The effect of cannabidiol on sevoflurane minimum alveolar concentration reduction produced by morphine in rats

ObjectiveTo investigate the effect of cannabidiol (CBD) on sevoflurane minimum alveolar concentration (MAC_SEV) reduction produced by morphine in rats.Study designRandomized, blinded trial.AnimalsA total of 75 male Wistar Han rats weighing 276 ± 23 g (mean and standard deviation), aged 3 months.MethodsCannabidiol (CBD) was prepared in an ethanol-solutol-saline vehicle. Animals were randomly divided into 15 groups and given an intraperitoneal bolus of 1, 3, 5, 6.5, 7.5 or 10 mg kg^?1 of CBD alone (CBD1, CBD3, CBD5, CBD6.5, CBD7.5 and CBD10 respectively) or combined with 5 mg kg^?1 of morphine (MOR+CBD1, MOR+CBD3, MOR+CBD5, MOR+CBD6.5, MOR+CBD7.5 and MOR+CBD10). While three controls groups: MOR+saline, MOR+vehicle and vehicle were given an intraperitoneal bolus of morphine with saline, morphine with vehicle or vehicle alone respectively. The MAC_SEV was determined from alveolar gas samples at the time of tail clamp application. The MAC_SEV reduction was analyzed using a one-way ANOVA followed by Tukey’s test. Additionally, Kruskal-Wallis test for non-normally-distributed data was performed. Data are presented as mean ± standard deviation. P < 0.05ResultsThe mean MAC_SEV was not reduced by the action of CBD administered alone, but the addition of morphine to the different doses of CBD significantly reduced the MAC_SEV. That reduction was greatest in the MOR+CBD1, MOR+CBD7.5 and MOR+CBD10 groups (29 ± 5%, 32 ± 5% and 30 ± 6% respectively), less in MOR+CBD3 and MOR+CBD6.5 groups (24 ± 3% and 26 ± 4% respectively) and least in MOR+CBD5 group (17 ± 2%). However, only the MOR+CBD5 group was statistically significantly different from MOR+CBD1, MOR+CBD7.5 and MOR+CBD10 groups.Conclusions and clinical relevanceMAC_SEV in rat was unaltered by the action of CBD alone, the reduction in MAC_SEV produced by morphine was not enhanced by the addition of CBD at the doses studied.     

Combined effects of dexmedetomidine and vatinoxan infusions on minimum alveolar concentration and cardiopulmonary function in sevoflurane-anesthetized dogs

ObjectiveTo evaluate the effects of combined infusions of vatinoxan and dexmedetomidine on inhalant anesthetic requirement and cardiopulmonary function in dogs.Study designProspective experimental study.MethodsA total of six Beagle dogs were anesthetized to determine sevoflurane minimum alveolar concentration (MAC) prior to and after an intravenous (IV) dose (loading, then continuous infusion) of dexmedetomidine (4.5 μg kg^–1 hour^–1) and after two IV doses of vatinoxan in sequence (90 and 180 μg kg^–1 hour^–1). Blood was collected for plasma dexmedetomidine and vatinoxan concentrations. During a separate anesthesia, cardiac output (CO) was measured under equivalent MAC conditions of sevoflurane and dexmedetomidine, and then with each added dose of vatinoxan. For each treatment, cardiovascular variables were measured with spontaneous and controlled ventilation. Repeated measures analyses were performed for each response variable; for all analyses, p < 0.05 was considered significant.ResultsDexmedetomidine reduced sevoflurane MAC by 67% (0.64 ± 0.1%), mean ± standard deviation in dogs. The addition of vatinoxan attenuated this to 57% (0.81 ± 0.1%) and 43% (1.1 ± 0.1%) with low and high doses, respectively, and caused a reduction in plasma dexmedetomidine concentrations. Heart rate and CO decreased while systemic vascular resistance increased with dexmedetomidine regardless of ventilation mode. The co-administration of vatinoxan dose-dependently modified these effects such that cardiovascular variables approached baseline.Conclusions and clinical relevanceIV infusions of 90 and 180 μg kg^–1 hour^–1 of vatinoxan combined with 4.5 μg kg^–1 hour^–1 dexmedetomidine provide a meaningful reduction in sevoflurane requirement in dogs. Although sevoflurane MAC-sparing properties of dexmedetomidine in dogs are attenuated by vatinoxan, the cardiovascular function is improved. Doses of vatinoxan >180 μg kg^–1 hour^–1 might improve cardiovascular function further in combination with this dose of dexmedetomidine, but beneficial effects on anesthesia plane and recovery quality may be lost.     

在猪肺泡巨噬细胞上Notch信号通路调控LPS诱导的炎性反应研究

Notch信号通路可以与TLR信号通路相互作用,协作调控炎性因子的产生以及巨噬细胞的激活。然而,在猪巨噬细胞上,Notch信号通路是如何调控炎性反应的还不清楚。本研究以LPS/TLR4诱导炎性反应为模型,利用猪肺泡巨噬细胞来研究LPS处理对Notch信号通路的影响及Notch信号通路对LPS诱导炎性反应的调控作用。结果显示:LPS处理增加配体Jagged1、Jagged2和Dll4的表达,并上调下游靶基因Hey1的表达;Notch信号通路调控LPS诱导的炎性反应。本研究结果不仅明确了在猪巨噬细胞上Notch信号通路调控LPS诱导的炎性反应,而且为将来揭示Notch信号通路在猪相关细菌感染中的作用奠定基础。     

Comparison of the efficacy of two ventilatory strategies in improving arterial oxygen tension and content in anaesthetized sheep

ObjectiveTo compare F-shunt and oxygen content indices in sheep ventilated with a positive end-expiratory pressure (PEEP) of 5 cmH₂O alone or preceded by a stepwise alveolar recruitment manoeuvre (ARM).Study designRandomized crossover design.AnimalsA total of six nonpregnant Brogna ewes weighing 34–47 kg, undergoing thoracolumbar magnetic resonance scan.MethodsIn medetomidine-sedated sheep, anaesthesia was induced with propofol and maintained with isoflurane 1.1% ± 0.1% and an inspired oxygen fraction (FiO₂) of 0.4. Animals were placed in left lateral recumbency and, after 10 minutes of spontaneous breathing, mechanically ventilated with 5 cmH₂O of PEEP with (group ARM) or without (group PEEP) a stepwise recruitment manoeuvre. Maintaining a fixed driving pressure of 15 cmH₂O, PEEP was increased from 0 to 20 cmH₂O every 3 minutes in 5 cmH₂O increments. In each sheep, arterial blood samples were collected to measure arterial gases and to calculate F-shunt, PaO₂/alveolar oxygen partial pressure (PAO₂) and PaO₂/FIO₂ during spontaneous breathing before mechanical ventilation (T₀), after 20 minutes of ventilation (T₂₀) and during spontaneous breathing at extubation (T_ext).ResultsBoth ventilatory strategies improved the arterial oxygen content although four animals in group PEEP showed oxygen content compatible with hypoxia compared with group ARM. F-shunt values were not statistically different at any time point in sheep that underwent only PEEP ventilation while they decreased at T₂₀ and T_ext compared with T₀ in group ARM. At extubation F-shunt was statistically lower in sheep that underwent an ARM. Mechanical ventilation improved PaO₂/PAO₂ and PaO₂/FIO₂ but they did not differ between groups.Conclusionsand clinical relevance The stepwise ARM evaluated in this study improved oxygenation indices and decreased F-shunt. This effect was maintained at extubation compared with sheep that were ventilated with only PEEP 5 cmH₂O.     

Pneumothorax in cats with a clinical diagnosis of feline asthma: 5 cases (1990–2000)

Objective: This paper characterizes the clinical findings in 5 cats with feline asthma complicated by concurrent pneumothorax. Design: Retrospective study. Medical records of cats with concurrent diagnoses of asthma and pneumothorax that were presented to the Veterinary Hospital of the University of Pennsylvania from 1990 to 2000 were reviewed. Results: Of 421 cases of feline asthma, 5 cats fulfilled the inclusion criteria (1.2%). All 5 had respiratory distress at presentation. One cat was panting, and the other 4 cats had respiratory rates of 28, 52, 58 and 120 breaths per minute (bpm), respectively (mean RR 65±39 bpm). Historical findings included untreated chronic cough (n=3), previously treated asthma (n=1), and no previous illness (n=1). Thoracocentesis was performed in 4/5 cats, and 3 of those cats required thoracostomy tubes. Four cats required immediate oxygen supplementation, and 1 of those cats required ventilation. All 5 cats had evidence of pneumothorax on initial radiographs. Follow‐up radiographs revealed partial or complete resolution of pneumothorax in 4 cats which were discharged alive with total hospitalization of 2–7 days, but were then lost to follow‐up. One cat was euthanized because it could not be weaned off mechanical ventilation, and necropsy confirmed end‐stage feline asthma and emphysema. Conclusion: Small airway obstruction can predispose asthma patients to increased alveolar pressure, emphysema, and spontaneous pneumothorax, which can lead to dyspnea in affected cats. The short‐term outcome in these cats was good despite the severity of dyspnea at presentation.     

Characteristics of the relationship between plasma ketamine concentration and its effect on the minimum alveolar concentration of isoflurane in dogs

OBJECTIVE: To characterize the shape of the relationship between plasma ketamine concentration and minimum alveolar concentration (MAC) of isoflurane in dogs. STUDY DESIGN: Retrospective analysis of previous data. ANIMALS: Four healthy adult dogs. METHODS: The MAC of isoflurane was determined at five to six different plasma ketamine concentrations. Arterial blood samples were collected at the time of MAC determination for measurement of plasma ketamine concentration. Plasma concentration/effect data from each dog were fitted to a sigmoid inhibitory maximum effect model in which MAC(c)= MAC(0) - (MAC(0)-MAC(min)) x C(gamma)/EC(50)(gamma)+C(gamma), where C is the plasma ketamine concentration, MAC(c) is the MAC of isoflurane at plasma ketamine concentration C, MAC(0) is the MAC of isoflurane without ketamine, MAC(min) is the lowest MAC predicted during ketamine administration, EC(50) is the plasma ketamine concentration producing 50% of the maximal MAC reduction, and gamma is a sigmoidicity factor. Nonlinear regression was used to estimate MAC(min), EC(50), and gamma. RESULTS: Mean +/- SEM MAC(min), EC(50) and gamma were estimated to be 0.11 +/- 0.01%, 2945 +/- 710 ng mL(-1) and 3.01 +/- 0.84, respectively. Mean +/- SEM maximal MAC reduction predicted by the model was 92.20 +/- 1.05%. CONCLUSIONS: The relationship between plasma ketamine concentration and its effect on isoflurane MAC has a classical sigmoid shape. Maximal MAC reduction predicted by the model is less than 100%, implying that high plasma ketamine concentrations may not totally abolish gross purposeful movement in response to noxious stimulation in the absence of inhalant anesthetics. CLINICAL RELEVANCE: The parameter estimates reported in this study will allow clinicians to predict the expected isoflurane MAC reduction from various plasma ketamine concentrations in an average dog.     

The effects of ketamine on the minimum alveolar concentration of isoflurane in cats

OBJECTIVES: To determine the minimum alveolar concentration (MAC) of isoflurane during the infusion of ketamine. STUDY DESIGN: Prospective, experimental trial. ANIMALS: Twelve adult spayed female cats weighing 5.1 +/- 0.9 kg. METHODS: Six cats were anesthetized with isoflurane in oxygen, intubated and attached to a circle-breathing system with mechanical ventilation. Catheters were placed in a peripheral vein for the infusion of fluids and ketamine, and the jugular vein for blood sampling for the measurement of ketamine concentrations. An arterial catheter was placed to allow blood pressure measurement and sampling for the measurement of PaCO2, PaO2 and pH. PaCO2 was maintained between 29 and 41 mmHg (3.9-5.5 kPa) and body temperature was kept between 37.8 and 39.3 degrees C. Following instrumentation, the MAC of isoflurane was determined in triplicate using a tail clamp method. A loading dose (2 mg kg(-1) over 5 minutes) and an infusion (23 microg kg(-1) minute(-1)) of ketamine was started and MAC was redetermined starting 30 minutes later. Two further loading doses and infusions were used, 2 mg kg(-1) and 6 mg kg(-1) with 46 and 115 microg kg(-1) minute(-1), respectively and MAC was redetermined. Cardiopulmonary measurements were taken before application of the noxious stimulus. The second group of six cats was used for the measurement of steady state plasma ketamine concentrations at each of the three infusion rates used in the initial study and the appropriate MAC value determined from the first study. RESULTS: The MAC decreased by 45 +/- 17%, 63 +/- 18%, and 75 +/- 17% at the infusion rates of 23, 46, and 115 microg kg(-1) minute(-1). These infusion rates corresponded to ketamine plasma concentrations of 1.75 +/- 0.21, 2.69 +/- 0.40, and 5.36 +/- 1.19 microg mL(-1). Arterial blood pressure and heart rate increased significantly with ketamine. Recovery was protracted. CONCLUSIONS AND CLINICAL RELEVANCE: The MAC of isoflurane was significantly decreased by an infusion of ketamine and this was accompanied by an increase in heart rate and blood pressure. Because of the prolonged recovery in our cats, further work needs to be performed before using this in patients.     

Lung aeration and volumes following alveolar recruitment maneuvers with three airway pressures in healthy anesthetized and mechanically ventilated Beagle dogs

ObjectiveTo compare the effects of three recruitment airway pressures (RP_aw) on lung aeration and volumes in mechanically ventilated dogs during propofol anesthesia.Study designProspective, crossover randomized experimental study.AnimalsA total of eight healthy anesthetized experimental Beagle dogs in dorsal recumbency.MethodsDogs were mechanically ventilated with a tidal volume of 15 mL kg^–1 and zero positive end-expiratory pressure and 100% oxygen. Three maneuvers consisting of a 30 second inspiration at RP_aws of 15 (RP_aw15), 25 (RP_aw25) and 35 (RP_aw35) cmH₂O were performed randomly, 15 minutes apart. Changes in lung aeration and lung deformation were compared with end-expiratory baseline (before the application of each RP_aw) and between-RP_aws using computed tomography scans and calculations of global lung strain. Between-group comparisons were performed with one-way anova for repeated measures followed by Tukey test for multiple comparisons. A p value < 0.05 was considered significant.ResultsThe amount of nonaeration was minimal (<1%) at baseline and not different with the application of the RP_aws. The amount of hypoaeration and normoaeration during baseline decreased with all RP_aws (p < 0.001). There was no difference between RP_aws regarding hypoaeration (all p > 0.999), whereas normoaeration was higher at RP_aw15 than RP_aw25 and RP_aw35 (p < 0.009). Compared with baseline, the fraction of hyperaerated alveoli increased with each RP_aw (p < 0.001) and was lower during RP_aw15 than RP_aw25 and RP_aw35 (both p ≤ 0.007). Global lung strain was lower during RP_aw15 than at higher RP_aw (p < 0.001).Conclusions and clinical relevanceA RP_aw of 15 cmH₂O for 30 seconds was the recommended RP_aw because it was as effective at reversing hypoaeration as RP_aws of 25 and 35 cmH₂O but with less hyperaeration and potential for overdistension of the lungs in this particular population of dogs with negligible atelectasis.     

Profiling microRNA expression in bovine alveolar macrophages using RNA-seq

MicroRNAs (miRNAs) are important regulators of gene expression and are known to play a key role in regulating both adaptive and innate immunity. Bovine alveolar macrophages (BAMs) help maintain lung homeostasis and constitute the front line of host defense against several infectious respiratory diseases, such as bovine tuberculosis. Little is known, however, about the role miRNAs play in these cells. In this study, we used a high-throughput sequencing approach, RNA-seq, to determine the expression levels of known and novel miRNAs in unchallenged BAMs isolated from lung lavages of eight different healthy Holstein–Friesian male calves. Approximately 80 million sequence reads were generated from eight BAM miRNA Illumina sequencing libraries, and 80 miRNAs were identified as being expressed in BAMs at a threshold of at least 100 reads per million (RPM). The expression levels of miRNAs varied over a large dynamic range, with a few miRNAs expressed at very high levels (up to 800,000 RPM), and the majority lowly expressed. Notably, many of the most highly expressed miRNAs in BAMs have known roles in regulating immunity in other species (e.g. bta-let-7i, bta-miR-21, bta-miR-27, bta-miR-99b, bta-miR-146, bta-miR-147, bta-miR-155 and bta-miR-223). The most highly expressed miRNA in BAMs was miR-21, which has been shown to regulate the expression of antimicrobial peptides in Mycobacterium leprae-infected human monocytes. Furthermore, the predicted target genes of BAM-expressed miRNAs were found to be statistically enriched for roles in innate immunity. In addition to profiling the expression of known miRNAs, the RNA-seq data was also analysed to identify potentially novel bovine miRNAs. One putatively novel bovine miRNA was identified. To the best of our knowledge, this is the first RNA-seq study to profile miRNA expression in BAMs and provides an important reference dataset for investigating the regulatory roles miRNAs play in this important immune cell type.     

Effects of a constant‐rate infusion of dexmedetomidine on the minimal alveolar concentration of sevoflurane in ponies

Reasons for performing study: Dexmedetomidine has been administered in the equine as a constant‐rate infusion (CRI) during inhalation anaesthesia, preserving optimal cardiopulmonary function with calm and coordinated recoveries. Inhalant anaesthetic sparing effects have been demonstrated in other species, but not in horses. Objectives: To determine the effects of a CRI of dexmedetomidine on the minimal alveolar concentration (MAC) of sevoflurane in ponies. Methods: Six healthy adult ponies were involved in this prospective, randomised, crossover, blinded, experimental study. Each pony was anaesthetised twice (3 weeks washout period). After induction with sevoflurane in oxygen (via nasotracheal tube), the ponies were positioned on a surgical table (T0), and anaesthesia was maintained with sevoflurane (expired sevoflurane fraction 2.5%) in 55% oxygen. The ponies were randomly allocated to treatment D (dexmedetomidine 3.5 µg/kg bwt i.v. [T10–T15] followed by a CRI of dexmedetomidine at 1.75 µg/kg bwt/h) or treatment S (bolus and CRI of saline at the same volume and rate as treatment D). After T60, MAC determination, using a classic bracketing technique, was initiated. Stimuli consisted of constant‐current electrical stimuli at the skin of the lateral pastern region. Triplicate MAC estimations were obtained and averaged in each pony. Monitoring included pulse oximetry, electrocardiography, anaesthetic gas monitoring, arterial blood pressure measurement and arterial blood gases. Normocapnia was maintained by mechanical ventilation. Analysis of variance (treatment and period as fixed factors) was used to detect differences between treatments (α= 0.05). Results: An intravenous (i.v.) dexmedetomidine CRI decreased mean ± s.d. sevoflurane MAC from 2.42 ± 0.55 to 1.07 ± 0.21% (mean MAC reduction 53 ± 15%). Conclusions and potential relevance: A dexmedetomidine CRI at the reported dose significantly reduces the MAC of sevoflurane.