Temporal tracking of cysteine 34 oxidation of plasma albumin as a biomarker of muscle damage following a bout of eccentric exercise.

PURPOSE: Exercise-induced muscle damage (EIMD) results in the generation of reactive oxygen species (ROS), but little is known about the temporal profile of change in ROS post-EIMD and how ROS levels relate to the onset of and recovery from EIMD. Our primary aim was to examine the effect of EIMD on the pattern of change in the blood level of thiol-oxidised albumin, a marker of oxidative stress. METHODS: Seven male participants were subjected on separate days to eccentric muscle contraction to cause EIMD or a no-exercise condition. After each session, the participants collected daily dried blood spots to measure thiol-oxidised albumin and returned to the laboratory every 2 days for the assessment of indirect markers of EIMD, namely maximal voluntary contraction (MVC), delayed onset muscle soreness (DOMS), creatine kinase (CK), and myoglobin. RESULTS: Eccentric exercise resulted in a significant decrease in MVC and increase in DOMS, CK, myoglobin, and thiol-oxidised albumin with the latter reaching above baseline level within 24-48 h post-exercise. All the markers of EIMD returned to baseline level within 6 days post-exercise, but not the level of thiol-oxidised albumin which remained elevated for 10 days after exercise. There was a moderate correlation between changes in thiol-oxidised albumin and DOMS, but no significant relationship between any other markers of muscle damage. CONCLUSION: The levels of thiol-oxidised albumin increase in response to EIMD and remain elevated for several days post-exercise. The temporal pattern of change in the level of thiol-oxidised albumin suggests that this may be a useful biomarker of muscle repair post-EIMD.

Hydroxyethyl starch 130/0.4 (6%) and succinylated gelatine (4%) interfere with refractometry in dogs with haemorrhagic shock.

OBJECTIVE: To determine if low molecular weight synthetic colloid fluids administered to dogs interfere with refractometric estimates of total plasma protein (TPPr) and urine osmolality (UOsm). STUDY DESIGN: Experimental study. ANIMALS: Eighteen healthy Greyhound dogs. METHODS: Anaesthetized Greyhounds subjected to haemorrhage for 60 minutes were given 80 mL kg-1 of Plasma-Lyte 148 (CRYST), or 20 mL kg-1 of hydroxyethyl starch 130/0.4 (HES) or succinylated gelatine (GELO) (n = 6 per group) intravenously over 20 minutes. Refractometric (TPPr) and biuret total plasma protein (TPPb) were measured before haemorrhage (Baseline), at end of shock (Shock), immediately (T20), then 40 minutes (T60), 100 minutes (T120) and 160 minutes (T180) after fluid administration. Urine specific gravity (USG) and UOsm were measured at all time points except T20. Estimated UOsm (eUOsm) was calculated from USG. Bias and limits of agreement (LOA) for TPPr versus TPPb, and eUOsm versus UOsm were calculated at each time point. RESULTS: For dogs given CRYST and GELO, median TPPr and TPPb decreased in parallel, with a small consistent TPP bias (CRYST range of bias, 0.38-0.67 g dL-1; GELO range of bias, 0.42-0.58 g dL-1). Dogs given HES showed divergence between median TPPr and TPPb after T20, with a peak bias at T20 of 1.62 g dL-1 (LOA 1.29-1.95). Dogs given HES and GELO had markedly increased USG [HES peak median USG at T180 of 1.119 (Q1-Q3 1.103-1.122); GELO peak median USG at T120 of 1.114 (Q1-Q3 1.082-1.119)], with large increases in bias between eUOsm and UOsm [HES peak bias at T60 of 2995 mOsm kg-1 (LOA 2032-3958 mOsm kg-1); GELO peak bias at T120 of 2465 mOsm kg-1 (LOA 940-3990 mOsm kg-1)]. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of HES and GELO to dogs with haemorrhagic shock interferes with refractometric measurements for at least 3 hours after administration.

Clinical Use of Canine Thawed Refrigerated Plasma: A Historical Case Series.

Thawed plasma (TP) refers to defrosted fresh frozen plasma stored refrigerated. TP is used in human medicine for the rapid provision of coagulation factors and resuscitation of haemorrhagic shock, but its use in dogs is poorly described. The objectives of this historical case series were to describe the reasons for TP transfusion, treatment outcomes, and adverse events associated with canine TP transfusions in a veterinary teaching hospital. We hypothesised that TP would be used most commonly for the treatment of haemorrhage secondary to anticoagulant rodenticide intoxication and trauma. Blood bank plasma transfusion logs were searched to identify dogs that received at least one unit of TP between December 2015 and June 2021. Briefly, 166 dogs received a total of 262 units of TP. Anticoagulant rodenticide intoxication (37/166, 22.3%) was the most common reason for transfusion, followed by traumatic haemorrhage (23, 13.9%) and spontaneous haemoperitoneum (22, 13.2%). The majority of dogs received one unit of TP (111/166, 67.1%) and pRBCs were commonly simultaneously transfused with TP (65, 39.2%). Severe prolongations of prothrombin time and activated partial thromboplastin time were reduced following TP transfusions. Allergic reactions were the most common transfusion reaction (19/166, 11.4%). Most dogs survived to discharge (101/166, 60.8%).

The hemostatic profile of cold-stored whole blood from non-greyhound and greyhound dogs over 42 days.

Objectives: To compare the hemostatic characteristics of cold-stored whole blood (CSWB) from non-greyhound dogs (NGD) and greyhound dogs (GD) over 42 days of storage, notably, platelet closure time (PCT) (NGD only), manual platelet count (PLT) (GD only), ellagic acid (INTEM) and tissue factor activated (EXTEM) rotational thromboelastometry, prothrombin (PT) and activated partial thromboplastin time (aPTT), fibrinogen concentration (FIB), and the activities of factors (F) FII, FV, FVII, FVIII, FIX, FX, FXIII antigen (FXIII:Ag), and von Willebrand factor antigen (vWF:Ag). Design: Whole blood from 10 NGD and 10 GD, was refrigerated in CPD blood bags at 4°C for 42 days. Blood was analyzed before refrigeration (day 0) and at day 1 (d1), 3, 5, 7, 10, 14, 17, 21, 24, 28, 31, 35, 38, and 42. Multivariate linear mixed effects models were created to evaluate coagulation parameters over time and compare NGD and GD. Data are summarized as estimated marginal means with 95% confidence intervals. Significance was set at P < 0.05. Results: The PCT for all NGD CSWB was above the device limit by d7. The PLT for GD CSWB did not change during storage. The mean alpha-angle for INTEM and EXTEM decreased to <50% of baseline at d38 and d31 for NGD, and d31 and d17 for GD CSWB. The mean maximum clot firmness (MCF) for INTEM and EXTEM reduced to <50% of baseline at d42 and d28 for both GD and NGD. PT and aPTT for NGD and GD increased over time. For NGD CSWB, the mean FVIII and vWF:Ag activities decreased to <50% of baseline at d7 and d28, respectively, and FIB reached 0.982 g/dL by d24. For GD CSWB, FVIII, FXIII:Ag and FV activities decreased to <50% of baseline by d3, d38, and d38, respectively, and FIB was 0.982 g/dL at baseline. Alpha-angle and MCF for both INTEM and EXTEM, and activities for FII, FV, FIX, FXIII:Ag were significantly lower, and vWF:Ag was significantly higher overall in GD CSWB compared with NGD. A significant difference in the pattern of change over time was detected between NGD and GD in EXTEM alpha-angle, INTEM and EXTEM MCF, FII, and FVIII activities. Conclusions: The in vitro viscoelastic parameters of GD and NGD CSWB declines over 42 days, but numerous hemostatic parameters (INTEM and EXTEM alpha-angle and MCF, activity of FII, FV, FV, FVII, FIX, FX, FXIII:Ag, vWF:Ag, and FIB) remain within 50% of baseline for more than 14 days. CSWB from GD compared to NGD has reduced hemostatic activity overall, but a similar pattern of decline for most parameters over time.

Allergy, inflammation, hepatopathy and coagulation biomarkers in dogs with suspected anaphylaxis due to insect envenomation.

Objectives: To compare concentrations of biomarkers of; allergy [mast cell tryptase (MCT) and histamine], inflammation [interleukin (IL)-6,-10, and-18, CXCL8, CCL2, keratinocyte chemoattractant (KC), C-reactive protein (CRP)], endothelial glycocalyx shedding (hyaluronan), coagulation [prothrombin time, activated partial thromboplastin time, fibrinogen concentration, and von Willebrand Factor antigen, protein C (PC) and antithrombin (AT) activity], and hepatopathy [alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and total bilirubin] between dogs with anaphylaxis after suspected insect exposure, dogs with critical illness, and healthy dogs. Design: This was a single center prospective clinical observational comparative biomarker study that included 25 dogs with anaphylaxis (evidence of insect exposure, acute dermatological signs, and other organ involvement), 30 dogs with other critical illness, and 20 healthy dogs. Differences across groups in biomarker concentrations were tested using one-way ANOVA or Kruskal-Wallis test, with significant P values (<0.05) reported for pairwise differences detected by post-hoc tests. Logistic regression models were used to calculate the area under the receiver operator characteristic curve (AUROC) for discrimination between anaphylaxis and non-anaphylactic illness. Results: Histamine concentration was significantly higher in the anaphylaxis group than the healthy (P < 0.001) and critically ill groups (P < 0.001), whereas no differences in MCT were detected amongst groups. Biomarker concentrations that were increased relative to healthy dogs in both the anaphylaxis and critically ill groups included IL-10 (P < 0.001 and P = 0.007, respectively), CCL2 (P = 0.007 and P < 0.001, respectively) and AST (both P < 0.001), whereas only the critically ill group had significantly increased CRP (P < 0.001), IL-6 (P < 0.001), KC (P < 0.001), ALP (P < 0.001), and fibrinogen (P = 0.016) concentrations, compared to the healthy group. Only dogs with anaphylaxis had significantly higher hyaluronan (P = 0.021) and ALT (P = 0.021) concentrations, and lower PC (P = 0.030) and AT (P = 0.032) activities, compared to healthy dogs. Both CRP and histamine concentration showed good discrimination between anaphylaxis and other critical illness, with an AUROC of 0.96 (95% CI 0.91-1) and 0.81 (95% CI 0.69-0.93), respectively. Conclusions: This preliminary study in dogs with anaphylaxis after suspected insect exposure, found evidence of an early innate immune response, glycocalyx shedding and anticoagulant consumption. Both CRP and histamine showed potential clinical utility for differentiation between anaphylaxis and other critical illness.

Biomarkers of Coagulation and Inflammation in Dogs after Randomized Administration of 6% Hydroxyethyl Starch 130/0.4 or Hartmann's Solution.

Synthetic colloid fluids containing hydroxyethyl starch (HES) have been associated with impairment of coagulation in dogs. It is unknown if HES causes coagulation impairment in dogs with naturally occurring critical illness. This study used banked plasma samples from a blinded, randomized clinical trial comparing HES and balanced isotonic crystalloid for bolus fluid therapy in 39 critically ill dogs. Blood was collected prior to fluid administration and 6, 12, and 24 h thereafter. Coagulation biomarkers measured at each time point included prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen concentration, and the activities of coagulation factors V, VII, VIII, IX, and X, von Willebrand factor antigen, antithrombin, and protein C. Given the links between coagulation and inflammation, cytokine concentrations were also measured, including interleukins 6, 8, 10, and 18, keratinocyte-derived chemokine, and monocyte chemoattractant protein-1. Data were analyzed with linear mixed effects models. No significant treatment-by-time interactions were found for any biomarker, indicating that the pattern of change over time was not modified by treatment. Examining the main effect of time showed significant changes in several coagulation biomarkers and keratinocyte-derived chemokines. This study could not detect evidence of coagulation impairment with HES.

Effect of leukoreduction on inflammation in critically ill dogs receiving red blood cell transfusions: A randomized blinded controlled clinical trial.

BACKGROUND: Prestorage leukoreduction of red blood cell (RBC) bags prevents accumulation of pro-inflammatory mediators and experimentally attenuates post-transfusion inflammation in healthy dogs. However, the effect of leukoreduction on post-transfusion inflammation in critically ill dogs is unclear. HYPOTHESIS: Dogs transfused with leukoreduced (LR) RBC will have lower concentrations of leukocytes, interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and C-reactive protein (CRP) within 24 hours of post-transfusion compared to dogs transfused with nonleukoreduced (NLR) RBC. ANIMALS: Sixty-one RBC-transfused dogs (LR = 34, NLR = 27). METHODS: Randomized, blinded, controlled preliminary clinical trial. Blood bag processing was randomized to create identically appearing LR and NLR bags. Group allocation occurred with transfusion of the oldest compatible RBC bag. Blood samples were collected pretransfusion and at 8 and 24 hours post-transfusion for leukocyte count, IL-6, IL-8, MCP-1, and CRP. Data were analyzed on an intention-to-treat basis using linear mixed effects models. Significance was set at P < .05. RESULTS: No significant differences were found between groups in concentrations of leukocytes (P = .93), IL-6 (P = .99), IL-8 (P = .75), MCP-1 (P = .69), or CRP (P = .18) over time. Eleven LR dogs (32%) and 4 NLR dogs (15%) were euthanized in the hospital (P = .14). No natural deaths occurred. CONCLUSIONS AND CLINICAL IMPORTANCE: No differences in inflammation biomarker concentrations were detected over time between dogs transfused with LR or NLR RBC, but heterogeneity likely hampered the ability to detect a difference with this sample size. The novel randomization and enrollment protocol was successfully implemented across 2 participating institutions and will be easily scaled up for a future multicenter clinical trial.

Stability of ex vivo coagulation factor activity in never-frozen and thawed refrigerated canine plasma stored for 42 days.

OBJECTIVE: The primary objective of this study was to document coagulation factor activity in canine "NEVER-FROZEN" and "THAWED" refrigerated plasma for the purposes of defining recommended expiration dates. We hypothesized that NEVER-FROZEN and THAWED refrigerated plasma would maintain >50% activity of coagulation factors V (FV), VII (FVII), VIII (FVIII), IX (FIX), X (FX), and von Willebrand factor antigen (vWF) and a concentration of fibrinogen above the lower bound of the reference interval (>0.982 g/L) for greater than 14 days but less than 42 days. DESIGN: Prospective laboratory-based study. SETTING: University teaching hospital blood bank. ANIMALS: Ten canine plasma units derived from healthy client-owned blood donors. INTERVENTIONS: Serial sampling (days 0, 1, 3, 5, 7, 10, 14, 17, 21, 24, 28, 32, 35, 39, 42) from NEVER-FROZEN and THAWED refrigerated canine plasma units was conducted for measurement of activities of FV, FVII, FVIII, FIX, FX, vWF, and fibrinogen concentrations using the ACL TOP 300. Plasma was defined as "suitable for transfusion" at a given time point if the entire 95% confidence interval for each factor was above 50% activity and above a fibrinogen concentration of 0.982 g/L. MEASUREMENTS AND MAIN RESULTS: The lower bounds of the FVIII and vWF confidence intervals were above 50% up to and including day 32 for NEVER-FROZEN refrigerated plasma and day 28 for THAWED refrigerated plasma. Confidence intervals for FV, FVII, FIX, and FX remained above 50% activity at all time points. The lower bound of the fibrinogen concentration was <0.982 g/L on day 39 for NEVER-FROZEN refrigerated plasma and on day 35 for THAWED refrigerated plasma. CONCLUSIONS: Refrigerated canine plasma from these 10 dogs retained coagulation factor activity above the limit that we defined as suitable for transfusion for up to 32 days when NEVER-FROZEN and 28 days when THAWED. Further studies should evaluate the clinical outcomes and effects on coagulation factor activity of dogs receiving refrigerated plasma transfusions.

2022 Update of the Consensus on the Rational Use of Antithrombotics and Thrombolytics in Veterinary Critical Care (CURATIVE) Domain 1- Defining populations at risk.

OBJECTIVES: To expand the number of conditions and interventions explored for their associations with thrombosis in the veterinary literature and to provide the basis for prescribing recommendations. DESIGN: A population exposure comparison outcome format was used to represent patient, exposure, comparison, and outcome. Population Exposure Comparison Outcome questions were distributed to worksheet authors who performed comprehensive searches, summarized the evidence, and created guideline recommendations that were reviewed by domain chairs. The revised guidelines then underwent the Delphi survey process to reach consensus on the final guidelines. Diseases evaluated in this iteration included heartworm disease (dogs and cats), immune-mediated hemolytic anemia (cats), protein-losing nephropathy (cats), protein-losing enteropathy (dogs and cats), sepsis (cats), hyperadrenocorticism (cats), liver disease (dogs), congenital portosystemic shunts (dogs and cats) and the following interventions: IV catheters (dogs and cats), arterial catheters (dogs and cats), vascular access ports (dogs and cats), extracorporeal circuits (dogs and cats) and transvenous pacemakers (dogs and cats). RESULTS: Of the diseases evaluated in this iteration, a high risk for thrombosis was defined as heartworm disease or protein-losing enteropathy. Low risk for thrombosis was defined as dogs with liver disease, cats with immune-mediated hemolytic anemia, protein-losing nephropathy, sepsis, or hyperadrenocorticism. CONCLUSIONS: Associations with thrombosis are outlined for various conditions and interventions and provide the basis for management recommendations. Numerous knowledge gaps were identified that represent opportunities for future studies.

2022 Update of the Consensus on the Rational Use of Antithrombotics and Thrombolytics in Veterinary Critical Care (CURATIVE) Domain 6: Defining rational use of thrombolytics.

OBJECTIVES: To systematically review available evidence and establish guidelines related to the use of thrombolytics for the management of small animals with suspected or confirmed thrombosis. DESIGN: PICO (Population, Intervention, Control, and Outcome) questions were formulated, and worksheets completed as part of a standardized and systematic literature evaluation. The population of interest included dogs and cats (considered separately) and arterial and venous thrombosis. The interventions assessed were the use of thrombolytics, compared to no thrombolytics, with or without anticoagulants or antiplatelet agents. Specific protocols for recombinant tissue plasminogen activator were also evaluated. Outcomes assessed included efficacy and safety. Relevant articles were categorized according to level of evidence, quality, and as to whether they supported, were neutral to, or opposed the PICO questions. Conclusions from the PICO worksheets were used to draft guidelines, which were subsequently refined via Delphi surveys undertaken by the Consensus on the Rational Use of Antithrombotics and Thrombolytics in Veterinary Critical Care (CURATIVE) working group. RESULTS: Fourteen PICO questions were developed, generating 14 guidelines. The majority of the literature addressing the PICO questions in dogs is experimental studies (level of evidence 3), thus providing insufficient evidence to determine if thrombolysis improves patient-centered outcomes. In cats, literature was more limited and often neutral to the PICO questions, precluding strong evidence-based recommendations for thrombolytic use. Rather, for both species, suggestions are made regarding considerations for when thrombolytic drugs may be considered, the combination of thrombolytics with anticoagulant or antiplatelet drugs, and the choice of thrombolytic agent. CONCLUSIONS: Substantial additional research is needed to address the role of thrombolytics for the treatment of arterial and venous thrombosis in dogs and cats. Clinical trials with patient-centered outcomes will be most valuable for addressing knowledge gaps in the field.

Intravenous Fluid Administration and the Coagulation System.

Intravenous fluid administration in veterinary patients can alter coagulation function by several mechanisms. Both crystalloid and colloid fluids cause hemodilution, reducing platelet count and plasma coagulation protein concentrations. Hemodilution is associated with a hypercoagulable effect at low dilutions and a hypocoagulable effect at higher dilutions. Composition of crystalloid fluids likely has a minor effect, primarily dependent on fluid ion composition. Hypertonic crystalloids may also cause hypocoagulability. Colloids, both synthetic and natural, can cause hypocoagulability by several mechanisms beyond the effects of hemodilution. These include impaired platelet function, decreased plasma coagulation factor activity, impaired fibrin formation and crosslinking, and accelerated fibrinolysis. The vast majority of the veterinary literature investigates the hypocoagulable effects of hydroxyethyl starch-containing fluids using in vitro, experimental, and clinical studies. However, results are inconsistent, likely due to the varying doses and physicochemical properties of the specific fluid products across studies. In addition, some evidence exists for hypocoagulable effects of gelatin and albumin solutions. There is also evidence that these colloids increase the risk of clinical bleeding in people. Limitations of the veterinary evidence for the hypocoagulable effects of colloid fluids include a predominance of in vitro studies and in vivo studies using healthy subjects, which exclude the interaction of the effects of illness. Therefore, clinical relevance of these effects, especially for low-molecular-weight hydroxyethyl starch, is unknown. Firm recommendations about the most appropriate fluid to use in clinical scenarios cannot be made, although it is prudent to limit the dose of synthetic colloid in at-risk patients. Clinicians should closely monitor relevant coagulation assays and for evidence of hemorrhage in at-risk patients receiving any type of fluid therapy, especially in large volumes.

Prospective randomized controlled blinded clinical trial evaluating biomarkers of acute kidney injury following 6% hydroxyethyl starch 130/0.4 or Hartmann's solution in dogs.

OBJECTIVE: To evaluate the effect of 6% hydroxyethyl starch (HES) 130/0.4, compared with a Hartmann's solution control (CRYST), on urine biomarkers of acute kidney injury (AKI) in dogs prescribed a fluid bolus. DESIGN: Randomized, controlled, blinded clinical trial January 2018 to February 2019. SETTING: University teaching hospital. ANIMALS: Forty client-owned dogs. INTERVENTIONS: Dogs prescribed a fluid bolus were randomized to receive at least 10 mL/kg of HES or CRYST with clinicians and investigators blinded to fluid type. Study fluid was used for further boluses as required in the following 24 hours, to a limit of 40 mL/kg total, after which fluid administration was open-label. MEASUREMENTS AND MAIN RESULTS: Urine was collected prior to and 6, 12, and 24 hours after the first study fluid bolus. Urine concentrations of AKI biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, kidney injury molecule-1 (KIM), clusterin, and osteopontin were measured using a magnetic bead multiplexed assay. Osmolality-indexed biomarker concentrations were compared between groups over time with linear mixed-effects models, with P < 0.05 considered significant. The mean volume of study fluid administered was not significantly different between groups (HES: 23.1 mL/kg, CRYST: 25.9 mL/kg; P = 0.47, t-test). There were no significant differences between groups in change over time of osmolality-indexed urine concentrations of NGAL (P = 0.91), cystatin C (P = 0.95), KIM (P = 0.77), clusterin (P = 0.63), or osteopontin (P = 0.91). The maximum Veterinary Acute Kidney Injury (VAKI) score up to 7 days during hospitalization (P = 1.0) and in-hospital mortality (P = 0.49) were not significantly different between groups, as compared by Fisher's exact test. CONCLUSIONS: There were no differences in change over time of urine AKI biomarkers in dogs treated with 10 - 40 mL/kg HES or CRYST over 24 hours. Larger clinical trials with patient-centered outcomes are required to investigate the safety of HES in dogs.

A randomised controlled trial of succinylated gelatin (4%) fluid on urinary acute kidney injury biomarkers in cardiac surgical patients.

BACKGROUND: Fluid resuscitation is frequently required for cardiac surgical patients admitted to the intensive care unit. The ideal fluid of choice in regard to efficacy and safety remains uncertain. Compared with crystalloid fluid, colloid fluid may result in less positive fluid balance. However, some synthetic colloids are associated with increased risk of acute kidney injury (AKI). This study compared the effects of succinylated gelatin (4%) (GEL) with compound sodium lactate (CSL) on urinary AKI biomarkers in patients after cardiac surgery. METHODS: Cardiac surgical patients who required an intravenous fluid bolus of at least 500 mL postoperatively were randomly allocated to receive GEL or CSL as the resuscitation fluid of choice for the subsequent 24 h. Primary outcomes were serial urinary neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C concentrations measured at baseline, 1 h, 5 h and 24 h after enrolment, with higher concentrations indicating greater kidney injury. Secondary biomarker outcomes included urinary clusterin, α1-microglobulin and F2-isoprostanes concentrations. Differences in change of biomarker concentration between the two groups over time were compared with mixed-effects regression models. Statistical significance was set at P < 0.05. RESULTS: Forty cardiac surgical patients (n = 20 per group) with similar baseline characteristics were included. There was no significant difference in the median volume of fluid boluses administered over 24 h between the GEL (1250 mL, Q1-Q3 500-1750) and CSL group (1000 mL, Q1-Q3 500-1375) (P = 0.42). There was a significantly greater increase in urinary cystatin C (P < 0.001), clusterin (P < 0.001), α1-microglobulin (P < 0.001) and F2-isoprostanes (P = 0.020) concentrations over time in the GEL group, compared to the CSL group. Change in urinary NGAL concentration (P = 0.68) over time was not significantly different between the groups. The results were not modified by adjustment for either urinary osmolality or EuroSCORE II predicted risk of mortality. CONCLUSIONS: This preliminary randomised controlled trial showed that use of succinylated gelatin (4%) for fluid resuscitation after cardiac surgery was associated with increased biomarker concentrations of renal tubular injury and dysfunction, compared to crystalloid fluid. These results generate concern that use of intravenous gelatin fluid may contribute to clinically relevant postoperative AKI. Trial registration ANZCTR.org.au, ACTRN12617001461381. Registered on 16th October, 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373619&isReview=true .

Corrigendum: Hypocoagulability and Platelet Dysfunction Are Exacerbated by Synthetic Colloids in a Canine Hemorrhagic Shock Model.

[This corrects the article DOI: 10.3389/fvets.2018.00279.].

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.

Hypocoagulability and Platelet Dysfunction Are Exacerbated by Synthetic Colloids in a Canine Hemorrhagic Shock Model.

Background: Hemorrhagic shock and volume replacement can alter coagulation. Synthetic colloids, hydroxyethyl starch (HES), and gelatin, may enhance hypocoagulability. Our primary objective was to describe the effect of four fluid products on coagulation in canine hemorrhagic shock. Our secondary objective was to compare measurements of coagulation during shock to baseline in all dogs. Methods: Anesthetized greyhounds subjected to atraumatic hemorrhage for 60 min were administered 20 mL kg-1 of either fresh whole blood (FWB), 6% HES 130/0.4, 4% succinylated gelatin (GELO), or 80 mL kg-1 of isotonic crystalloid over 20 min (n = 6 per group). Platelet closure time (PCT), rotational thromboelastometry (ROTEM) and plasma coagulation assays were measured at baseline, end of hemorrhage (shock), and 40 (T60), and 160 (T180) min after study fluid. ROTEM parameters included clotting time (CT), clot formation time (CFT), alpha angle, maximum clot firmness (MCF), lysis index at 60 min (LI60), and thrombodynamic potential index (TPI) for INTEM, EXTEM, FIBTEM (MCF only), and APTEM (LI60 only) profiles. Plasma coagulation assays included prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen concentration and activities of factor VII (FVII), factor VIII (FVIII), and von Willebrand Factor antigen (vWF). Between-group differences were tested using linear mixed models with post-hoc between-group comparisons (Bonferroni-Holm corrected). Differences between baseline and shock were tested using paired t-tests. Significance was set at P < 0.05. Results: GELO showed longer PCT at T60, compared with FWB and CRYST, and at T180, compared with all other groups. HES showed longer EXTEM CT at T60, compared with all other groups. HES showed lower INTEM and EXTEM MCF at T60 and lower INTEM MCF at T180, compared with FWB. Some plasma coagulation assays showed greater hypocoagulability with HES. Comparing shock to baseline, EXTEM CT, INTEM CFT, EXTEM CFT, PT, and FVIII significantly increased and PCT, INTEM CT, INTEM MCF, EXTEM MCF, EXTEM LI60, EXTEM TPI, FIBTEM MCF, APTT, fibrinogen, FVII, and vWF significantly decreased. Conclusions: In dogs with hemorrhagic shock, volume replacement with GELO caused mild platelet dysfunction and HES was associated with coagulation changes consistent with hypocoagulability, beyond effects of hemodilution. Shock alone produced some evidence of hypocoagulability.