microvesiculation than the other groups (P = 0.015) although tubular injury scores were comparable. CONCLUSION: In dogs with hemorrhagic shock, GELO was associated with greater magnitude increases in urine biomarkers of AKI and more frequent marked tubular microvesiculation, compared with FWB, CRYST, and HES.

Starch Wars-New Episodes of the Saga. Changes in Regulations on Hydroxyethyl Starch in the European Union.

After a safety review of hydroxyethyl starch (HES) solutions in 2013, restrictions on the use of HES were introduced in the European Union (EU) to reduce the risk of kidney injury and death in certain patient populations. Similar restrictions were introduced by the Food and Drug Administration in the United States and other countries. In October 2017, a second safety review of HES solutions was triggered by the European pharmacovigilance authorities based on a request by the Swedish Medical Products Agency to completely suspend HES. After several meetings and repeated evaluations, the recommendation to ban HES was ultimately not endorsed by the responsible committee; however, there was a vote for more restricted access to the drug and rigorous monitoring of policy adherence. This review delineates developments in the European pharmacovigilance risk assessment of HES solutions between 2013 and 2018. In addition, the divergent experts' opinions and the controversy surrounding this official assessment are described. As the new decisions might influence the availability of HES products for veterinary patients, potential alternatives to HES solutions, such as albumin solutions and gelatin, are briefly discussed.

An in vitro comparison of the effects of voluven (6% hydroxyethyl starch 130/0.4) and hespan (6% hydroxyethyl starch 670/0.75) on measures of blood coagulation in canine blood.

OBJECTIVE: To assess primary and secondary hemostasis following in vitro dilution of canine whole blood (WB) with hydroxyethyl starch (HES) 130/0.4 and HES 670/0.75. DESIGN: In vitro experimental study. SETTING: Private practice, teaching hospital. ANIMALS: Twenty-five healthy dogs. INTERVENTIONS: Each dog underwent venipuncture and 18 mL of venous blood was sampled once. MEASUREMENTS AND MAIN RESULTS: Collected blood was separated in 4 aliquots. Aliquot A served as baseline sample. The remaining tubes of WB were diluted with 0.9% saline, HES 670/0.75 and HES 130/0.4 at a ratio of 1:5.5. Dilutional effects were evaluated using prothrombin time (PT), activated partial thromboplastin time (aPTT), packed cell volume (PCV), thromboelastography (TEG), and platelet closure time (Ct), which was measured using a platelet function analyzer (PFA). Clot strength (ie, G value) was calculated from measured TEG values. Significant increases in PT (P < 0.05) and aPTT (P < 0.05) were documented following WB dilution with saline. Dilution of WB with HES 670/0.75 and HES 130/0.4 resulted in significant hypocoagulable changes in K, MA and G (P < 0.05) compared to baseline and saline. When comparing saline to HES 670/0.75, both R and K values were significantly increased (P < 0.05). K value was significantly increased (P < 0.05) when comparing baseline to HES 130/0.4 and HES 670/0.75. Ct (P < 0.05) was significantly prolonged after WB dilution with HES solutions but not after saline. CONCLUSIONS: Dilution of WB with HES 670/0.75 and HES 130/0.4 resulted in changes in primary and secondary hemostasis. Although there were small differences between saline and HES 670/0.75, no differences between HES solutions were evident in this small study. This may suggest there would be minimal increases in bleeding risk when either solution is administered to dogs at low doses. Clinical relevance of our findings requires further investigation.

Current Trends in Volume Replacement Therapy and the Use of Synthetic Colloids in Small Animals-An Internet-Based Survey (2016).

The use of synthetic colloids (SCs), particularly hydroxyethyl starch (HES), in people has changed in recent years following new evidence raising concerns about their efficacy and safety. Although fluid therapy guidelines for small animals are often extrapolated from human medicine, little information exists on current practice in veterinary medicine. The objective of the present study was to investigate current fluid selection, use of plasma volume expanders including SCs, and recent changes in their use in small animal practice. An Internet-based survey was conducted, inviting veterinarians to report their practices in fluid resuscitation and colloid osmotic pressure support, their choice of SC, and perceived adverse effects and contraindications associated with SC use. There were 1,134 respondents from 42 countries, including 46% general practitioners and 38% diplomates. Isotonic crystalloids, HES, and hypertonic saline were chosen by most respondents for fluid resuscitation, and HES by 75% of respondents for colloid osmotic support. Dextran and gelatin were used by some European respondents. Human serum albumin was used more than canine albumin but 45% of respondents, particularly those from Australia and New Zealand, used no albumin product. The majority (70%) of respondents changed their practice regarding SCs in recent years (mostly by limiting their use), largely due to safety concerns. However, only 27% of respondents worked in an institution that had a general policy on SC use. Impaired renal function, coagulopathy, and hypertension were most often considered contraindications; impaired coagulation tests and increased respiratory rate were the most frequently perceived adverse effects. The use of HES remains widespread practice in small animals, regardless of geographic location. Nevertheless, awareness of safety issues and restrictions on the use of SCs imposed in human medicine seems to have prompted a decrease in use of SCs by veterinarians. Given the paucity of evidence regarding efficacy and safety, and differences in cohorts between human and veterinary critical care patients, studies are needed to establish evidence-based guidelines specific for dogs and cats.