Ron Johnson

A comparison of 3 anesthetic protocols for 24 hours of mechanical ventilation in cats

Objective To compare the recovery times, recovery quality, and cardiovascular (CV) effects of 3 anesthetic protocols during 24 hours of mechanical ventilation (MV) in healthy cats. Design Prospective, randomized, crossover study. Setting Research laboratory at a veterinary teaching hospital. Animals Six healthy intact male purpose-bred cats. Interventions Each cat was randomly assigned to receive 3 anesthetic protocols for 24 hours of MV; Protocol K consisted of ketamine, Protocol P, propofol; and Protocol PK, propofol plus fixed-rate low-dose ketamine. Each infusion drug dose was adjusted using a sedation scoring system. All protocols included fixed doses of fentanyl (10 μg/kg/h) and midazolam (0.5 mg/kg/h). Measurements and Main Results Drug doses and recovery times were recorded. Recovery quality was scored. Blood gas results, CV parameters, and frequency of bradycardia or hypotension requiring interventions were recorded. The mean d dose ± standard error of K was 81.3 ± 3.3 μg/kg/m. The median dose (95% cardiac index) of propofol (μg/kg/m) in PK was 16.0 (13.1, 19.6) and in P was 48.1 (39.3, 58.9). P necessitated significantly more propofol than PK (P < 0.05). Protocol K (35.6 ± 3.2 hours) had significantly longer times to full recovery compared to P (18.2 ± 3.2 hours). Protocol K had significantly longer times to head up, crawling, and standing compared to P and PK. Cats sedated with PK (2.33 ± 0.47) required significantly more interventions for hypotension than K (0.50 ± 0.47). Protocol P (3.2 ± 0.4) and PK (1.4 ± 0.3) required significantly more interventions for bradycardia compared to K (0.8 ± 0.3). When comparing protocol K to P and PK, significant differences in blood pressure, lactate, oxygen delivery, and oxygen consumption were noted. Conclusions Cats anesthetized with P had shorter times to full recovery compared to K. Cats anesthetized with K required fewer interventions for bradycardia or hypotension but had longer recovery times compared to P or PK. Protocol PK reduced the propofol dose required to maintain optimal anesthesia.OBJECTIVE To compare the recovery times, recovery quality, and cardiovascular (CV) effects of 3 anesthetic protocols during 24 hours of mechanical ventilation (MV) in healthy cats. DESIGN Prospective, randomized, crossover study. SETTING Research laboratory at a veterinary teaching hospital. ANIMALS Six healthy intact male purpose-bred cats. INTERVENTIONS Each cat was randomly assigned to receive 3 anesthetic protocols for 24 hours of MV; Protocol K consisted of ketamine, Protocol P, propofol; and Protocol PK, propofol plus fixed-rate low-dose ketamine. Each infusion drug dose was adjusted using a sedation scoring system. All protocols included fixed doses of fentanyl (10 μg/kg/h) and midazolam (0.5 mg/kg/h). MEASUREMENTS AND MAIN RESULTS Drug doses and recovery times were recorded. Recovery quality was scored. Blood gas results, CV parameters, and frequency of bradycardia or hypotension requiring interventions were recorded. The mean d dose ± standard error of K was 81.3 ± 3.3 μg/kg/m. The median dose (95% cardiac index) of propofol (μg/kg/m) in PK was 16.0 (13.1, 19.6) and in P was 48.1 (39.3, 58.9). P necessitated significantly more propofol than PK (P < 0.05). Protocol K (35.6 ± 3.2 hours) had significantly longer times to full recovery compared to P (18.2 ± 3.2 hours). Protocol K had significantly longer times to head up, crawling, and standing compared to P and PK. Cats sedated with PK (2.33 ± 0.47) required significantly more interventions for hypotension than K (0.50 ± 0.47). Protocol P (3.2 ± 0.4) and PK (1.4 ± 0.3) required significantly more interventions for bradycardia compared to K (0.8 ± 0.3). When comparing protocol K to P and PK, significant differences in blood pressure, lactate, oxygen delivery, and oxygen consumption were noted. CONCLUSIONS Cats anesthetized with P had shorter times to full recovery compared to K. Cats anesthetized with K required fewer interventions for bradycardia or hypotension but had longer recovery times compared to P or PK. Protocol PK reduced the propofol dose required to maintain optimal anesthesia.

Characteristics of myogenic reactivity in isolated rat mesenteric veins

Mechanisms of mechanically induced venous tone and its interaction with the endothelium and key vasoactive neurohormones are not well established. We investigated the contribution of the endothelium, l-type voltage-operated calcium channels (L-VOCCs), and PKC and Rho kinase to myogenic reactivity in mesenteric vessels exposed to increasing transmural pressure. The interaction of myogenic reactivity with norepinephrine (NE) and endothelin-1 (ET-1) was also investigated. Pressure myography was used to study isolated, cannulated, third-order rat mesenteric small veins and arteries. NE and ET-1 concentration response curves were constructed at low, intermediate, and high transmural pressures. Myogenic reactivity was not altered by nitric oxide synthase inhibition with N(ω)-nitro-L-arginine (L-NNA; 100 μM) or endothelium removal in both vessels. L-VOCCs blockade (nifedipine, 1 μM) completely abolished arterial tone, while only partially reducing venous tone. PKC (chelerythrine, 2.5 μM) and Rho kinase (Y27632, 3 μM) inhibitors largely abolished venous and arterial myogenic reactivity. There was no significant difference in the sensitivity of NE or ET-1-induced contractions within vessels. However, veins were more sensitive to NE and ET-1 when compared with corresponding arteries at low, intermediate, and high transmural pressures, respectively. These results suggest that 1) myogenic factors are important contributors to net venous tone in mesenteric veins; 2) PKC and Rho activation are important in myogenic reactivity in both vessels, while l-VOCCs play a limited role in the veins vs. the arteries, and the endothelium does not appear to modulate myogenic reactivity in either vessel type; and 3) mesenteric veins maintain an enhanced sensitivity to NE and ET-1 compared with the arteries when studied under conditions of changing transmural distending pressure.

Comparison of continuous infusion with intermittent bolus administration of cefotaxime on blood and cavity fluid drug concentrations in neonatal foals

Healthy neonatal foals were treated with cefotaxime by bolus (40 mg/kg i.v. q6h for 12 doses; n=10) or by infusion (loading dose of 40 mg/kg i.v. followed by continuous infusion of a total daily dose of 160 mg/kg per 24 h for 3 days; n=5). Population pharmacokinetics was determined, and concentrations in cavity fluids were measured at steady state (72 h). Highest measured serum drug concentration in the bolus group was 88.09 μg/mL and minimum drug concentration (C(min)) was 0.78 μg/mL at 6-h postadministration (immediately before each next dose), whereas infusion resulted in a steady-state concentration of 16.10 μg/mL in the infusion group. Mean cefotaxime concentration in joint fluid at 72 h was higher (P=0.051) in the infusion group (5.02 μg/mL) compared to the bolus group (0.78 μg/mL). Drug concentration in CSF at 72 h was not different between groups (P=0.243) and was substantially lower than serum concentrations in either group. Insufficient data on pulmonary epithelial lining fluid were available to compare the methods of administration for cefotaxime in this cavity fluid. Results support continuous drug infusion over bolus dosing in the treatment for neonatal foal septicemia to optimize time that cefotaxime concentration exceeds the minimum inhibitory concentration of common equine pathogens.

Analysis of phenylbutazone residues in horse tissues with and without enzyme-hydrolysis by LC-MS/MS.

Phenylbutazone (PBZ) is permitted to be used for the treatment of musculoskeletal pain and inflammation in race horses but it is not approved for use in horses destined for human consumption. In a recent study initiated in our laboratory to study the disposition of PBZ and its oxyphenbutazone (OXPBZ) metabolite in equine tissues, we compared the effect of an additional enzymatic hydrolysis step with ß-glucuronidase on the results of the analysis for PBZ without enzymatic hydrolysis. Incurred tissue samples obtained from a female horse dosed with PBZ at 8.8 mg/kg for 3 days and sacrificed 6 days following the last administration were used for this study. Liver, kidney, and muscle tissues were collected, extracted, cleaned up on a silica-based solid-phase extraction (SPE) preceded by a weak-anion exchange SPE and analyzed with our in-house validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for PBZ and OXPBZ. Addition of the hydrolysis step resulted in a significant increase in recovery of both PBZ and OXPBZ residues.

Systemic absorption and adverse ocular and systemic effects after topical ophthalmic administration of 0.1% diclofenac to healthy cats

OBJECTIVE To quantify plasma concentrations and determine adverse ocular, renal, or hepatic effects associated with repeated topical ophthalmic application of 0.1% diclofenac to healthy cats. ANIMALS 8 healthy sexually intact male cats. PROCEDURES A randomized, placebo-controlled crossover study was conducted. A topical formulation of 0.1% diclofenac was administered 4 times/d for 7 days to 4 cats, and artificial tear (control) solution was administered to the other 4 cats. After a 12-day washout period, cats received the other treatment. Ophthalmic examinations were performed daily. Plasma samples were obtained on days 1 and 7 for pharmacokinetic analysis. A CBC, serum biochemical analysis, urinalysis, determination of urine protein-to-creatinine ratio, and determination of glomerular filtration rate were performed before the start of the study and after each 7-day treatment period. RESULTS Mild conjunctival hyperemia was the only adverse ocular effect detected. Maximal drug concentration and area under the curve were significantly higher on day 7 than on day 1. Diclofenac-treated cats had a significantly lower glomerular filtration rate than did control-treated cats after the second but not after the first treatment period, presumably associated with iatrogenic hypovolemia. CONCLUSIONS AND CLINICAL RELEVANCE Topical ophthalmic administration of 0.1% diclofenac was well tolerated in healthy cats, with only mild signs of ocular irritation. Detectable systemic concentrations of diclofenac were achieved with accumulation over 7 days. Systemic absorption of diclofenac may be associated with reduced glomerular filtration rate, particularly in volume-contracted animals. Topical ophthalmic 0.1% diclofenac should be used with caution in volume-contracted or systemically ill cats.

Effects of Acute Transmural Pressure Elevation on Endothelium-Dependent Vasodilation in Isolated Rat Mesenteric Veins

Background/Aims: The vascular regulatory function of the endothelium can be impaired by increases in transmural pressure (TMP). We tested the hypothesis that increasing TMP impairs the endothelial dilator function of rat mesenteric small veins (MSVs). Methods: In PGF2α-preconstricted MSVs, bradykinin (BK), sodium nitroprusside (SNP) and S-Nitroso-N-acetylpenicillamine (SNAP) concentration-response curves were generated at intermediate (6 mm Hg) and high (12 mm Hg) pressures. BK-induced vasodilation was examined in the absence and presence of nitric oxide synthase inhibitor [N^ω-nitro-<smlcap>L</smlcap>-arginine (<smlcap>L</smlcap>-NNA), 100 µ<smlcap>M</smlcap>], cyclooxygenase inhibitor (indomethacin, 1 µ<smlcap>M</smlcap>), and large (BK_Ca, paxilline, 500 n<smlcap>M</smlcap>) and small (SK_Ca, apamin, 300 n<smlcap>M</smlcap>) conductance Ca²⁺-activated K⁺ channel blockers. Results: BK, SNP and SNAP responses were not altered by TMP increases. BK-induced vasodilation was significantly reduced by <smlcap>L</smlcap>-NNA, indomethacin, apamin and paxilline at 6 mm Hg and <smlcap>L</smlcap>-NNA at 12 mm Hg, and was further reduced by coapplication of apamin and/or paxilline with <smlcap>L</smlcap>-NNA compared with responses obtained with either blocker. Endothelium removal completely abolished BK-induced vasodilation. Conclusion: Venous endothelial dilator function is not affected by TMP elevation. BK-induced vasodilation is completely dependent on the presence of functional endothelial cells and mediated in part by nitric oxide, BK_Ca and SK_Ca channels, while the participation of prostacyclin may be important at intermediate pressures.

Single-dose pharmacokinetics of oxytetracycline and penicillin G in tammar wallabies (Macropus eugenii)

The pharmacokinetics of oxytetracycline and penicillin G was investigated in tammar wallabies (Macropus eugenii). Groups of eight healthy tammar wallabies were administered i.v. oxytetracycline hydrochloride (40 mg/kg), i.m. long-acting-oxytetracycline (20 mg/kg), i.v. sodium penicillin G (30 mg/kg), or i.m. procaine/benzathine penicillin G (30 mg/kg). Plasma concentrations of oxytetracycline were determined using high-performance liquid chromatography. Pharmacokinetic parameters were comparable to those reported for eutherians of equivalent size and suggest that the practice of adjusting allometrically scaled doses to account for the lower metabolic rate of marsupials may not be valid. Long-acting oxytetracycline and penicillin G both demonstrated depot effects. However, the plasma concentrations achieved question the therapeutic efficacy of the long-acting preparations.

The Analysis of Phenylbutazone and Its Active Metabolite, Oxyphenbutazone, in Equine Tissues (Muscle, Kidney, and Liver), Urine, and Serum by LC-MS/MS

This study reports the use of two validated LC with tandem MS (MS/MS) methods to study the residue depletion profile of phenylbutazone (PBZ) and its metabolite oxyphenbutazone (OXPBZ) from equine serum, urine, and muscle, kidney, and liver tissues. One LC-MS/MS method, with an LOQ of 1.0 ng/mL for PBZ and 2.0 ng/mL for OXPBZ, was used for the analysis of the two drugs in the biological fluids (equine urine and serum); the other LC-MS/MS method, with an LOQ of 0.5 ng/g for PBZ and OXPBZ, was used for the analysis of the drugs in the equine tissue samples. PBZ was administered intravenously to two horses dosed with 8.8 mg/kg PBZ once daily for 4 days and sacrificed humanely at a slaughter plant 7 days after the last drug administration. Urine, serum, and kidney, liver, and muscle tissues were collected from the two horses and shipped on ice to the laboratory and stored at -20°C until analysis. The concentrations of PBZ and OXPBZ residues in the biological fluid and tissue samples collected at slaughter were measured with the two validated LC-MS/MS methods using deuterated internal standards. The results demonstrate that the validated methods are fit for studying the depletion kinetics of PBZ residues in equine tissues and biological fluids.

Antihistaminic and cardiorespiratory effects of diphenhydramine hydrochloride in anesthetized dogs undergoing excision of mast cell tumors

OBJECTIVE To evaluate the effects of IV diphenhydramine hydrochloride administration on cardiorespiratory variables in anesthetized dogs undergoing mast cell tumor (MCT) excision. DESIGN Randomized, blinded clinical trial. ANIMALS 16 client-owned dogs with MCTs. PROCEDURES In a standardized isoflurane anesthesia session that included mechanical ventilation, dogs received diphenhydramine hydrochloride (1 mg/kg [0.45 mg/lb], IV; n = 8) or an equivalent volume of saline (0.9% NaCl) solution (IV; control treatment; 8) 10 minutes after induction. Cardiorespiratory variables were recorded throughout anesthesia and MCT excision, and blood samples for determination of plasma diphenhydramine and histamine concentrations were collected prior to premedication (baseline), throughout anesthesia, and 2 hours after extubation. RESULTS Cardiorespiratory values in both treatment groups were acceptable for anesthetized dogs. Mean ± SD diastolic arterial blood pressure was significantly lower in the diphenhydramine versus control group during tumor dissection (52 ± 10 mm Hg vs 62 ± 9 mm Hg) and surgical closure (51 ± 10 mm Hg vs 65 ± 9 mm Hg). Mean arterial blood pressure was significantly lower in the diphenhydramine versus control group during surgical closure (65 ± 12 mm Hg vs 78 ± 11 mm Hg), despite a higher cardiac index value. Plasma histamine concentrations were nonsignificantly higher than baseline during maximal manipulation of the tumor and surgical preparation in the diphenhydramine group and during surgical dissection in the control group. CONCLUSIONS AND CLINICAL RELEVANCE IV administration of diphenhydramine prior to MCT excision had no clear clinical cardiorespiratory benefits over placebo in isoflurane-anesthetized dogs.

Effects of acepromazine or dexmedetomidine on fentanyl disposition in dogs during recovery from isoflurane anesthesia

OBJECTIVE To describe fentanyl pharmacokinetics during isoflurane anesthesia and on recovery from anesthesia with concurrent administration of acepromazine, dexmedetomidine or saline in dogs. STUDY DESIGN Experimental blinded, randomized, crossover study. ANIMALS Seven adult hound dogs. METHODS Dogs were administered intravenous (IV) fentanyl as a bolus (5 μg kg(-1)) followed by an infusion (5 μg kg(-1) hour(-1)) for 120 minutes during isoflurane anesthesia and emergence from anesthesia, and for 60 minutes after extubation during recovery from anesthesia. At the time of extubation, dexmedetomidine (2.5 μg kg(-1)), acepromazine (0.05 mg kg(-1)) or saline were administered IV. Venous blood was sampled during the maintenance and recovery periods. Fentanyl plasma concentrations were measured using high-performance liquid chromatography-mass spectrometry and population pharmacokinetic analyses were performed. RESULTS Mean fentanyl plasma concentrations were 1.6-4.5 ng mL(-1) during isoflurane anesthesia and 1.6-2.0 ng mL(-1) during recovery from anesthesia. Recovery from isoflurane anesthesia without sedation was associated with an increase in the volume of the central compartment from 0.80 to 1.02 L kg(-1). After administration of acepromazine, systemic clearance of fentanyl increased from 31.5 to 40.3 mL minute(-1) kg(-1) and the volume of the central compartment increased from 0.70 to 0.94 L kg(-1). Administration of dexmedetomidine did not significantly change fentanyl pharmacokinetics. Inter-individual variability for fentanyl parameter estimates in all treatments ranged from 2.2% to 54.5%, and residual error ranged from 6.3% to 13.4%. CONCLUSIONS AND CLINICAL RELEVANCE The dose rates of fentanyl used in this study achieved previously established analgesic plasma concentrations for the duration of the infusion. Despite alterations in fentanyl pharmacokinetics, differences in fentanyl plasma concentrations among treatments during recovery from anesthesia were small and were unlikely to be of clinical significance.