Long-term Anesthesia Research Articles

Treatment of closed rib fractures with long-term anesthesia

Since 1956 we have been treating rib fractures with 5% oil solution of novocaine base. A solution of novocaine base in peach oil is available in 5 ml ampoules.

Analysis of pH and electrolytes in blood and ruminal fluid, including kidney function tests, in sheep undergoing long-term surgical procedures

BackgroundThe physiology of sheep as small ruminants is remarkably different from monogastric animals especially regarding the forestomach system. Using sheep for surgical procedures during scientific research thereby presents an exceptional setting for the anaesthetist. Long-term anaesthesia generally demands deprivation of food to reduce the risk of bloat in sheep. This might influence the energy and electrolyte balance. In horses and companion animals, close monitoring of mean arterial blood pressure, capnography and blood gas analysis are common procedures during long-term surgery. However, few data are available on reference ranges for blood gas in sheep and these cover only short periods of anaesthesia. To the authors’ knowledge, there is no study available that includes the monitoring of electrolytes and pH in ruminal fluid and kidney function tests in sheep undergoing long term anaesthesia. Thereby, the aim of the present study was to gather data on blood parameters, and data on ruminal fluid and kidney function during long-term anaesthesia in sheep. Data were obtained from eight sheep undergoing the invasive surgical procedure of left pneumonectomy and auto-transplantation or isolated left lung perfusion. After a 19-h fasting period, the animals were administered xylazine and ketamine and then intubated and maintained in general anaesthesia under artificial ventilation using isoflurane in oxygen. Blood samples were evaluated during 9 h of anaesthesia; ruminal fluid and kidney function tests were evaluated during 7 h of anaesthesia.ResultsBlood parameters such as electrolytes and partial pressure of carbon dioxide revealed few changes, yet blood glucose decreased and beta-hydroxybutyric acid increased significantly. All animals showed an elevated arterial pH and bicarbonate concentration despite artificial ventilation. In ruminal fluid, the pH significantly decreased and no significant changes in electrolytes occurred. Kidney function tests revealed no significant changes in any of the animals. However, fractional excretion of water and phosphate was slightly increased. One animal showed severe complications due to hypokalaemia.ConclusionInvasive surgery under long-term anaesthesia in sheep is possible without great imbalances of arterial pH and electrolytes. Nevertheless, potassium concentrations should be monitored carefully, as a deficiency can lead to life-threatening complications. The operated sheep tended not to develop metabolic acidosis and the mean kidney function could be maintained within the physiological range throughout anaesthesia. However, slight elevations in renal fractional water and phosphate excretion could suggest an early tubular reabsorption dysfunction. In ruminal fluid, acidification occurred, though no significant changes were observed in l- and d-lactate levels or in electrolyte concentrations. To our knowledge, the role of the rumen in storing fluids and balancing electrolytes in the blood has not yet been documented during anaesthesia. However, the importance of the rumen for fluid equilibrium in sheep indicates the necessity for routine monitoring and further research.

Clinical and pharmacological approaches to the choice of a drug for a tension-type headache relief

The purpose of this study is a comparative analysis of the pharmacodynamic and pharmacokinetic parameters of ibuprofen and paracetamol as a part of fixed dose combination and as monotherapy in tension type headaches. Comparative dissolution kinetics test; Comparative analysis of pharmacokinetic parameters using the PubMed/MEDLINE database. The median Tmax of ibuprofen as a part of a fixed-dose combination and as a monotherapy is 75 minutes. The median Tmax of paracetamol is 30 min when taken in a fixed dose combination and 40 min as a monotherapy. In patients who received the fixed dose combination, the concentration of ibuprofen in the blood plasma after 10 minutes 6.64 g/ml-1; after 20 minutes 16.81 g/ml-1, while when taken in the same dose in as a monotherapy, respectively, 0.58 and 9.00 g/ml-1. The mean plasma concentrations of paracetamol after 10 and 20 minutes in patients receiving the fixed combination were 5.43 and 14.54 g/ml-1, respectively, compared with 0.33 and 9.19 g/ml-1 for paracetamol as monotherapy. dissolution kinetics test of the Paracytolgin: after 5 minutes, 20% of paracetamol passed into the solution in a system with a pH of 1.2; in a system with a pH of 4.5 36.4%; in a system with a pH of 6.8 33.5%; after 10 minutes, respectively 68.5, 98.0 and 89.6%. After 15 minutes, almost complete dissolution was noted in all systems: 98.5, 98.8 and 100.5%, respectively. The combination of ibuprofen and paracetamol makes it possible to enhance the analgesic effect as a result of additive action by the help of central mechanisms. The fixed dose combination of ibuprofen and paracetamol significantly increases the rate of absorption of paracetamol, which has potential therapeutic benefits in terms of a faster analgesias onset. The fixed dose combination of ibuprofen and paracetamol provides faster and long-term anaesthesia with a comparatively lower dosage of each analgesic.

Tailored Pharmacokinetic model to predict drug trapping in long-term anesthesia

IntroductionIn long-term induced general anesthesia cases such as those uniquely defined by the ongoing Covid-19 pandemic context, the clearance of hypnotic and analgesic drugs from the body follows anomalous diffusion with afferent drug trapping and escape rates in heterogeneous tissues. Evidence exists that drug molecules have a preference to accumulate in slow acting compartments such as muscle and fat mass volumes. Currently used patient dependent pharmacokinetic models do not take into account anomalous diffusion resulted from heterogeneous drug distribution in the body with time varying clearance rates. ObjectivesThis paper proposes a mathematical framework for drug trapping estimation in PK models for estimating optimal drug infusion rates to maintain long-term anesthesia in Covid-19 patients. We also propose a protocol for measuring and calibrating PK models, along with a methodology to minimize blood sample collection. MethodsWe propose a framework enabling calibration of the models during the follow up of Covid-19 patients undergoing anesthesia during their treatment and recovery period in ICU. The proposed model can be easily updated with incoming information from clinical protocols on blood plasma drug concentration profiles. Already available pharmacokinetic and pharmacodynamic models can be then calibrated based on blood plasma concentration measurements. ResultsThe proposed calibration methodology allow to minimize risk for potential over-dosing as clearance rates are updated based on direct measurements from the patient. ConclusionsThe proposed methodology will reduce the adverse effects related to over-dosing, which allow further increase of the success rate during the recovery period.

Comparison of Anesthetic Efficacy of Lidocaine and Bupivacaine in Spinal Anesthesia in Chickens.

Lidocaine is used for epidural and spinal anesthesia in various animal species. The ideal drug for epidural and spinal anesthesia should have a long effective duration in addition to a fast onset of action, and adequate analgesia and muscle relaxation. Despite the delayed onset of action, bupivacaine provides a longer duration of anesthesia than lidocaine. The purpose of this study was to compare the onset to effect and duration of action between lidocaine and bupivacaine for spinal anesthesia in broiler chickens. Thirty-two, 8-week-old, female Ross broiler chickens were randomly divided into 4 groups of 8: 1) 2 mg/kg lidocaine (L); 2) 0.1 mg/kg bupivacaine (B0.1); 3) 0.25 mg/kg bupivacaine (B0.25); and 4) 0.5 mg/kg bupivacaine (B0.5). After aseptic preparation, a 23-gauge spinal needle was inserted into the synsacrococcygeal space of the chickens with correct needle placement confirmed by a sudden loss of resistance. Spinal anesthesia was performed with the aforementioned doses of lidocaine and bupivacaine. The respiratory rate and cloacal temperature were measured every 10 minutes in each chicken until the anesthetic effect was no longer present. The onset to effect and the duration of action were calculated for each bird based on the pinch test at predetermined time intervals. The results are demonstrated as mean ± SD. The onset of action for bupivacaine (9 ± 1.41, 4.33 ± 1.15, and 3.33 ± 1.23 minutes in B0.1, B0.25, and B0.5 groups, respectively) was significantly delayed compared with that of lidocaine (1.37 ± 0.52 minutes). The duration of action of B0.5 (54 ± 6.08 minutes) was significantly longer than that of any other group (17.87 ± 3.18, 11 ± 1.41, and 18 ± 4.36 min in L, B0.1, and B0.25 groups, respectively). The results showed that a spinal injection of 0.5 mg/kg bupivacaine produces approximately 55 minutes of spinal anesthesia in these broiler chickens, which is much longer than the 18 minutes of anesthesia provided by 2 mg/kg lidocaine. Considering the various disease conditions that affect the cloacal area of birds, one can use each of these anesthetic drugs for either short-term or long-term spinal anesthesia in chickens and possibly other avian species.

Efficiency of Laparoscopic Treatment of the Stricture of the Bowl-ureter Segment in Combination with Urolithiasis

Stricture of the bowl-ureter segment (BUS) is one of the common pathologies in urology. Quite often in urological practice narrowing of BUS is accompanied by urolithiasis. In adults, according to various authors, the combination of these two serious pathologies occurs in 16-25 % of observations. For a long period, reconstructive-plastic surgery on BUS was a category of complex surgical interventions, required long-term intubation anesthesia, accompanied by a wide opening of the retroperitoneal space with careful allocation of the BUS area. Patients were in the hospital for a long time. Progress in the development of endoscopic equipment has contributed to the active introduction into clinical practice of minimally invasive techniques. Today, an increasing number of urologists are favoring different methods of laparoscopic plastics of BUS structures. But, both in the domestic and in the foreign literature, there are few works that would present advantages, complications, disadvantages of laparoscopic BUS plastic in combination with laparoscopic pyelolithotomy in patients with BUS complicated. This paper presents an analysis of our treatment of patients with BUS strictures in combination with urolithiasis.The objective: analysis and evaluation of the effectiveness of laparoscopic MCC plastics in combination with laparoscopic pyelolithotomy in patients with MCC obstruction complicated by SCC.Materials and methods. For the period from 2013 to 2019 41 patients with the above pathology were laparoscopically operated in the clinic of theInstitute ofUrology of the National Academy of Medical Sciences ofUkraine, including 25 men and 16 women. Their age ranged from 18 to 66 years. The length of the strictures – from 0.3 to1 cm. The size of the concretions varied from 0.5 to1.5 cm. One patient was found to be a coral stone of8.6 cm in size. There were no complications. The average length of stay in the hospital was 5.4 days.Results. In the distant postoperative period, there was no recurrence of BUS stricture and stone formation, stabilization or improvement of the secretory function of the kidney on the side of the plastic was noted. The effectiveness of our use of this method was 90.2 %, which allows us to consider it as the «gold» standard in the treatment of the above pathology.Conclusion. The use of laparoscopic plastics in combination with laparoscopic pyelolithotomy has made it possible to achieve good clinical results both in the immediate and long-term postoperative period. Timely surgery allowed us to achieve positive results in all patients with hydronephrotic transformation due to BUS stricture and complicated urolithiasis.

Long-term local anesthesia of the superior laryngeal nerve in the treatment of bronchial asthma

Aim. A priority method of long-term local anesthesia of the superior laryngeal nerve in the treatment of bronchial asthma is proposed. Materials and methods. For long-term relief of bronchospasm in patients with asthma, blockade of the superior laryngeal nerve was performed with a 0.5% solution of novocaine mixed with ethyl rectified 96o alcohol. This method has been tested in the clinic in 8 patients (experimental group). The control group consisted of 7 patients who received only 0.5% novocaine solution in the region of the superior laryngeal nerve. All 15 patients were diagnosed with bronchial asthma of infectious-allergic genesis of moderate severity. Results. After the traditional novocaine blockade in all patients in the control group, the clinical and spirographic indicators of the course of asthma improved, but this improvement was short-term (up to 15 days). After long-term local anesthesia in the patients of the main group, the episodes of bronchospasm disappeared in all patients, and the indicators of the lung function after 15 days of examination were significantly higher than the baseline and in patients in the control group. All patients in the main group were examined after 4 months: in 2 patients, asthma attacks occurred once a day, in the rest of the patients no asthma attacks were noted, the spirographic parameters were significantly higher than before treatment. Conclusion. The effectiveness of the developed method of long-term local anesthesia (prolonged blockade) of the superior laryngeal nerve with 0.5% novocaine solution mixed with ethyl rectified 96o alcohol, confirmed by clinical and spirographic methods, has been demonstrated.

Anesthesia for rabbits submitted to experimental surgeries: Report of a series of eight anesthesias

Anesthesia for laboratory animals is a matter of biomedical concern and one of the most present dilemmas in the current bioethical debate. The use of anesthetic agents in experimental surgery aims at analgesia and restraining the animal, in order to achieve a reasonable degree of muscle relaxation and to produce sufficient analgesia. This practice requires the use of protocols for the administration of safe and efficient doses. Eight New Zealand rabbits were submitted to laparotomies demonstrating the surgical technique discipline of the local medical course. For pre-anesthetic medication, acepromazine 1 mg.kg-1 associated with ketamine 15 mg.kg-1 was used subcutaneously. Anesthesia was maintained with isoflurane and oxygen under a laryngeal mask in a Mapleson D anesthesia system and under spontaneous breathing. Hydration was performed with 10 ml.kg-1 saline every hour. A thermal mattress was used. Precordial stethoscope, pulse oximetry and clinical parameters were used for monitoring. For euthanasia, ketamine 10 mg.kg-1 associated with potassium chloride 19.1% 1 ml.kg-1 was used intravenously. The average weight of the rabbits was 2721.25 ± 275.01 grams and the duration of the anesthetic procedure was 120 ± 87 minutes. Discussion. In long-term anesthesia, such as laparotomies, the use of pre-anesthetic medication and then anesthetic induction by the combination of agents is recommended. However, anesthetic management requires monitoring to prevent insufficient or excessive doses from occurring.

Preparation of Tetrodotoxin Extracellular Nanoparticles and Its Long-Term Local Anesthesia

Tetrodotoxin (TTX) can be applied in local anesthesia by blocking the sodium channel on the cell membrane. However, TTX can cause systemic toxicity and neurotoxicity, which limits its application. In this study, we prepared tetrodotoxin-Extracellular vesicles (TTX-EVs) and evaluated their capability to achieve long-term local anesthesia without nervous system or systemic damage. Anesthesia effects and safety of TTX-EVs were evaluated by sciatic nerve block and neurobehavioral test, respectively. The local toxicity was evaluated by histological score of injection site and characterization of sciatic nerve. Systemic toxicity was assessed for side nerve injury and mortality. We found that when TTX was 10 μg/mL (3 μg/0.3 mL), the average duration of sensory block of TTX-EVs was 4.23 hours, much longer than that of free drugs (P < 0.001). This TTX-EVs complex had minimal muscle toxicity and inflammation, and had no change in the percentage or diameter of unmyelinated nerve fiber compared with the blank group. In conclusion, the entrapped TTX can prolong the nerve block time obviously, and the sustained-release carrier will not cause the neurotoxicity or systemic toxicity.

Dexmedetomidine and levobupivacaine co-loaded, transcriptional transactivator peptide modified nanostructured lipid carriers or lipid–polymer hybrid nanoparticles, which performed better for local anesthetic therapy?

Local anesthetics (LAs) have been widely applied in clinic for regional anesthesia, postoperative analgesia, and management of acute and chronic pain. Nanostructured lipid carriers (NLCs) and lipid–polymer hybrid nanoparticles (LPNs) are reported as good choices for LA therapy. Transactivated transcriptional activator (TAT) was reported as a modifier for the topical delivery of drugs. In the present study, TAT modified, levobupivacaine (LEV) and dexmedetomidine (DEX) co-delivered NLCs (TAT-LEV&DEX-NLCs, T-L&D-N) and LPNs (TAT-LEV&DEX-LPNs, T-L&D-L) were designed and compared for the LA therapy. T-L&D-L exhibited better efficiency in improving the skin permeation, analgesic time, and pain control intensity than T-L&D-N both in vitro and in vivo. On the other side, T-L&D-N also improved the therapeutic effect of drugs to a large extent. These two systems both exhibited superiority in some respects. TAT modified LPNs are more promising platform for the long-term local anesthesia.

Effects of Long-term Anesthesia, Blood Sampling, Transportation, and Infection Status on Hearts and Brains in Pigs Inoculated with Staphylococcus aureus and Used for Imaging Studies.

Laboratory animals are widely used in imaging studies, including infection, heart, and brain research. Compared with rodents, pigs are especially useful because of their large organ sizes, ability to tolerate long-term anesthesia, and substantial blood volume, which allows repeated blood sampling. These factors are particularly important in positron emission tomography studies of potential new radioactive tracers, because the scans often are prolonged; in addition, kinetic studies involving repeated blood sampling may be performed to establish the optimal scan time. However, protracted studies may affect the cardiovascular system, brain, and other organs. This raises the question of how to monitor and counteract the effects of longterm anesthesia in pigs in a typical experimental setting yet prevent introducing bias into the experiment. To address this question, we investigated the effects of long-term anesthesia (maximum, 18 h), repeated blood sampling (maximum of 20 mL blood per kilogram body weight), and road transportation (as long as 1.5 h between 2 imaging centers) on key variables of lung, heart, and brain function in the context of a well-established pig model of Staphylococcus aureus infection. Pulse rate, oxygen saturation, body temperature, arterial pressure of CO₂, and urine production were stable during anesthesia for at least 16 h, whereas blood glucose slowly decreased. Hct and leukocyte count decreased due to repeated blood sampling. During road transportation, blood lactate levels increased 5 fold and arterial pressure of O₂ decreased by 50%. Repeated CT scans, necropsy results, and histopathology findings documented progressive lung changes and acute cardiac necrosis. No lesions indicative of hypoxia were found in brain. The study data show that the typical monitoring parameters do not fully depict the cardiovascular state of pigs during prolonged anesthesia. We recommend streamlining experimental protocols for imaging studies in pigs to avoid organ pathology.

Sevoflurane plays a reduced role in cognitive impairment compared with isoflurane: limited effect on fear memory retention

Isoflurane and sevoflurane are both inhalation anesthetics, but in clinical application, sevoflurane has been considered to be less suitable for long-term anesthesia because of its catabolic compounds and potential nephrotoxicity. Nevertheless, recent studies have shown that these two inhalation anesthetics are similar in hepatorenal toxicity, cost, and long-term anesthetic effect. Moreover, sevoflurane possibly has less cognitive impact on young mice. In this study, C57BL/6 mice aged 8-10 weeks were exposed to 1.2% isoflurane or 2.4% sevoflurane for 6 hours. Cognitive function and memory were examined in young mice using the novel object recognition, contextual fear conditioning, and cued-fear extinction tests. Western blot assay was performed to detect expression levels of D1 dopamine receptor, catechol-O-methyltransferase, phospho-glycogen synthase kinase-3β, and total glycogen synthase kinase-3β in the hippocampus. Our results show that impaired performance was not detected in mice exposed to sevoflurane during the novel object recognition test. Contextual memory impairment in the fear conditioning test was shorter in the sevoflurane group than the isoflurane group. Long-term sevoflurane exposure did not affect memory consolidation, while isoflurane led to memory consolidation and reduced retention. Downregulation of hippocampal D1 dopamine receptors and phosphorylated glycogen synthase kinase-3β/total glycogen synthase kinase-3β and upregulation of catechol-O-methyltransferase may be associated with differing memory performance after exposure to isoflurane or sevoflurane. These results confirm that sevoflurane has less effect on cognitive impairment than isoflurane, which may be related to expression of D1 dopamine receptors and catechol-O-methyltransferase and phosphorylation of glycogen synthase kinase-3β in the hippocampus. This study was approved by the Institutional Animal Care and Use Committee, Nanjing University, China on November 20, 2017 (approval No. 20171102).

GLYX-13 pretreatment ameliorates long-term isoflurane exposure-induced cognitive impairment in mice.

Accumulating evidence indicates that inhalation anesthetics induce or increase the risk of cognitive impairment. GLYX-13 (rapastinel) acts on the glycine site of N-methyl-D-aspartate receptors (NMDARs) and has been shown to enhance hippocampus-dependent learning and memory function. However, the mechanisms by which GLYX-13 affects learning and memory function are still unclear. In this study, we investigated these mechanisms in a mouse model of long-term anesthesia exposure. Mice were intravenously administered 1 mg/kg GLYX-13 at 2 hours before isoflurane exposure (1.5% for 6 hours). Cognitive function was assessed using the contextual fear conditioning test and the novel object recognition test. The mRNA expression and phosphorylated protein levels of NMDAR pathway components, N-methyl-D-aspartate receptor subunit 2B(NR2B)-Ca2+/calmodulin dependent protein kinase II (CaMKII)-cyclic adenosine monophosphate response element binding protein (CREB), in the hippocampus were evaluated by quantitative RT-PCR and western blot assay. Pretreatment with GLYX-13 ameliorated isoflurane exposure-induced cognitive impairment and restored NR2B, CaMKII and CREB mRNA and phosphorylated protein levels. Intracerebroventricular injection of KN93, a selective CaMKII inhibitor, significantly diminished the effect of GLYX-13 on cognitive function and NR2B, CaMKII and CREB levels in the hippocampus. Taken together, our findings suggest that GLYX-13 pretreatment alleviates isoflurane-induced cognitive dysfunction by protecting against perturbation of the NR2B/CaMKII/CREB signaling pathway in the hippocampus. Therefore, GLYX-13 may have therapeutic potential for the treatment of anesthesia-induced cognitive dysfunction. This study was approved by the Experimental Animal Ethics Committee of Drum Tower Hospital affiliated to the Medical College of Nanjing University, China (approval No. 20171102) on November 20, 2017.

Long-term anesthetic analgesic effects: Comparison of tetracaine loaded polymeric nanoparticles, solid lipid nanoparticles, and nanostructured lipid carriers in vitro and in vivo

Local anesthetics (LAs) are drugs that promote the reversible blocking of neural transmission by inhibiting the excitation conduction process in peripheral nerves. Tetracaine (TTC) is one of the most common topical anesthetics used in general practice and was applied to provide long-term anesthesia. In this research, poly(L-lactide) nanoparticles (PLA NPs), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) were utilized to construct TTC loaded nanosystems. The mean sizes, drug loading efficiency, cytotoxicity, skin permeation ability, and anesthetic analgesic effect were evaluated and compared in vitro and in vivo. The average particle sizes of blank PLA NPs, SLNs, and NLCs were 93.2, 100.9 and 110.4 nm, respectively. At all the concentrations, PLA NPs, SLNs, and NLCs showed a moderate effect on cell viability. TTC NLCs exhibited the most prominent in vivo efficiency in improving the skin permeation, analgesic time and pain control intensity. Other experiments proved that TTC PLA NPs showed advantages in serum stability and TTC SLNs illustrated the best in vitro permeation efficiency. These three kinds of nano-systems had their own superiority in some respects. Conclusion could be made that in this study, TTC NLCs is the promising system for the long-term anesthesia.

Validation of a methodology for neuro-urological and lumbosacral stimulation studies in domestic pigs: a humanlike animal model.

Spinal cord injuries (SCIs) result in loss of movement and sensory feedback, but also organ dysfunction. Nearly all patients with complete SCI lose bladder control and are prone to kidney failure if intermittent catheterization is not performed. Electrical stimulation of sacral spinal roots was initially considered to be a promising approach for restoring continence and micturition control, but many patients are discouraged by the need for surgical deafferentation as it could lead to a loss of sensory functions and reflexes. Nevertheless, recent research findings highlight the renewed interest in spinal cord stimulation (SCS). It is thought that synergic recruitment of spinal fibers could be achieved by stimulating the spinal neural networks involved in regulating physiological processes. Paradoxically, most of these recent studies focused on locomotor issues, while few addressed visceral dysfunction. This could at least partially be attributed to the lack of methodological tools. In this study, the authors aim to fill this gap by presenting a comprehensive method for investigating the potential of SCS to restore visceral functions in domestic pigs, a large-animal model considered to be a close approximation to humans. This methodology was tested in 7 female pigs (Landrace pig breed, 45-60 kg, 4 months old) during acute experiments. A combination of morphine and propofol was used for anesthesia when transurethral catheterization and lumbosacral laminectomy (L4-S4) were performed. At the end of the operation, spinal root stimulation (L6-S5) and urodynamic recordings were performed to compare the evoked responses with those observed intraoperatively in humans. Nervous excitability was preserved despite long-term anesthesia (mean 8.43 ± 1.5 hours). Transurethral catheterization and conventional laminectomy were possible while motor responses (gluteus muscle monitoring) were unaffected throughout the procedure. Consistent detrusor (approximately 25 cm H2O) and sphincter responses were obtained, whereas spinal root stimulation elicited detrusor and external urethral sphincter co-contractions similar to those observed intraoperatively in humans. Pigs represent an ideal model for SCS studies aimed at visceral function investigation and restoration because of the close similarities between female domestic pigs and humans, both in terms of anatomical structure and experimental techniques implemented. This article provides methodological keys for conducting experiments with equipment routinely used in clinical practice.

Circadian rhythm resynchronization improved isoflurane-induced cognitive dysfunction in aged mice

Postoperative cognitive dysfunction (POCD) is a common clinical phenomenon characterized by cognitive deficits in patients after anesthesia and surgery. Advanced age is a significant independent risk factor for POCD. We previously reported that in young mice, sleep–wake rhythm is involved in the isoflurane-induced memory impairment. In present study, we sought to determine whether advanced age increased the risk of POCD through aggravated and prolonged post-anesthetic circadian disruption in the elderly. We constructed POCD model by submitting the mice to 5-h 1.3% isoflurane anesthesia from Zeitgeber Time (ZT) 14 to ZT19. Under novel object recognition assay (NOR) and Morris water maze (MWM) test, We found 5-h isoflurane anesthesia impaired the cognition of young mice for early 3 days after anesthesia but damaged the aged for at least 1 week. With Mini-Mitter continuously monitoring, a 3.22 ± 0.75 h gross motor activity acrophase delay was manifested in young mice on D1, while in the aged mice, the gross motor activity phase shift lasted for 3 days, consistent with the body temperature rhythm trends of change. Melatonin has been considered as an effective remedy for circadian rhythm shift. In aged mice, melatonin was pretreated intragastrically at the dose of 10 mg/kg daily for 7 consecutive days before anesthesia. We found that melatonin prevented isoflurane-induced cognitive impairments by restoring the locomotor activity and temperature circadian rhythm via clock gene resynchronization. Overall, these results indicated that Long-term isoflurane anesthesia induced more aggravated and prolonged memory deficits and circadian rhythms disruption in aged mice. Melatonin could prevent isoflurane-induced cognitive impairments by circadian rhythm resynchronization.

Evaluation of a method for isocapnic hyperventilation: a clinical pilot trial.

Isocapnic hyperventilation (IHV) is a method that shortens time to extubation after inhalation anaesthesia using hyperventilation (HV) without lowering airway CO2 . In a clinical trial on patients undergoing long-duration sevoflurane anaesthesia for major ear-nose-throat (ENT) surgery, we evaluated the utility of a technique for CO2 delivery (DCO2 ) to the inspiratory limb of a closed breathing circuit, during HV, to achieve isocapnia. Fifteen adult ASA 1-3 patients were included. After end of surgery, mechanical HV was started by doubling baseline minute ventilation. Simultaneously, CO2 was delivered and dosed using a nomogram developed in a previous experimental study. Time to extubation and eye opening was recorded. Inspired (FICO2 ) and expired (FETCO2 ) CO2 and arterial CO2 levels were monitored during IHV. Cognition was tested pre-operatively and at 20, 40 and 60 min after surgery. A DCO2 of 285 ± 45 ml/min provided stable isocapnia during HV (13.5 ± 4.1 l/min). The corresponding FICO2 level was 3.0 ± 0.3%. Time from turning off the vaporizer (1.3 ± 0.1 MACage) to extubation (0.2 ± 0.1 MACage) was 11.3 ± 1.8 min after 342 ± 131 min of anaesthesia. PaCO2 and FETCO2 remained at normal levels during and after IHV. In 85% of the patients, post-operative cognition returned to pre-operative values within 60 min. In this cohort of patients, a DCO2 nomogram for IHV was validated. The patients were safely extubated shortly after discontinuing long-term sevoflurane anaesthesia. Perioperatively, there were no adverse effects on arterial blood gases or post-operative cognition. This technique for IHV can potentially be used to decrease emergence time from inhalation anaesthesia.

Cardiopulmonary effects of anaesthesia maintained by propofol infusion versus isoflurane inhalation in cheetahs (Acinonyx jubatus)

ObjectiveTo compare the cardiopulmonary effects of propofol total intravenous anaesthesia (TIVA) with isoflurane in cheetahs (Acinonyx jubatus) to evaluate feasibility for field use. Study designProspective clinical study. AnimalsA group of 24 adult cheetahs, 12 per group. MethodsCheetahs were immobilized with zolazepam/tiletamine (1.2 mg kg−1) and medetomidine [40 μg kg−1, both intramuscular (IM)] by darting. A maintenance protocol of propofol TIVA (group P) or isoflurane inhalation (group I) was assigned randomly to each cheetah. Anaesthesia was maintained for at least 60 minutes. Cheetahs breathed spontaneously throughout; oxygen was supplemented at 3 L minute−1. Cardiopulmonary parameters were recorded at 5 minute intervals and three arterial blood gas samples were analysed. Following maintenance, atipamezole was administered IM (200 μg kg−1) and recovery was observed. Data are reported as mean±standard deviation; variables over time were compared using a linear mixed model (fixed: time, treatment; random: cheetah). ResultsLack of response to manipulations was maintained in all cases (end-tidal isoflurane percentage 1.1±0.1%, propofol rate maintained at 0.1 mg kg−1 minute−1). The heart and respiratory rates were acceptable throughout maintenance. The end-tidal carbon dioxide tension increased slowly [44.0±5.0 mmHg (5.87±0.67 kPa)] with no differences between groups. All cheetahs were initially markedly hypertensive [mean arterial blood pressure (MAP): (163±17 mmHg)]. The MAP normalized for group I (125±30 mmHg) but remained high for group P (161±17 mmHg) (p < 0.001). Arterial carbon dioxide tension [48.9±14.6 mmHg (6.52±1.95 kPa)] never differed between groups. Initial arterial oxygen tension indicated borderline hypoxaemia, but improved with oxygen supplementation. Recovery time was 10.8±5.0 and 51.9±23.5 minutes for group I and group P, respectively. Conclusions and clinical relevanceBoth protocols provided acceptable cardiopulmonary values. Propofol may be an alternative to isoflurane for field use, but the prolonged recovery may make it less suitable for long-term anaesthesia.

Premedication with fentanyl-midazolam improves sevoflurane anesthesia for surgical intervention in laboratory mice.

Balanced anesthesia allows for a reduced dosage of each component, while inducing general anesthesia of sufficient depth with potentially fewer side effects. Here, we compare two anesthetic protocols combining sevoflurane anesthesia with pre-medication (ketamine [K] or fentanyl-midazolam [FM]) to a sevoflurane monoanesthesia (S) concerning their ability to provide reliable anesthesia suitable for moderate surgery in laboratory mice. Twenty-one female C57BL/6J mice assigned randomly to one of three protocols underwent a 50-min anesthesia and a sham embryo transfer. Heart rate and core body temperature were continuously recorded by telemetry intra-operatively and for three days pre- and three days post-surgery. Intra-operative respiratory rate was determined by counting thorax movements. Body weight, food, and water intake were measured daily for three days pre- and three days post-surgery. The heart rate in the KS group remained at baseline level throughout the 50-min of anesthesia and surgery. FMS caused a lower heart rate and S alone caused a higher heart rate compared to baseline values. Intra-operative body temperature was at baseline levels in all groups. A decreased respiratory rate was observed in all groups compared to baseline values obtained from resting mice of the same strain, sex and age-distribution. Surgical stimuli induced no significant changes in heart rate and respiratory rate in the KS or FMS group but significant respiratory alteration in the S group compared to baseline values obtained 10 s before applying the stimulus. Post-operative heart rate was above baseline values in all groups; with a significant deviation in the S group. There were no changes in body weight, food, and water intake. In summary, FMS was superior to KS and S for moderate surgery in laboratory mice resulting in less inter-individual variability in response to painful stimuli. Fentanyl and midazolam reduced the depressant effect of sevoflurane on the respiratory rate and the negative post-anesthetic effects on the heart rate. Impact statement With approximately 65 million animals used per year mice are still the most prevalent laboratory mammal species worldwide. In course of biomedical research projects approximately 40% of mice will undergo one or more short or long-term anesthesia. Sufficient anesthetic depth, cardiovascular stability, adequate analgesia, and short recovery times are essential requirements of anesthetic protocols to meet animal welfare. Anesthesia in mice and rats are only to be performed by personnel with appropriate basic training and experience. However, more and more adapted and advanced anesthetic protocols, required to answer very specific scientific questions, often exceed the skills acquired through basic training and present a major challenge to researchers. It is therefore of great importance to further develop and evaluate safe and reliable anesthetic protocols as presented in this study to provide new perspectives on this challenging problem.

CONTINUOUS INTRAVENOUS INFUSION ANESTHESIA WITH MEDETOMIDINE, KETAMINE, AND MIDAZOLAM AFTER INDUCTION WITH A COMBINATION OF ETORPHINE, MEDETOMIDINE, AND MIDAZOLAM OR WITH MEDETOMIDINE, KETAMINE, AND BUTORPHANOL IN IMPALA (AEPYCEROS MELAMPUS).

In order to develop a long-term anesthesia for flighty antelope species in field situations, two different protocols for induction and maintenance with an intravenous infusion were evaluated in wild-caught impala ( Aepyceros melampus ). Ten adult female impala were induced with two induction protocols: one consisted of 0.2 mg/kg medetomidine, 4 mg/kg ketamine, and 0.15 mg/kg butorphanol (MKB) and one consisted of 0.375 mg/kg etorphine, 0.2 mg/kg medetomidine, and 0.2 mg/kg midazolam (EMM). In both treatments, anesthesia was maintained with a continuous intravenous infusion (CII) at an initial dose rate of 1.2 μg/kg per hr medetomidine, 2.4 mg/kg per hr ketaminen and 36 μg/kg per hr midazolam. Partial reversal was achieved with naltrexone (2 : 1 mg butorphanol; 20 : 1 mg etorphine) and atipamezole (5 : 1 mg medetomidine). Evaluation of anesthesia included respiratory rate, heart rate, rectal temperature, arterial blood pressure, oxygen saturation, end tidal carbon dioxide tension, and tidal volume at 5-min intervals, palpebral reflex and response to painful stimuli at 15-min intervals, and arterial blood gases at 30-min intervals. Plasma cortisol concentration was determined after induction and before reversal. Duration and quality of induction and recovery were evaluated. EMM caused a faster induction of 9.5 ± 2.9 min compared to 11.0 ± 6.4 min in MKB. Recovery was also quicker in EMM (EMM: 6.3 ± 5.4 min; MKB: 9.8 ± 6.0 min). However, EMM also produced more cardiopulmonary side effects, including hypoxemia and hypercapnia, and calculated oxygenation indices (PaCO2-PETCO2) were worse than in MKB. One animal died after induction with EMM. The CII provided surgical anesthesia in 7 of 10 animals in MKB and in 9 of 9 animals in EMM for 120 min. In conclusion, the MKB induction protocol had advantages for prolonged anesthesia in impala with significantly less cardiopulmonary depression compared to EMM. The comparably decreased anesthetic depth could easily be adjusted by an increase of the CII.