Evaluation of Therapeutic Use of Antifibrinolytics in Cats.

Limited data are available regarding the use of the antifibrinolytic drugs tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) in cats. This study aimed to evaluate the indications for the use of TXA and EACA in cats and to describe dosing regimens used, occurrence of adverse events, and patient outcomes. This was a retrospective multicenter study. Medical databases were searched for feline patients billed for TXA or EACA between 2015 and 2021. Thirty-five cats met the inclusion criteria; 86% received TXA and 14% received EACA. The most common indication was nontraumatic hemorrhage (54%), followed by traumatic hemorrhage (17%) and elective surgery (11%). The median dose was 10 mg/kg for TXA and 50 mg/kg for EACA. Overall, 52% of cats survived to discharge. Potential adverse events were noted in 7/35 (20%) patients. Of these, 29% survived to discharge. No standardized dosing regimen was identified; rather, dose, dosing interval, and duration of administration varied markedly between patients. Administration was potentially associated with severe adverse events, although the retrospective design makes it difficult to establish a causal association with antifibrinolytic use. This study provides a base for future prospective studies by giving an insight into the use of antifibrinolytic drugs in cats.

Selective mitochondrial antioxidant MitoTEMPO reduces renal dysfunction and systemic inflammation in experimental sepsis in rats.

BACKGROUND: Excess mitochondrial reactive oxygen species (mROS) in sepsis is associated with organ failure, in part by generating inflammation through the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. We determined the impact of a mitochondrial-targeted antioxidant (MitoTEMPO) on mitochondrial dysfunction in renal proximal tubular epithelial cells, peritoneal immune cell function ex vivo, and organ dysfunction in a rat model of sepsis. METHODS: The effects of MitoTEMPO were assessed ex vivo using adenosine triphosphate and lipopolysaccharide-stimulated rat peritoneal immune cells and fresh rat kidney slices exposed to serum from septic rats. We assessed mROS production and phagocytotic capacity (flow cytometry), mitochondrial functionality (multiphoton imaging, respirometry), and NLRP3 inflammasome activation in cell culture. The effect of MitoTEMPO on organ dysfunction was evaluated in a rat model of faecal peritonitis. RESULTS: MitoTEMPO decreased septic serum-induced mROS (P<0.001) and maintained normal reduced nicotinamide adenine dinucleotide redox state (P=0.02) and mitochondrial membrane potential (P<0.001) in renal proximal tubular epithelial cells ex vivo. In lipopolysaccharide-stimulated peritoneal immune cells, MitoTEMPO abrogated the increase in mROS (P=0.006) and interleukin-1ß (IL-1ß) (P=0.03) without affecting non-mitochondrial oxygen consumption or the phagocytotic-induced respiratory burst (P>0.05). In vivo, compared with untreated septic animals, MitoTEMPO reduced systemic IL-1ß (P=0.01), reduced renal oxidative stress as determined by urine isoprostane levels (P=0.04), and ameliorated renal dysfunction (reduced serum urea (P<0.001) and creatinine (P=0.05). CONCLUSIONS: Reduction of mROS by a mitochondria-targeted antioxidant reduced IL-1ß, and protected mitochondrial, cellular, and organ functionality after septic insults.

A key metabolic integrator, coenzyme A, modulates the activity of peroxiredoxin 5 via covalent modification.

Peroxiredoxins (Prdxs) are antioxidant enzymes that catalyse the breakdown of peroxides and regulate redox activity in the cell. Peroxiredoxin 5 (Prdx5) is a unique member of Prdxs, which displays a wider subcellular distribution and substrate specificity and exhibits a different catalytic mechanism when compared to other members of the family. Here, the role of a key metabolic integrator coenzyme A (CoA) in modulating the activity of Prdx5 was investigated. We report for the first time a novel mode of Prdx5 regulation mediated via covalent and reversible attachment of CoA (CoAlation) in cellular response to oxidative and metabolic stress. The site of CoAlation in endogenous Prdx5 was mapped by mass spectrometry to peroxidatic cysteine 48. By employing an in vitro CoAlation assay, we showed that Prdx5 peroxidase activity is inhibited by covalent interaction with CoA in a dithiothreitol-sensitive manner. Collectively, these results reveal that human Prdx5 is a substrate for CoAlation in vitro and in vivo, and provide new insight into metabolic control of redox status in mammalian cells.

Evaluation of the dynamic predictors of fluid responsiveness in dogs receiving goal-directed fluid therapy.

OBJECTIVES: Goal-directed fluid therapy (GDFT) based on pulse pressure variation (PPV) was used in anaesthetized dogs undergoing abdominal surgeries. The aims were 1) to evaluate the success rate of the PPV ≥13% in detecting fluid responsiveness [delta stroke volume (ΔSV) ≥10%]; 2) to assess the correlation between PPV, systolic pressure variation (SPV), Plethysmograph Variability Index (PVI) and central venous pressure (CVP) and 3) to establish the threshold value for the PVI that would predict a PPV value of ≥13% and indirectly discriminate responders from nonresponders to fluid therapy. STUDY DESIGN: Clinical, prospective, interventional study. ANIMALS: A total of 63 client-owned dogs scheduled for abdominal procedures. METHODS: PPV and SPV were calculated manually from the invasive blood pressure trace on the Datex monitor. PVI was recorded from the Masimo pulse oximeter. Fluid challenge (10 mL kg-1 Compound Sodium Lactate) was performed when PPV was ≥13% and/or mean arterial pressure (MAP) < 60 mmHg. Fluid responsiveness was assessed by the transoesophageal Doppler probe. Cardiovascular parameters (heart rate, MAP, PPV, SPV, PVI, SV and if available, CVP) were measured before and after each fluid intervention. RESULTS: PPV ≥ 13% reliably predicted fluid responsiveness in 82.9% of cases. There was positive correlation between PPV and SPV (r = 0.84%), PPV and logPVI (r = 0.46) as well as SPV and logPVI (r = 0.45). Noninvasive PVI value ≥13% should predict PPV threshold value (13%) with 97% sensitivity and 68% specificity. There was no statistically significant correlation between PPV and CVP. CONCLUSIONS: PPV is a useful clinical tool to detect occult hypovolaemia and predict cardiovascular response to fluid challenge. Use of PPV is recommended as a part of GDFT in dogs undergoing abdominal procedures.

Extracorporeal liver assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study.

BACKGROUND & AIMS: In acute liver failure, severity of liver injury and clinical progression of disease are in part consequent upon activation of the innate immune system. Endotoxaemia contributes to innate immune system activation and the detoxifying function of albumin, critical to recovery from liver injury, is irreversibly destroyed in acute liver failure. University College London-Liver Dialysis Device is a novel artificial extracorporeal liver assist device, which is used with albumin infusion, to achieve removal and replacement of dysfunctional albumin and reduction in endotoxaemia. We aimed to test the effect of this device on survival in a pig model of acetaminophen-induced acute liver failure. METHODS: Pigs were randomised to three groups: Acetaminophen plus University College London-Liver Dialysis Device (n=9); Acetaminophen plus Control Device (n=7); and Control plus Control Device (n=4). Device treatment was initiated two h after onset of irreversible acute liver failure. RESULTS: The Liver Dialysis Device resulted in 67% reduced risk of death in acetaminophen-induced acute liver failure compared to Control Device (hazard ratio=0.33, p=0.0439). This was associated with 27% decrease in circulating irreversibly oxidised human non-mercaptalbumin-2 throughout treatment (p=0.046); 54% reduction in overall severity of endotoxaemia (p=0.024); delay in development of vasoplegia and acute lung injury; and delay in systemic activation of the TLR4 signalling pathway. Liver Dialysis Device-associated adverse clinical effects were not seen. CONCLUSIONS: The survival benefit and lack of adverse effects would support clinical trials of University College London-Liver Dialysis Device in acute liver failure patients.

Development and translation of thiometallate sulfide donors using a porcine model of coronary occlusion and reperfusion.

Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs.

Defining sepsis in small animals.

OBJECTIVE: To discuss the definitions of sepsis in human and veterinary medicine. DESIGN: International, multicenter position statement on the need for consensus definitions of sepsis in veterinary medicine. SETTING: Veterinary private practice and university teaching hospitals. ANIMALS: Dogs and cats. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sepsis is a life-threatening condition associated with the body's response to an infection. In human medicine, sepsis has been defined by consensus on 3 occasions, most recently in 2016. In veterinary medicine, there is little uniformity in how sepsis is defined and no consensus on how to identify it clinically. Most publications rely on modified criteria derived from the 1991 and 2001 human consensus definitions. There is a divergence between the human and veterinary descriptions of sepsis and no consensus on how to diagnose the syndrome. This impedes research, hampers the translation of pathophysiology insights to the clinic, and limits our abilities to optimize patient care. It may be time to formally define sepsis in veterinary medicine to help the field move forward. In this narrative review, we present a synopsis of prior attempts to define sepsis in human and veterinary medicine, discuss developments in our understanding, and highlight some criticisms and shortcomings of existing schemes. CONCLUSIONS: This review is intended to serve as the foundation of current efforts to establish a consensus definition for sepsis in small animals and ultimately generate evidence-based criteria for its recognition in veterinary clinical practice.

A reproducible, clinically relevant, intensively managed, pig model of acute liver failure for testing of therapies aimed to prolong survival.

BACKGROUND: A clinically relevant, translational large animal model of acute liver failure (ALF) is required for testing of novel therapies to prolong survival in acute liver failure, to permit spontaneous liver recovery or to act as a bridge to transplantation. AIMS: The aim was to establish a pig model of acetaminophen-induced ALF that mimics the human clinical syndrome, is managed as in a human intensive care unit and has a predictable survival time. METHODS: Nine female pigs were anaesthetised and instrumented for continuous intensive care monitoring and management using: target-driven protocols for treatment of cardiovascular collapse, metabolic acidosis and electrolyte abnormalities; intermittent positive pressure ventilation; and continuous renal replacement therapy. Six animals were induced to ALF with acetaminophen (paracetamol). Three animals acted as controls. RESULTS: Irreversible acute liver failure, defined as rise in prothrombin time >3 times normal, occurred 19.3 ± 1.8 h after the onset of acetaminophen administration. Death occurred predictably 12.6 ± 2.7 h thereafter, with acute hepatocellular necrosis in all animals. Clinical progression of liver failure mimicked the human condition including development of coagulopathy, intracranial hypertension, hyperammonaemia, cardiovascular collapse, elevation in creatinine, metabolic acidosis and hyperlactataemia. In addition, cardiovascular monitoring clearly demonstrated progressive cardiac dysfunction in ALF. CONCLUSIONS: A reproducible, clinically relevant, intensively managed, large animal model of acute liver failure, with death as a result of multi-organ failure, has been successfully validated for translational studies of disease progression and therapies designed to prolong survival in man.

Appetite Stimulant and Anti-Emetic Effect of Mirtazapine Transdermal Ointment in Cats Affected by Lymphoma Following Chemotherapy Administration: A Multi-Centre Retrospective Study.

In humans, mirtazapine can prevent chemotherapy-induced nausea and vomiting (CINV) and improve cancer patients' quality of life (QoL). This drug is being increasingly used as an appetite stimulant in cats. The hypothesis of this retrospective study was that mirtazapine could reduce the incidence of CINV and weight loss in feline patients affected by lymphoma. The objectives were to report the use of mirtazapine transdermal ointment and assess the incidence of gastrointestinal (GI) toxicity and weight loss in cats diagnosed with lymphoma and receiving chemotherapy. Transdermal mirtazapine was topically administered to the inner surface of the pinna (2 mg/cat/daily) for 14 days following chemotherapy administration. Data recorded from 20 patients were collected. Different grades of GI toxicity were shown in 8/20 (40%) patients. Body weight (BW), body condition score (BCS), and muscle condition score (MCS) improved in 12/20 (60%), 6/20 (30%), and 2/20 (10%) cats, respectively. Mirtazapine-induced adverse events (AEs) occurred in 4/20 (20%) cats and did not require mirtazapine discontinuation. Substantial weight loss was not encountered, suggesting that patients had an adequate food intake after chemotherapy administration. Transdermal mirtazapine ointment was considered safe and well tolerated.

Point seroprevalence of canine influenza virus H3N8 in dogs participating in a flyball tournament in Pennsylvania.

OBJECTIVE: To determine the seroprevalence of antibody against canine influenza virus H3N8 in a group of pet dogs that participate in flyball in Pennsylvania. DESIGN-SEROLOGIC SURVEY: Animals-Dogs attending a flyball tournament in Downingtown, Pa, from November 13 to 14, 2009. Procedures-Blood samples were collected from dogs following owner consent. Medical, travel, and activity history of the dogs for the previous 10.5 months was obtained from owners. Serum was harvested and submitted to Cornell University Diagnostic Laboratory for measurement of antibody against canine influenza virus H3N8 via hemagglutination inhibition testing. RESULTS: Serum samples were obtained from 100 of 256 dogs participating in the flyball event. Although 3 of the 100 (3%) samples had positive results for antibody against canine influenza, none of the associated dogs had respiratory signs of infection (eg, coughing, sneezing, or nasal or ocular discharge) in the 10.5 months prior to testing. Eleven dogs had a history of respiratory signs, but none of those dogs had antibody against canine influenza H3N8. In addition, none of the study dogs had been vaccinated against canine influenza H3N8. CONCLUSIONS AND CLINICAL RELEVANCE: Although canine influenza is considered enzootic in certain areas of the country (eg, Pennsylvania or New York), this study identified a low seroprevalence in dogs considered at high risk for infection given their life conditions and geographic origins. More research is warranted to elucidate the prevalence of exposure to the H3N8 virus in competitive sporting dogs and determine whether vaccination is warranted in such dogs.

Complications and outcome of cats with congenital extrahepatic portosystemic shunts treated with thin film: Thirty-four cases (2008-2017).

BACKGROUND: Congenital extrahepatic portosystemic shunts (CEHPSS) are rare in cats. Outcome after attenuation of CEHPSS with thin film has been described in a small number of cases. OBJECTIVES: To describe the clinical presentation, postoperative complications, and outcome of cats treated with thin film to attenuate CEHPSS. ANIMALS: Thirty-four cats with CEHPSS were identified from the database of 3 institutions over 9 years. METHODS: Retrospective study. Medical records were reviewed to identify cats with a diagnosis of a CEHPSS that underwent surgical attenuation. Congenital extrahepatic portosystemic shunts were suspected from clinical signs, clinicopathologic findings, and diagnostic imaging, and confirmed at exploratory laparotomy. Cats treated with thin film band attenuation were included. Postoperative complications and follow-up were recorded. RESULTS: Complications were recorded in 11 of 34 cats. Deaths related to CEHPSS occurred in 6 of 34; 4 cats did not survive to discharge. Persistent seizures were the cause of death in 4 cats. Seizures were recorded in 8 of 34 cats after surgery; all these cats received preoperative antiepileptic drugs. Serum bile acid concentrations normalized in 25 of 28 of the cats for which data was available. Three cats had persistently increased serum bile acid concentrations and underwent a second exploratory laparotomy. One had a patent shunt, the other 2 had multiple acquired portosystemic shunts. Median follow-up was 8 months (0.5-84 months). CONCLUSIONS AND CLINICAL IMPORTANCE: Congenital extrahepatic portosystemic shunts attenuation using thin film in cats carries a good short- and mid-term prognosis if they survive the postoperative period. Seizures were the most common cause of death.

The role of mitochondria in sepsis-induced cardiomyopathy.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Myocardial dysfunction, often termed sepsis-induced cardiomyopathy, is a frequent complication and is associated with worse outcomes. Numerous mechanisms contribute to sepsis-induced cardiomyopathy and a growing body of evidence suggests that bioenergetic and metabolic derangements play a central role in its development; however, there are significant discrepancies in the literature, perhaps reflecting variability in the experimental models employed or in the host response to sepsis. The condition is characterised by lack of significant cell death, normal tissue oxygen levels and, in survivors, reversibility of organ dysfunction. The functional changes observed in cardiac tissue may represent an adaptive response to prolonged stress that limits cell death, improving the potential for recovery. In this review, we describe our current understanding of the pathophysiology underlying myocardial dysfunction in sepsis, with a focus on disrupted mitochondrial processes.

Description of the Use of Plasma Exchange in Dogs With Cutaneous and Renal Glomerular Vasculopathy.

Cutaneous and renal glomerular vasculopathy (CRGV) is a rare disease affecting dogs, with a recent apparent increase in prevalence since 2012 in the UK. This disease is characterized by a vasculopathy affecting small vessels of the kidney and skin, leading to thrombotic microangiopathy. The underlying etiology remains unknown although clinicopathological and histological findings resemble features of certain forms of thrombotic microangiopathy in people, for which plasma exchange (PEX) is considered an important component of therapy. The objective of the present study is to describe the use of PEX as adjunctive treatment in dogs diagnosed with CRGV. A retrospective review of dogs diagnosed with CRGV between 2014 and 2016 treated with PEX was performed. Clinical records were reviewed and data relating to signalment, diagnostic tests and management strategies were summarized. Information and complications relating to PEX were recorded. Six dogs were diagnosed with CRGV (n = 2 ante-mortem, n = 4 post-mortem) and underwent PEX as part of their therapy. All dogs had cutaneous lesions and were azotemic with oliguria or anuria. All dogs underwent at least one PEX cycle; one dog had a single cycle PEX, three dogs two cycles PEX, and two dogs had one cycle PEX and one cycle of prolonged intermittent renal replacement treatment. Complications seen during PEX therapy included hypothermia (n = 4), tachycardia (n = 2), hypotension (n = 2), and hypocalcemia (n = 6). Two dogs survived to discharge, the remaining four dogs were euthanized. The positive outcome in two dogs treated with PEX despite the reported high mortality rate once acute kidney injury with oliguria/anuria occurs does not confirm success of this treatment. However, survival in two dogs that were initially oligoanuric highlights that further consideration and evaluation of PEX for this patient group is warranted for this specific disease. Additional studies are urgently needed to identify the underlying etiology of CRGV before more targeted therapies can be developed. Based on our findings, further evaluation of the role of PEX in this specific disease are warranted.

Hypercoagulability progresses to hypocoagulability during evolution of acetaminophen-induced acute liver injury in pigs.

Increases in prothrombin time (PT) and international normalised ratio (INR) characterise acute liver injury (ALI) and failure (ALF), yet a wide heterogeneity in clotting abnormalities exists. This study defines evolution of coagulopathy in 10 pigs with acetaminophen (APAP)-induced ALI compared to 3 Controls. APAP administration began at 0 h and continued to 'ALF', defined as INR >3. In APAP pigs, INR was 1.05 ± 0.02 at 0 h, 2.15 ± 0.43 at 16 h and > 3 at 18 ± 1 h. At 12 h thromboelastography (TEG) demonstrated increased clot formation rate, associated with portal vein platelet aggregates and reductions in protein C, protein S, antithrombin and A Disintegrin and Metalloprotease with Thrombospondin type 1 repeats-13 (ADAMTS-13) to 60%, 24%, 47% and 32% normal respectively. At 18 ± 1 h, INR > 3 was associated with: hypocoagulable TEG profile with heparin-like effect; falls in thrombin generation, Factor V and Factor VIII to 52%, 19% and 17% normal respectively; further decline in anticoagulants; thrombocytopenia; neutrophilia and endotoxemia. Multivariate analysis, found that ADAMTS-13 was an independent predictor of a hypercoagulable TEG profile and platelet count, endotoxin, Protein C and fibrinogen were independent predictors of a hypocoagulable TEG profile. INR remained normal in Controls. Dynamic changes in coagulation occur with progression of ALI: a pro-thrombotic state progresses to hypocoagulability.

Management of acute kidney injury with continuous venovenous haemodiafiltration in a cat.

Continuous renal replacement therapy is an emerging technique for the treatment of acute kidney injury (AKI). Data regarding its use in cats are limited. This report describes the use of a novel continuous renal replacement therapy (CRRT) system for the treatment of AKI in a cat. A 1.3-year-old cat developed uraemic signs following the administration of a non-steroidal anti-inflammatory agent for the treatment of a suspect traumatic episode. CRRT was provided with a Prismaflex Gambro machine used in continuous venovenous haemodiafiltration mode, with an AN-69 surface-treated membrane, synthetic colloid priming and heparin anticoagulation. Two treatment cycles were performed, totalling 51 h of CRRT. The treatment was effective in controlling uraemic signs, and no major complications were noted. Owing to financial constraints the owners declined further CRRT treatments, and on day 8 of hospitalisation, owing to the lack of significant clinical improvement, humane euthanasia was performed. The set-up detailed in this report provides a viable option for the initial treatment of cats with AKI.