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General anesthesia is characterized by reversible loss of consciousness accompanied by transient amnesia. Yet, long-term memory impairment is an undesirable side effect. How different types of general anesthetics (GAs) affect the hippocampus, a brain region central to memory formation and consolidation, is poorly understood. Using extracellular recordings, chronic 2-photon imaging, and behavioral analysis, we monitor the effects of isoflurane (Iso), medetomidine/midazolam/fentanyl (MMF), and ketamine/xylazine (Keta/Xyl) on network activity and structural spine dynamics in the hippocampal CA1 area of adult mice. GAs robustly reduced spiking activity, decorrelated cellular ensembles, albeit with distinct activity signatures, and altered spine dynamics. CA1 network activity under all 3 anesthetics was different to natural sleep. Iso anesthesia most closely resembled unperturbed activity during wakefulness and sleep, and network alterations recovered more readily than with Keta/Xyl and MMF. Correspondingly, memory consolidation was impaired after exposure to Keta/Xyl and MMF, but not Iso. Thus, different anesthetics distinctly alter hippocampal network dynamics, synaptic connectivity, and memory consolidation, with implications for GA strategy appraisal in animal research and clinical settings.

Medetomidine, a veterinary α2-adrenergic agonist, has recently emerged as an adulterant in the non-medical opioid supply, yet human exposure has remained poorly characterized. We conducted a pragmatic retrospective cohort analysis utilizing chart review and liquid chromatography–tandem mass spectrometry (LC-MS/MS) toxicology testing on available urine samples from patients presenting to two hospitals in Philadelphia, PA, who fit two clinical phenotypes, intoxication or withdrawal. Samples also underwent glucuronidase pre-treatment to assess impact on the yield of medetomidine and xylazine metabolite detection. Testing identified universal exposure to medetomidine (58/58 samples) via the 3-hydroxy-medetomidine (3-OH-M) metabolite, post glucuronidase treatment and variable xylazine exposure (40/58 samples). Importantly, 32% of medetomidine exposures would have been missed without enzymatic pre-treatment. Patients exhibited two distinct clinical phenotypes: intoxication, characterized primarily by sedation; bradycardia; and often hypotension, and withdrawal, presenting with life-threatening tachycardia; hypertension and often encephalopathy. Notably, clinical phenotype correlated with urinary concentrations of 3-OH-M but not xylazine. These findings underscore the critical need for heightened clinical awareness and need for contemporaneous toxicologic screening mechanisms for medetomidine exposure, emphasizing its distinct clinical presentations and the potential public health implications posed by its widespread adulteration in illicit opioids.

Background Alpha2-adrenoceptor agonists such as medetomidine induce hyperglycemia, glucosuria, and polyuria. We evaluated the ability of vatinoxan, a peripherally acting alpha2-adrenoceptor antagonist, to mitigate these side effects in male Wistar rats ( N  = 31). To explore its impact on two common sedation protocols in laboratory rats, a randomized, controlled experimental study was conducted comprising four groups: medetomidine (0.25 mg/kg) and midazolam (2.0 mg/kg) (MM; N  = 8), MM + fentanyl (0.01 mg/kg) (MMF; N  = 8), MM vatinoxan (MMV; N  = 7), and MMF + vatinoxan (MMFV; N  = 8). Blood glucose concentration (BG) was measured repeatedly between 10 and 60 min after treatment administration, and total urine output and body weight change were assessed. Additionally, urine glucose concentration (UG) was measured at 45 and 75 min. Results Pooled BG was significantly higher in non-vatinoxan treated rats [19.8 ± 3.6 mmol/L (mean ± SD) with MM + MMF compared with 10.3 ± 1.2 mmol/L with MMV + MMFV] ( P  < 0.001). Similarly, urine output was greater without vatinoxan [median 22.9 (minimum–maximum) 10.6–32.9) vs. 2.8 (0.0–7.4) ml/kg/h] ( P  < 0.001). Vatinoxan also reduced UG [33.3 (0.6–33.3) vs. 1.4 (0.9–3.2) mmol/L] ( P  < 0.01) and body weight loss. Fentanyl did not significantly alter these outcomes. Rats were sufficiently sedated after all treatments. Conclusions The findings demonstrate that vatinoxan effectively mitigates hyperglycemia, polyuria and glucosuria induced by medetomidine-based sedation protocols in adult, male Wistar rats.

Background This study evaluated the influence of repeated anaesthesia using isoflurane (ISO, 2–3 Vol%), ketamine-xylazine (KX, 100 mg·kg −1  + 5 mg·kg −1 , i.m.) or a combination of medetomidine-midazolam-fentanyl (MMF, 0.15 mg·kg −1  + 2.0 mg·kg −1  + 0.005 mg·kg −1 , i.m.) on heart rate (HR), arterial blood pressure (BP), body temperature (BT), duration of anaesthetic intervals and body weight (BW) in Wistar rats. Rats were instrumented with a telemetric system for the measurement of systolic, diastolic and mean arterial pressure (SAP, DAP, MAP), pulse pressure (PP), HR and BT during induction, maintenance and recovery of anaesthesia. Each anaesthesia was performed six times within three weeks. KX was not antagonized, but ISO delivery was terminated 40 minutes after induction and MMF was reversed with atipamezole-flumazenil-naloxone (AFN, 0.75 mg·kg −1  + 0.2 mg·kg −1  + 0.12 mg·kg −1 , s.c.). Results With repeated anaesthesia, ISO showed a decrease of HR and BP. A significant decrease of PP could be observed with repeated anaesthesia using MMF. HR and BP were not affected by repeated KX anaesthesia, but we noted a reduction of sleeping time and BW. Neither MMF nor ISO showed significant differences in the duration of anaesthetic intervals and BW. With KX we observed tissue necrosis at the injection site and surgical tolerance was not achieved in 25% of the anaesthesias performed. Conclusion HR, BP values, BT, duration of anaesthetic intervals and BW were affected differently by repeated anaesthesia performed with ISO, KX or MMF. ISO produced a reproducible anaesthesia, thereby being suitable for repeated use, but with a decrease of HR and BP throughout the six anaesthesias. The use of ISO in cases where these parameters should be unaffected is therefore not advised. The inability to produce a surgical tolerance, the reduction of sleeping time and BW, as well as the tissue necrosis are significant contraindications for a repeated use of KX. Only mild changes of BP were found with repeated MMF anaesthesia, so it seems suitable for serial use, unless the high BP and the low HR during the surgical plane of anaesthesia are undesirable for a special procedure.

We conducted thirteen immobilizations of previously collared hibernating two- to four-year-old brown bears (Ursus arctos) weighing 21-66 kg in central Sweden in winter 2010 and 2011 for comparative physiology research. Here we report, for the first time, an effective protocol for the capture and anesthesia of free-ranging brown bears during hibernation and an assessment of the disturbance the captures caused. Bears were darted in anthill, soil, or uprooted tree dens on eleven occasions, but two bears in rock dens fled and were darted outside the den. We used medetomidine at 0.02-0.06 mg/kg and zolazepam-tiletamine at 0.9-2.8 mg/kg for anesthesia. In addition, ketamine at 1.5 mg/kg was hand-injected intramuscularly in four bears and in six it was included in the dart at 1.1-3.0 mg/kg. Once anesthetized, bears were removed from the dens. In nine bears, arterial blood samples were analyzed immediately with a portable blood gas analyzer. We corrected hypoxemia in seven bears (PaO(2) 57-74 mmHg) with supplemental oxygen. We placed the bears back into the dens and antagonized the effect of medetomidine with atipamezole. Capturing bears in the den significantly increased the risk of den abandonment. One of twelve collared bears that were captured remained at the original den until spring, and eleven, left their dens (mean ± standard deviation) 3.2±3.6 (range 0.5-10.5) days after capture. They used 1.9±0.9 intermediate resting sites, during 6.2±7.8 days before entering a new permanent den. The eleven new permanent dens were located 730±589 m from the original dens. We documented that it was feasible and safe to capture hibernating brown bears, although they behaved differently than black bears. When doing so, researchers should use 25% of the doses used for helicopter darting during the active period and should consider increased energetic costs associated with den abandonment.

Arrhythmias are critical contributors to cardiovascular morbidity and mortality. Therapies are mainly symptomatic and often insufficient, emphasizing the need for basic research to unveil the mechanisms underlying arrhythmias and to enable better and ideally causal therapies. In translational approaches, mice are commonly used to study arrhythmia mechanisms in vivo. Experimental electrophysiology studies in mice are performed under anesthesia with medetomidine/midazolam/fentanyl (MMF) and isoflurane/fentanyl (IF) as commonly used regimens. Despite evidence of adverse effects of individual components on cardiac function, few data are available regarding the specific effects of these regimens on cardiac electrophysiology in mice. Here we present a study investigating the effects of MMF and IF narcosis on cardiac electrophysiology in vivo in C57BL/6N wild-type mice. Telemetry transmitters were implanted in a group of mice, which served as controls for baseline parameters without narcosis. In two other groups of mice, electrocardiogram and invasive electrophysiology studies were performed under narcosis (with either MMF or IF). Basic electrocardiogram parameters, heart rate variability parameters, sinus node and atrioventricular node function, and susceptibility to arrhythmias were assessed. Experimental data suggest a remarkable influence of MMF on cardiac electrophysiology compared with IF and awake animals. While IF only moderately reduced heart rate, MMF led to significant bradycardia, spontaneous arrhythmias, heart rate variability alterations as well as sinus and AV node dysfunction, and increased inducibility of ventricular arrhythmias. On the basis of these observed effects, we suggest avoiding MMF in mice, specifically when studying cardiac electrophysiology, but also whenever a regular heartbeat is required for reliable results, such as in heart failure or imaging research.Tomsits and colleagues investigated the effects of medetomidine/midazolam/fentanyl and isoflurane/fentanyl narcosis on murine cardiac autonomic nervous activity and electrophysiology. The results show that, compared with medetomidine/midazolam/fentanyl narcosis, isoflurane/fentanyl narcosis seems to have no effect on cardiac autonomic nervous function and less influence on cardiac electrophysiology.

Two hundred and twelve dogs were treated either intravenously or intramuscularly with either dexmedetomidine or medetomidine in a randomised double-blinded multicentre clinical study during procedures such as dental care, radiography and otitis treatment. Sedative, analgesic and cardiorespiratory parameters and body temperature were assessed for three hours after the treatments. Approximately half the dogs were given atipamezole intramuscularly after the completion of the procedure, and the other dogs were allowed to recover spontaneously. Dexmedetomidine and medetomidine induced similar clinical effects, and the procedure was completed successfully in 97 per cent of cases. There were few adverse side effects, but they included prolonged sedation, hypothermia, apnoea and bradycardia; no adverse effects were observed after the administration of atipamezole, which effectively reversed all the clinical effects of dexmedetomidine and medetomidine.

For treatment of hypoxemia, delivery of the minimum effective oxygen flow rate is advantageous during field anesthesia because it prolongs the life of the oxygen cylinder. Portable oxygen concentrators as the oxygen source require less logistical considerations than cylinders and are a safer alternative during helicopter field work because they are nonexplosive devices. The objective of this study was to evaluate low oxygen flow rates by continuous or pulsed intranasal delivery for treatment of hypoxemia in anesthetized white-tailed deer (Odocoileus virginianus). Nine captive adult female deer (body mass 56–72 kg) were physically restrained in a drop-floor chute and hand injected intramuscularly with medetomidine (0.1–0.14 mg/kg) and ketamine (2.5–4.3 mg/kg). Intranasal oxygen was delivered from an oxygen cylinder at continuous flow rates of 1 and 2 L/min or from a battery driven oxygen concentrator (EverGoTM Portable Oxygen Concentrator, Respironics®) with pulse-dose delivery (maximum capacity of 1.05 L/min). The pulse-dose setting (pulse volume 12–70 ml) was adjusted according to the respiratory rate. Arterial blood gases were analyzed before, during, and after O2 supplementation. A 10-min washout period was allowed between treatment groups. All three treatments adequately treated hypoxemia. The partial pressure of arterial oxygenation increased significantly from baseline values of 55 ± 10 to 115 ± 31 mm Hg during supplementation from the oxygen concentrator, to 138 ± 21 mm Hg during supplementation from the oxygen cylinder at 1 L/min, and to 201 ± 42 mm Hg at 2 L/min. In conclusion, low flow rates of intranasal oxygen supplemented continuously from an oxygen cylinder or by pulsed delivery from a portable oxygen concentrator effectively treated hypoxemia in anesthetized white-tailed deer.

The objective of this study was to gain better insight into factors associated with the capture-related mortality rate in cheetahs. A link to an online questionnaire was sent to zoo and wildlife veterinarians through the Species Survival Plan Programme and European Endangered Species Programme coordinators and via the ‘Wildlife VetNet’ Google group forum. The questionnaire consisted of 50 questions relating to the veterinarians’ country of residence and experience, the medicine combinations used, standard monitoring procedures, capture-related complications and mortalities experienced in this species under different capture conditions. In addition, necropsy data from the national wildlife disease database of the National Zoological Gardens of South Africa were examined for cases where anaesthetic death was listed as the cause of death in cheetahs. A total of 75 veterinarians completed the survey, with 38 from African countries and a combined total of 37 from Europe, the United States (US) and Asia. Of these, 24% (n = 18/75) had experienced at least one capture-associated cheetah mortality, with almost all of the fatalities (29/30) reported by veterinarians working in Africa. A lack of anaesthetic monitoring and the absence of supplemental oxygen were shown to be significant risk factors for mortality. Hyperthermia, likely to be associated with capture stress, was the most common reported complication (35%). The results suggest that free-ranging rather than habituated captive cheetahs are particularly at risk of dying during immobilisation and transport. The capture-related fatalities in this species do not appear to be associated with either the veterinarian’s level of clinical experience or the immobilisation agents used.

Physiologic variables during anesthesia with medetomidine–zolazepam–tiletamine were evaluated in 52 free-ranging brown bears (Ursus arctos) darted from a helicopter and in six captive brown bears darted at a zoo. During anesthesia, rectal temperature, respiratory rate, heart rate, and pulse oximetry derived hemoglobin oxygen saturation were recorded. Arterial blood samples were collected and immediately analyzed for evaluation of pulmonary gas exchange, acid–base status, and selected hematologic and plasma variables. At the end of anesthesia, atipamezole was administered intramuscularly at five times the medetomidine dose. Capture-induced hyperthermia and lactic acidemia were documented in free-ranging bears. Hypoxemia during anesthesia was documented in both free-ranging and captive bears. In free-ranging bears, rectal temperature, heart rate, lactate, hematocrit, and hemoglobin decreased significantly during anesthesia, whereas partial pressure of arterial carbon dioxide, pH, potassium, and glucose increased. Yearlings had a significantly higher heart rate, pH, base excess, bicarbonate, and glucose, and had a significantly lower rectal temperature, sodium, hematocrit, and hemoglobin when compared with subadult and adult brown bears. In conclusion, alterations in pulmonary gas exchange and acid–base status in brown bears during anesthesia with medetomidine–zolazepam–tiletamine with the doses and capture methods used in this study were identified. Oxygen supplementation is recommended to counteract hypoxemia during anesthesia.