Effects of constant rate infusions of dexmedetomidine, remifentanil and their combination on minimum alveolar concentration of sevoflurane in dogs.

OBJECTIVE: To evaluate the effects of constant rate infusions (CRIs) of dexmedetomidine and remifentanil alone and their combination on minimum alveolar concentration (MAC) of sevoflurane in dogs. STUDY DESIGN: Randomized crossover experimental study. ANIMALS: A total of six (three males, three females) healthy, adult neutered Beagle dogs weighing 12.6 ± 1.4 kg. METHODS: Anesthesia was induced with sevoflurane in oxygen until endotracheal intubation was possible and anesthesia maintained with sevoflurane using positive-pressure ventilation. Each dog was anesthetized five times and was administered each of the following treatments: saline (1 mL kg-1 hour-1) or dexmedetomidine at 0.1, 0.5, 1.0 or 5.0 µg kg-1 loading dose intravenously over 10 minutes followed by CRI at 0.1, 0.5, 1.0 or 5.0 µg kg-1 hour-1, respectively. Following 60 minutes of CRI, sevoflurane MAC was determined in duplicate using an electrical stimulus (50 V, 50 Hz, 10 ms). Then, CRI of successively increasing doses of remifentanil (0.15, 0.60 and 2.40 µg kg-1 minute-1) was added to each treatment. MAC was also determined after 30 minutes equilibration at each remifentanil dose. Isobolographic analysis determined interaction from the predicted doses required for a 50% MAC reduction (ED50) with remifentanil, dexmedetomidine and remifentanil combined with dexmedetomidine, with the exception of dexmedetomidine 5.0 µg kg-1 hour-1, obtained using log-linear regression analysis. RESULTS: The sevoflurane MAC decreased dose-dependently with increasing infusion rates of dexmedetomidine and remifentanil. Remifentanil ED50 values were lower when combined with dexmedetomidine than those obtained during saline-remifentanil. Synergistic interactions between dexmedetomidine and remifentanil for MAC reduction occurred with dexmedetomidine at 0.5 and 1.0 µg kg-1 hour-1. CONCLUSIONS AND CLINICAL RELEVANCE: Combined CRIs of dexmedetomidine and remifentanil synergistically resulted in sevoflurane MAC reduction. The combination of dexmedetomidine and remifentanil effectively reduced the requirement of sevoflurane during anesthesia in dogs.

Nicardipine constant rate infusion alleviates the cardiovascular effects of dexmedetomidine infusions without affecting the minimal alveolar concentration in sevoflurane-anesthetized dogs.

Two randomized crossover trials evaluated the effects of nicardipine constant rate infusion (CRI) on 1) the anesthetic potency of sevoflurane and 2) the ability to attenuate dexmedetomidine-induced cardiovascular depression in anesthetized dogs. First, six healthy Beagle dogs weighing 11.7 ± 0.9 kg were allocated to one of three treatments that administered a CRI of carrier (saline) or dexmedetomidine 0.5 or 3.0 µg/kg/h following a loading dose. The minimum alveolar concentration (MAC) of sevoflurane was determined utilizing electric stimuli before and after the loading dose of nicardipine (20 µg/kg intravenously for 10 min), followed by CRI at 40 µg/kg/h with 60 min of equilibration. Subsequently, cardiovascular and blood gas variables were evaluated in another trial under sevoflurane anesthesia at the individual 1.5 MAC. After baseline measurements, the dogs were assigned to two treatments (dexmedetomidine CRI at 0.5 or 3.0 µg/kg/h following a loading dose) with sevoflurane doses adjusted to 1.5 times of MAC equivalent, and the measurements were repeated every 15 min for 120 min. After 60 min, nicardipine CRI at 40 µg/kg/h with a loading dose was added to the dexmedetomidine CRI. Dexmedetomidine infusions significantly decreased the sevoflurane MAC but nicardipine did not significantly alter the MAC either with or without dexmedetomidine CRI in dogs. Dexmedetomidine dose-dependently decreased the cardiac index and increased the systemic vascular resistance index; these effects were fully counteracted by concomitant nicardipine CRI. Nicardipine CRI can be useful for controlling the cardiovascular depression elicited by dexmedetomidine in anesthetized dogs without affecting the anesthetic potency of sevoflurane.

Evaluation of Skin Wound Healing with Biosheets Containing Somatic Stem Cells in a Dog Model: A Pilot Study.

The administration of mesenchymal stem cells (MSCs) has a positive effect on wound healing; however, the lack of adequate MSC engraftment at the wound site is a major limiting factor in current MSC-based therapies. In this study, a biosheet prepared using in-body tissue architecture (iBTA) was used as a material to address these problems. This study aimed to assess and evaluate whether biosheets containing somatic stem cells would affect the wound healing process in dogs. Biosheets were prepared by subcutaneously embedding molds in beagles. These were then evaluated grossly and histologically, and the mRNA expression of inflammatory cytokines, interleukins, and Nanog was examined in some biosheets. Skin defects were created on the skin of the beagles to which the biosheets were applied. The wound healing processes of the biosheet and control (no biosheet application) groups were compared for 8 weeks. Nanog mRNA was expressed in the biosheets, and SSEA4/CD105 positive cells were observed histologically. Although the wound contraction rates differed significantly in the first week, the biosheet group tended to heal faster than the control group. This study revealed that biosheets containing somatic stem cells may have a positive effect on wound healing.

Effect of fentanyl constant-rate infusions with or without medetomidine on the minimum infusion rate of propofol required to prevent motor movement in dogs.

Propofol is a potential injectable anesthetic agent used in total intravenous anesthesia. However, the sparing effect of fentanyl and medetomidine on the required propofol dose in dogs remains unclear. We aimed to investigate the effect of fentanyl constant-rate infusion (CRI) with or without medetomidine on the minimum infusion rate of propofol required to prevent motor movement (MIRNM) in dogs. Six healthy purpose-bred dogs were anesthetized on three occasions with propofol alone (loading dose [LD], 8 mg/kg to effect; initial infusion rate [IR], 0.70 mg/kg/min); propofol (LD, 6 mg/kg to effect; IR, 0.35 mg/kg/min) and fentanyl (LD, 2 µg/kg; IR, 0.10 µg/kg/min); or propofol (LD, 4 mg/kg to effect; IR, 0.25 mg/kg/min), fentanyl (LD, 2 µg/kg; IR, 0.10 µg/kg/min), and medetomidine (LD, 2 µg/kg; IR, 0.5 µg/kg/hr) under controlled ventilation. The MIRNM was determined by observing the response to a noxious electrical stimulus. Heart rate, blood pressure, and blood gas analyses were performed at 1, 2, 3, and 4 hr after initiating CRI. The MIRNM (mean [range]) was significantly lower in the propofol-fentanyl-medetomidine group (0.16 [0.10-0.27] mg/kg/min) than that in the propofol-alone group (0.63 [0.47-0.82] mg/kg/min) (P=0.0004). Fentanyl combined with medetomidine did not significantly decrease the mean arterial pressure in dogs receiving propofol CRI 1-3 hr after initiating CRI compared with propofol CRI alone (P>0.9999, P=0.1536, and P=0.0596, respectively), despite inducing a significantly lower heart rate.

Effects of Intravenous Pimobendan on Cardiovascular Parameters in Healthy Sedated Cats.

This study aimed to investigate the effects of intravenous pimobendan on cardiovascular function and to determine the appropriate dose for clinical usage in cats. Six purpose-bred cats received one of the following treatments: intravenous pimobendan at a single dose of 0.075 mg/kg (low dose [LD] group), 0.15 mg/kg (middle dose [MD] group), 0.3 mg/kg (high dose [HD] group), or saline at 0.1 mL/kg (placebo group). Echocardiography and blood pressure measurements were performed before and 5, 15, 30, 45, and 60 minute after drug administration for each treatment. In the MD and HD groups, the fractional shortening, peak systolic velocity, cardiac output, and heart rate increased significantly. There were no significant differences in blood pressure among the groups. Intravenous pimobendan at 0.15-0.3 mg/kg increased the fractional shortening, peak systolic velocity, cardiac output in healthy cats.

Magnetic resonance imaging findings of the primitive neuroectodermal tumour in lumbosacral spinal cord in a cat.

A 5-year-old, castrated, male domestic short-haired cat presented with neurological deficits in the pelvic limbs, back pain and dysuria. Magnetic resonance imaging showed a mass lesion caudal to the L4 vertebrae. In addition, suspected haemorrhage was observed at the cranial aspect of the mass. There was no evidence to support the presence of extravertebral intrusion or vertebral body, osteolysis. Dorsal laminectomy and durotomy were performed to debulk the intraspinal mass. Histopathological and immunohistochemical assessment revealed a primitive neuroectodermal tumour (PNET). To our knowledge, this is the first report to describe the clinical and pathological features and imaging diagnosis of intraspinal PNET without extraspinal invasion in a cat.

Variation in Diffusion Tensor Imaging Parameters in the Cervical and Thoracic Spinal Cord (C1-C5 and C6-T2) Segments of Normal Beagle Dogs.

This study aimed to determine the characteristics and reference values of each vertebra in the cervicothoracic region by performing diffusion tensor imaging (DTI) scans and analyzing DTI parameters in normal Beagle dogs. In five adult Beagles under anesthetic maintenance, DTI was performed using a 1.5-T magnetic resonance imaging (MRI) scanner. Axial DTI was performed using three overlapping slabs to cover the cervical and thoracic spinal cords. After post-processing, DTI parameters were calculated along the entire spinal cord. Among DTI parameters, fractional anisotropy, relative anisotropy, and axonal diffusivity significantly decreased in the caudal direction. However, the apparent diffusion coefficient, radial diffusivity, and mean diffusivity values were not significantly correlated with vertebral levels. We provide evidence for the existence of segment-dependent DTI parameters in the canine cervical spinal cord. Therefore, comparisons of DTI parameters between lesions at different vertebral levels should be avoided unless normative data are available. Furthermore, the DTI data obtained in this study may contribute to the development of a clinical reference for spinal cord evaluation in dogs using DTI parameters.

Distal renal tubular acidosis and lethargy associated with zonisamide treatment in a dog with idiopathic epilepsy.

A 3-year-old neutered male golden retriever administered zonisamide for the treatment of seizures showed lethargy and had normal anion gap metabolic acidosis with hypokalaemia, hyperchloremia, and alkaline urine. The serum zonisamide concentration was close to the upper limit, which raised a suspicion of adverse effects of zonisamide. This is the first report showing that the fractional excretion of bicarbonate after compensation for the plasma bicarbonate concentration by a sodium bicarbonate infusion was approximately 5%, indicating distal renal tubular acidosis (RTA). The serum zonisamide concentration decreased, and adverse effects were abated by reducing the zonisamide dosage. Diagnostic therapy with bicarbonate served as a means of compensating for bicarbonate deficiency and contributed to the clinical diagnosis of the condition in zonisamide-associated RTA in dogs.

Expression profile of immunoregulatory factors in canine tumors.

Cancers utilize a variety of molecules to escape host immune responses. Better understanding the immune environment surrounding cancer may facilitate application of innovative cancer immunotherapies, such as immune checkpoint inhibitors, to dogs as well as humans. In this study, we screened the expression of 20 immune regulatory molecules in diverse canine tumors (n = 59). Quantitative RT-PCR (qPCR) analysis revealed that some immune regulatory molecules, such as LGALS9 (coding Galectin-9) and CD48, were expressed in most canine tumors, but other molecules, such as CD274 (coding PD-L1), IL4I1, PVR, TNFSF18, ICOSLG, and TNFSF4, were rarely expressed. NECTIN2 was highly expressed in epithelial tumors but was low in non-epithelial tumors. In contrast, VSIR and CD200 expressions were low in epithelial tumors but high in non-epithelial tumors. Interestingly, several tumors expressed distinctive immunoregulatory factors. Hepatocellular carcinomas expressed FGL1, mast cell tumors expressed PDCD1LG2 (coding PD-L2), transitional cell carcinomas expressed VTCN1 (coding B7x), and lymphomas and squamous cell carcinomas expressed CD70. Consistent with qPCR results, immunofluorescence staining confirmed that hepatocellular carcinomas expressed FGL-1 protein. Thus, this study reveals the expression profile of immunoregulatory molecules in canine tumors and opens the door to better understanding the relationship between canine tumors and host immunity.

Cardiovascular and renal effects of constant rate infusions of remifentanil, dexmedetomidine and their combination in dogs anesthetized with sevoflurane.

We evaluated changes in cardiovascular and renal functions as well as arginine vasopressin (AVP) secretion, with remifentanil and dexmedetomidine administration alone or in combination in sevoflurane-anesthetized dogs. Six healthy adult Beagle dogs received one of the following four treatments in a randomized crossover study: saline (C), remifentanil alone at successively increasing doses (R; 0.15, 0.60, and 2.40 µg/kg/min), dexmedetomidine alone (D; 0.5 µg/kg intravenously for initial 10 min followed by a constant rate infusion at 0.5 µg/kg/hr), and a combination of remifentanil and dexmedetomidine at the above-mentioned doses (RD). Sevoflurane doses were adjusted to 1.5 times of minimum alveolar concentration (MAC) equivalent according to MAC-sparing effects with remifentanil and dexmedetomidine as previously reported. Cardiovascular measurements, renal function data, and plasma AVP concentrations were determined before and every 60 min until 180 min after drug administration as per each treatment. In the R, D and RD, heart rate significantly decreased and mean arterial pressure significantly increased from baseline or with C. Cardiac index significantly decreased and systemic vascular resistance index increased with D and RD. Oxygen extraction ratio, renal blood flow, and glomerular filtration rate were not affected. The plasma AVP concentrations significantly decreased in D and RD, but increased in R. Only in D, the natriuresis was elicited. The combination of remifentanil and dexmedetomidine in sevoflurane-anesthetized dogs was acceptable in terms of the hemodynamics, oxygenation, and renal function. Remifentanil may interfere with dexmedetomidine-induced diuresis and inhibition of AVP secretion.

Evaluation of bispectral index (BIS) as an indicator of central nervous system depression in horses anesthetized with propofol.

The bispectral index (BIS) was evaluated as an indicator of central nervous system (CNS) depression in horses anesthetized with propofol. Five non-premedicated horses were anesthetized with 7 mg/kg, IV propofol and the minimum infusion rate (MIR) of propofol required to maintain anesthesia was determined during intermittent positive pressure ventilation in each horse. The BIS was determined 20 min later and after stabilization at 2.0 MIR, 1.5 MIR, and 1.0 MIR. The BIS was also recorded after the cessation of propofol infusion when the horses regained spontaneous breathing and swallowing reflex. The MIR and plasma concentration (Cp) of propofol were 0.20 +/- 0.03 mg/kg/min and 17.5 +/- 4.0 microg/ml, respectively. The BIS value and Cp were 59 +/- 13 and 26.7 +/- 8.6 microg/ml at 2.0 MIR, 63 +/- 9 and 22.9 +/- 9.7 microg/ml at 1.5 MIR, 64 +/- 13 and 20.1 +/- 5.9 microg/ml at 1.0 MIR, 64 +/- 24 and 13.0 +/- 2.8 microg/ml at return of spontaneous breathing, and 91 +/- 4 and 11.0 +/- 3.4 microg/ml when the swallowing reflex returned, respectively. The BIS value was significantly less in anesthetized horses compared to horses once swallowing returned (p=0.025). The BIS value was significantly correlated with the propofol Cp (r=-0.625, p=0.001). There was not a significant difference in the BIS values during the MIR multiples of propofol. The BIS was a useful indicator of awakening but did not indicate the degree of CNS depression during propofol-anesthesia in horses.

The effect of remifentanil on the minimum alveolar concentration (MAC) and MAC derivatives of sevoflurane in dogs.

Remifentanil is an ultra-short-acting µ-opioid receptor agonist. The purpose of this study was to determine the relationship of the minimum alveolar concentration (MAC) of sevoflurane and other MAC derivatives, including the MAC for blocking adrenergic responses (MAC-BAR) and the MAC at which tracheal extubation is occurred (MAC-extubation), with or without remifentanil infusion. Six healthy adult beagle dogs were randomly anesthetized three times for determining the MAC-BAR (SEVMAC-BAR), MAC (SEVMAC), and MAC- extubation (SEVMAC-extubation) of sevoflurane under infusion of saline and remifentanil at rates of 0.15, 0.30, 0.60, 1.20, and 2.40 µg/kg/min. The ratio of the SEVMAC-BAR and SEVMAC and that of the SEVMAC-extubation and SEVMAC were not significantly different at baseline and during treatment. The MAC-BAR95 and MAC95 decreased in a dose-dependent manner until reaching 1.20 µg/kg/min, and the MAC-extubation5 decreased in a dose-dependent manner until reaching 0.60 µg/kg/min. The percentage reduction of SEVMAC-BAR, SEVMAC, and SEVMAC-extubation increased in a dose-dependent manner during remifentanil infusion. The heart rate significantly decreased in the MAC-BAR and MAC groups, and the systolic and mean arterial pressures increased after remifentanil infusion compared with the baseline values. Remifentanil infusion caused reduction of the SEVMAC-BAR, SEVMAC, and SEVMAC-extubation in a dose-dependent manner, and ceiling effects were observed in the dogs. Higher doses of remifentanil and sevoflurane were necessary for blocking the sympathetic response to the supramaximal stimulus to prevent movement and extubation in dogs.