Preliminary evaluation of the safety and efficacy of glucose solution infusion through the hepatic artery on irreversible electroporation focusing.

Due to electrical features of the tissue, such as impedance, which have a significant impact on irreversible electroporation (IRE) function, the administration of glucose solution 5% (GS5%) through the hepatic artery would focus IRE on scattered liver tumors. By creating a differential impedance between healthy and tumor tissue. This study aimed to determine the effects of the GS5% protocol on healthy liver tissue and its safety. 21 male Athymic nude rats Hsd: RH-Foxn1mu were used in the study. Animals were split into two groups. In group 1, a continuous infusion through the gastroduodenal artery of GS5% was performed to measure the impedance with a dose of 0.008 mL/g for 16 min. In group 2, the animals were divided into two subgroups for infusions of GS5%. Group 2.1, at 0.008 mL/g for 16 min. Group 2.2 at 0.03 mL/g for 4 min. Blood samples were collected after anesthesia has been induced. The second sample, after catheterization of the artery, and the third after the GS5% infusion. All the animals were sacrificed to collect histological samples. The survival rate during the experiment was 100%. A considerable impact on the impedance of the tissue was noticed, on average up to 4.31 times more than the baseline, and no side effects were observed after GS5% infusion. In conclusion, impedance alteration by Glucose solution infusion may focus IRE on tumor tissue and decrease IRE's effects on healthy tissue.

A clinically oriented computer model for radiofrequency ablation of hepatic tissue with internally cooled wet electrode.

PURPOSE: To improve the computer modelling of radiofrequency ablation (RFA) by internally cooled wet (ICW) electrodes with added clinically oriented features. METHODS: An improved RFA computer model by ICW electrode included: (1) a realistic spatial distribution of the infused saline, and (2) different domains to distinguish between healthy tissue, saline-infused tumour, and non-infused tumour, under the assumption that infused saline is retained within the tumour boundary. A realistic saline spatial distribution was obtained from an in vivo pig liver study. The computer results were analysed in terms of impedance evolution and coagulation zone (CZ) size, and were compared to the results of clinical trials conducted on 17 patients with the same ICW electrode. RESULTS: The new features added to the model provided computer results that matched well with the clinical results. No roll-offs occurred during the 4-min ablation. CZ transversal diameter (4.10 ± 0.19 cm) was similar to the computed diameter (4.16 cm). Including the tumour and saline infusion in the model involved (1) a reduction of the initial impedance by 10 - 20 Ω, (2) a delay in roll-off of 20 s and 70 - 100 s, respectively, and (3) 18 - 31% and 22 - 36% larger CZ size, respectively. The saline spatial distribution geometry was also seen to affect roll-off delay and CZ size. CONCLUSIONS: Using a three-compartment model and a realistic saline spatial distribution notably improves the match with the outcome of the clinical trials.

Long-term effectiveness of irreversible electroporation in a murine model of colorectal liver metastasis.

Irreversible electroporation (IRE) has recently gained in popularity as an ablative technique, however little is known about its oncological long-term outcomes. To determine the long-time survival of animals treated with a high dose of IRE and which histological changes it induces in tumoral tissue, IRE ablation was performed in forty-six athymic-nude mice with KM12C tumors implanted in the liver by applying electric current with different voltages (2000 V/cm, 1000 V/cm). The tumors were allowed to continue to grow until the animals reached the end-point criteria. Histology was harvested and the extent of tumor necrosis was semi-quantitatively assessed. IRE treatment with the 2000 V/cm protocol significantly prolonged median mouse survival from 74.3 ± 6.9 days in the sham group to 112.5 ± 15.2 days in the 2000 V/cm group. No differences were observed between the mean survival of the 1000 V/cm and the sham group (83.2 ± 16.4 days, p = 0.62). Histology revealed 63.05% ± 23.12 of tumor necrosis in animals of the 2000 V/cm group as compared to 17.50% ± 2.50 in the 1000 V/cm group and 25.6% ± 22.1 in the Sham group (p = 0.001). IRE prolonged the survival of animals treated with the highest electric field (2000 V/cm). The animals in this group showed significantly higher rate of tumoral necrosis.

Irreversible electroporation of the liver: is there a safe limit to the ablation volume?

Irreversible electroporation is a fast-growing liver ablation technique. Although safety has been well documented in small ablations, our aim is to assess its safety and feasibility when a large portion of liver is ablated. Eighty-seven mice were subjected to high voltage pulses directly delivered across parallel plate electrodes comprising around 40% of mouse liver. One group consisted in 55 athymic-nude, in which a tumor from the KM12C cell line was grown and the other thirty-two C57-Bl6 non-tumoral mice. Both groups were subsequently divided into subsets according to the delivered field strength (1000 V/cm, 2000 V/cm) and whether or not they received anti-hyperkalemia therapy. Early mortality (less than 24 hours post-IRE) in the 2000 V/cm group was observed and revealed considerably higher mean potassium levels. In contrast, the animals subjected to a 2000 V/cm field treated with the anti-hyperkalemia therapy had higher survival rates (OR = 0.1, 95%CI = 0.02-0.32, p < 0.001). Early mortality also depended on the electric field magnitude of the IRE protocol, as mice given 1000 V/cm survived longer than those given 2000 V/cm (OR = 4.7, 95%CI = 1.8-11.8, p = 0.001). Our findings suggest that ionic disturbances, mainly due to potassium alterations, should be warned and envisioned when large volume ablations are performed by IRE.

Doppler evaluation of the effects of propofol, etomidate and alphaxalone on fetoplacental circulation hemodynamics in the pregnant ewe.

INTRODUCTION: Umbilical artery (UA) hemodynamics reflect blood flow and vascular resistance in the placental circulation. We examined non-invasively the hemodynamic effects of propofol, etomidate, and alphaxalone on the placental circulation of a sheep model by means of UA Doppler ultrasonography. METHODS: Eleven sheep fetuses were examined at 90-109 days of gestation. UA Doppler ultrasound was performed before and after administration of a single intravenous bolus of propofol, etomidate, or alphaxalone. UA Doppler velocities (peak systolic velocity, end diastolic velocity, and mean velocity), vascular indices (pulsatility index, resistance index, and S/D ratio), blood flow, and fetal heart rate were recorded during the experimental period and UA Doppler waveforms were characterized. RESULTS: A laminar, parabolic, low resistance flow was observed in the UA of the sheep fetuses. No statistically significant changes were observed in the UA Doppler waveforms or in the UA Doppler hemodynamics after anesthesia induction. DISCUSSION: Changes in placental vascular resistance may alter the corresponding UA Doppler waveforms. When resistance in the fetal placenta increases, blood flow in the UA becomes more pulsatile. In the present study, umbilical arteries showed a parabolic flow with low resistance in all cases, as it occurs in normal human pregnancy. The administration of these anesthetics did not cause abnormalities in the normal UA Doppler pattern, inducing no changes in the resistance of the placenta in any case. CONCLUSION: These results suggest that intravenous anesthetic induction with propofol, etomidate, or alphaxalone does not cause significant detrimental effects on the placental circulation of the pregnant ewe.

Effects of ovariohysterectomy on intra-abdominal pressure and abdominal perfusion pressure in cats.

Intra-abdominal pressure (IAP) and abdominal perfusion pressure (APP) have shown clinical relevance in monitoring critically ill human beings submitted to abdominal surgery. Only a few studies have been performed in veterinary medicine. The aim of this study was to assess how pregnancy and abdominal surgery may affect IAP and APP in healthy cats. For this purpose, pregnant (n=10) and non-pregnant (n=11) queens undergoing elective spaying, and tomcats (n=20, used as controls) presented for neutering by scrotal orchidectomy were included in the study. IAP, mean arterial blood pressure (MAP), APP, heart rate and rectal temperature (RT) were determined before, immediately after, and four hours after surgery. IAP increased significantly immediately after abdominal surgery in both female groups when compared with baseline (P<0.05) and male (P<0.05) values, and returned to initial perioperative readings four hours after surgery. Tomcats and pregnant females (P<0.05) showed an increase in MAP and APP immediately after surgery decreasing back to initial perioperative values four hours later. A significant decrease in RT was appreciated immediately after laparotomy in both pregnant and non-pregnant queens. IAP was affected by abdominal surgery in this study, due likely to factors, such as postoperative pain and hypothermia. Pregnancy did not seem to affect IAP in this population of cats, possibly due to subjects being in early stages of pregnancy.

Effects of an intravenous bolus of alfaxalone versus propofol on intraocular pressure in sheep.

The objective of this prospective study was to determine the effects of a single intravenous bolus of alfaxalone in 2-hydroxypropyl-ß-cyclodextrin and propofol on the intraocular pressure (IOP) in sheep. Ten Ripollesa sheep with a bodyweight of 48.5 (6.8) kg (mean [sd]) were used in the study. Twenty-four hours before the experimental procedure, a complete ophthalmic examination was performed in all animals. The day of the study, intravenous alfaxalone (2 mg/kg) or propofol (6 mg/kg) was randomly administered in a cross-over design, with a washout period of two weeks. Measurements of IOP, globe position and pupil size were obtained at basal time, before induction (time 0) and at two, five, 10, 15, 20, 30, 45, 60, 90 and 120 minutes after drug administration. Occasional side effects and time to standing were also noted. Intravenous administration of alfaxalone and propofol in sheep resulted in no alteration of IOP. Nevertheless, a decrease in the pupil size was observed in both groups. This present study shows that alfaxalone and propofol, administrated as a single intravenous bolus, are good options for maintaining IOP during anaesthesia in sheep, although marked miosis was observed after administration.

The effects on cardio-respiratory and acid-base variables of the anaesthetic alfaxalone in a 2-hydroxypropyl-ß-cyclodextrin (HPCD) formulation in sheep.

The objective of this study was to determine the pharmacodynamic effects in sheep of the anaesthetic alfaxalone in a 2-hydroxypropyl-ß-cyclodextrin formulation. Seven Ripollesa sheep, weighing 43.0±6.6 kg, were used in the study. Twenty-four hours after instrumentation, the sheep were anesthetised with alfaxalone (2 mg/kg bodyweight IV) in cyclodextrin. Heart rate, arterial blood pressure, respiratory rate and arterial blood gases were recorded. Alfaxalone administration resulted in minimal cardio-respiratory depression. Time to standing from anaesthesia was 22.0±10.6 min. Apnoea was not observed in any of the sheep. Significant differences from baseline were not observed in respiratory rate or arterial blood pressure. Heart rate increased significantly (P<0.05) immediately after administration, returning to control values at 20 min. The calculated haemoglobin saturation (SO2) decreased significantly during the first 15 min after alfaxalone administration. The arterial pH decreased significantly during the first 30 min of the study, although no significant differences from basal values were observed in the arterial partial pressure of carbon dioxide (PaCO2). The results showed that alfaxalone in 2-hydroxypropyl-ß-cyclodextrin administered as an IV bolus at 2 mg/kg produced minimal adverse effects and an uneventful recovery from anaesthesia in sheep.

Plasma buprenorphine concentrations after the application of a 70 microg/h transdermal patch in dogs. Preliminary report.

The objective of the present study was to evaluate the plasma concentrations and pharmacokinetics of buprenorphine after transdermal application in dogs (n = 4). A 70 microg/h transdermal buprenorphine patch was applied to the ventral abdomen of four healthy beagles. Blood samples were collected through a preplaced jugular catheter before and at 1, 2, 4, 8, 12, 24, 36, 48 and every 6 h until 108 h after the patch application. Plasma buprenorphine concentrations were measured using a (125)I-labelled radioimmunoassay (RIA) assay. No adverse effects were observed in any of the dogs. Concentrations of buprenorphine were detected in plasma after the application of the transdermal buprenorphine patch on the four experimental animals. Buprenorphine plasma concentrations increased during the first 36 h and then remained in the 0.7-1.0 ng/mL range during the study period. A decrease in plasma buprenorphine concentration was not observed during the study. Although analgesia could not be demonstrated the present study shows the ability of buprenorphine transdermal delivery systems developed for human use to deliver measurable concetrations of buprenorphine in dogs.

Maternal and fetal effects of propofol anaesthesia in the pregnant ewe.

The objective of this study was to determine the effects of propofol (PRF) on maternal and fetal cardiopulmonary function during the last trimester of pregnancy. Six pregnant 2-3 year-old Ripollesa sheep, each weighing 78+/-8 kg were used in the study and prepared by placing catheters in the maternal jugular vein and carotid artery. A catheter was also placed in the fetal femoral artery. Twenty-four hours later the sheep were anaesthetized with PRF (6 mg/kg intravenous (IV) followed by a continuous infusion at a rate of 0.4 mg/kg/min for 60 min) and cardiopulmonary data collected. Further data were collected for 105 min following termination of the infusion. The maternal mean arterial pressure (MAP) and diastolic arterial pressure (DAP) were significantly decreased (P<0.05) during the first 15 min of the infusion period, while the maternal pH was also significantly decreased. Maternal PaCO(2) and PaO(2) were significantly increased throughout the total infusion period. It was further observed that the fetal pH decreased significantly, throughout the infusion period, whereas the fetal MAP, DAP and PaCO(2) were significantly increased during the first 15 min of the infusion, after which time all parameters returned to control values. No differences in either maternal or fetal parameters were observed between control and recovery times.

Effect of H1- and H2-receptor antagonists on the hemodynamic changes induced by the intravenous administration of ketamine in sevoflurane-anesthetized cats.

OBJECTIVE: The anesthetic ketamine has been reported to cause both an increase of the plasma histamine concentration, notably in cats, and a cardiovascular depression. The latter has been described in humans and in other species. However the relevance of the histamine fluctuation for the ketamine-induced hemodynamic changes has not been determined. SUBJECTS AND TREATMENT: We studied the contribution of histamine to the hemodynamic effects induced by IV ketamine (7 mg/kg) in 12 sevoflurane anesthetized cats, of which half had been pre-treated with combined H(1)- and H(2) -receptor antagonists. METHODS: The mean arterial pressure (MAP) and the heart rate (HR) from both untreated (group C) and pre-treated (group AH) cats were recorded before and after the ketamine administration. The plasma histamine concentration was also measured. RESULTS: Plasma histamine fluctuations in the control and the antihistamine-treated group followed a similar pattern (no statistical differences); an initial rise that peaked 2 min after ketamine injection (from 0.63 +/- 0.11 ng/ml to 2.22 +/- 0.69 ng/ml in the C group, and from 0.71 +/- 0.10 ng/ml to 1.09 +/- 0.28 ng/ml in the AH group) followed by an immediate decrease in plasma concentrations. As for the hemodynamic variables under analysis, in the control group ketamine administration was followed by an early 30.3 +/- 8.1% reduction (p < 0.005) in the MAP with no associated changes in the HR. In the antihistamine pre-treated group, ketamine caused a further decrease of the MAP (41.7 +/- 2.3%), and a significant (p < 0.01) 11.6 +/- 2.9% reduction of the HR. CONCLUSION: Ketamine in anesthetized cats triggers histamine release and induces cardiovascular depression. The depression is more pronounced under the blockade of histamine activity through histamine receptor antagonists.

Effects of epidural anaesthesia-analgesia on intravenous anaesthesia with propofol.

The main purpose of this study was to demonstrate that the use of epidural anaesthesia-analgesia reduces the amount of propofol necessary to maintain surgical anaesthesia in dogs during ovariohysterectomy. The study was carried out on 28 bitches undergoing ovariohysterectomy with general anaesthesia using an intravenous infusion of propofol. Dogs were allocated to one of two groups. Group 1 received systemic buprenorphine together with epidural analgesia using lidocaine and buprenophine, and in Group 2 systemic buprenorphine only was given. The mean propofol infusion rate was significantly lower in dogs with epidural analgesia (P < 0.0001). In addition, the mean endotracheal extubation time was significantly longer in dogs with epidural analgesia (P < 0.0001). No significant differences were detected in any of the physiological parameters measured.

Transplacental transfer of propofol in pregnant ewes.

Propofol is an injectable anaesthetic that is currently used both in veterinary and human medicine for the induction and maintenance of anaesthesia. Although little is known about the pharmacokinetics of propofol in fetuses, it is widely used in obstetric procedures, particularly in caesarean section. This study determines the pharmacokinetics of propofol in pregnant ewes in the last third of pregnancy, and placental transfer and pharmacokinetics in fetuses after the administration of a 6 mg/kg intravenous (i.v.) bolus (phase 1) or a 6 mg/kg i.v. bolus followed by continued infusion of 0.4 mg/kg/min. In ewes, the area under the blood concentration-time curve (AUC) and C(max) (8.6 mgh/mL and 9.5mg/mL, respectively) was higher than those of the fetus (1.6 mgh/mL and 1.19 mg/mL, respectively). The mean half-life was 0.5h in the dam and 1.1h in the fetus.

Placental transfer of albendazole sulphoxide enantiomers in sheep.

Albendazole sulphoxide (ABZSO) is an anthelmintic drug used in veterinary practice. Its molecule has a chiral centre in the sulphur atom and racemic formulations are always used. The kinetics of the ABZSO enantiomers in the last third of pregnancy in ewes, and the placental transfer to the fetus, were studied after a single-dose oral administration (7.5 mg/kg) of a racemic formulation. In mothers, the area under the plasma concentration-time curve (AUC) and C(max) values of (+)-ABZSO (42.4+/-10.5 microg/mL and 1.9+/-0.4 microg/mL, respectively) were higher than those of (-)-ABZSO (15.3+/-5.1 microg/mL and 1.0+/-0.3 microg/mL). The MRT values were 17.0+/-1.6 h for (+)-ABZSO and 13.1+/-1.8 h for (-)-ABZSO. Similar kinetic parameters were obtained in the fetus for both enantiomers, but the fetal concentrations were lower compared with values for the dam. The AUC ratio between (-)-ABZSO/(+)-ABZSO in the dam was 0.36 and in the fetuses 0.64, indicating a higher impairment for the (+)-enantiomer in its placental transfer to the fetus.