Halothane Anesthesia Research Articles

Long-term functional change of cryoinjury-induced detrusor underactivity and effects of extracorporeal shock wave therapy in a rat model.

To investigate the long-term functional change of cryoinjury-induced detrusor underactivity (DU) and the therapeutic potential of repeated low-energy shock wave therapy (LESW). Fifty-six female Sprague-Dawley rats were assigned into sham and cryoinjury of bladder with or without LESW (0.05 or 0.12mJ/mm2; 200 pulses; twice a week for 2weeks after cryoinjury). Under halothane anesthesia, an incision was made in lower abdomen, and cryoinjury was provoked by bilateral placement of a chilled aluminum rod on the bladder filled with 1ml saline. Measurement of contractile responses to KCl and carbachol in vitro, conscious voiding, and histological and protein changes were performed on week 1, 2, and 4 after cryoinjury. Cryoinjury of bladder induced a significant decrease in the detrusor contraction amplitude at week 1 (55.0%) and week 2 (57.2%), but the decrease in the contractile response to KCl and carbachol was only noted at week 1. At week 1, significantly increased COX-2 and TGF-β1 expression accompanied a decrease of VEGF and CGRP expression. At week 4, there was a partial recovery of voiding function and a significant increase in the Ki-67 staining. LESW treatment at higher energy level further amplified the Ki-67 staining and improved the recovery of contraction amplitude and the expression of TGF-β1 and VEGF. Cryoinjury of detrusor induces DU/UAB with functional impairment lasting for up to 4weeks, but the associated molecular changes are restored by 2weeks. LESW improved bladder wall composition, and hastened functional recovery from cryoinjury.

Characterization of microminipig as a laboratory animal for safety pharmacology study by analyzing fluvoxamine-induced cardiovascular and dermatological adverse reactions.

Fluvoxamine is a selective serotonin-reuptake inhibitor, of which IC50 values for serotonin- and noradrenaline-uptake process were reported to be 3.8 and 620nmol/L, respectively, also known to directly inhibit cardiac Na+, Ca2+, and K+ channels. We characterized microminipig as a laboratory animal by analyzing fluvoxamine-induced cardiovascular and dermatological responses under halothane anesthesia. Fluvoxamine maleate was infused in doses of 0.1, 1, and 10mg/kg over 10min with a pause of 20min (n = 4). The peak plasma concentrations were 35, 320, and 1906ng/mL, of which free plasma concentrations were estimated as 20, 187, and 1108nmol/L, respectively. The low and middle doses did not alter any cardiovascular variable. The high dose increased heart rate and mean blood pressure, prolonged QRS width, but shortened QT interval, whereas no significant change was detected in PR interval or QTcF. Moreover, it induced systemic erythema on the skin. Pretreatment of H1/5-HT2A antagonist cyproheptadine hydrochloride sesquihydrate in a dose of 0.3mg/kg significantly attenuated the fluvoxamine-induced pressor response; but tended to further enhance sinus automaticity, atrioventricular nodal conduction; and ventricular repolarization in addition to intraventricular conduction delay; whereas it markedly suppressed onset of systemic erythema (n = 4). In microminipigs, cardiovascular adverse effects of the high dose may be manifested as a sum of its inhibitory action on the cardiac ionic channels and its stimulatory effects on serotonergic and adrenergic systems, whereas dermatologic reaction can be induced primarily through H1/5-HT2A receptor-dependent mechanism. Thus, microminipigs may be used for analyzing such multifarious adverse events of clinical serotonergic pharmacotherapy.

Life-threatening Episodes of Malignant Hyperthermia Following Halothane Anesthesia in Three Children: A Case Series and Review of Literature.

ABSTRACTMalignant hyperthermia (MH) is an inherited, pharmacogenetic disorder of the skeletal muscle, characterized by dangerous hypermetabolic state after anesthesia with succinylcholine and/ or volatile halogenated anesthetic agents, clinically manifested as hyperpyrexia and related complications like tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, rigid muscles, rhabdomyolysis and disseminated intravascular coagulation (DIC). Here we present a series of three cases of MH, admitted in our hospital in a span of 8 months for three different operative procedures to be done under general anesthesia (cleft lip repair, Duhamel's operation for Hirschsprung's disease and surgical repair of development dysplasia of hip), who developed probable hyperthermia owing to Halothane being used as an anesthetic agent.How to cite this articleLaha S, Giri PP, Saha A, Gupta PP, De A. Life-threatening Episodes of Malignant Hyperthermia Following Halothane Anesthesia in Three Children: A Case Series and Review of Literature. Indian Journal of Critical Care Medicine, January 2019;23(1):47-50.

Simulations of general anaesthetics in membranes at raised pressures: the search for mechanisms for pressure reversal of general anaesthetics

ABSTRACT Experiments have shown that general anaesthetics lose their efficacy at pressures of around 20 MPa, but their efficacy is recovered at pressures of around 40 MPa. Molecular dynamics simulations of the general anaesthetic halothane in DMPC or POPC bilayers show that halothane aggregates inside the membrane at 20 MPa, but not at atmospheric pressure, nor at 40 MPa. The parallelism in effects suggests that aggregation could conceivably be the mechanism for pressure reversal. Further molecular dynamics simulations of another general anaesthetic, isoflurane, in POPC show that isoflurane does not aggregate at 20 MPa. This and other quantitative considerations show that general anaesthetic aggregation inside the membrane could not be the mechanism for pressure reversal.

Charles Walter Suckling. 24 July 1920—30 October 2013

Charles Walter Suckling (1920–2013) is most remembered for being the discoverer of the inhalant anaesthetic halothane, which revolutionized anaesthesia and surgical practice. He was born in Teddington, Middlesex, but grew up largely in Wallasey, Merseyside, where his father was a cargo superintendent for imports from Australia produced by one of Charles’s maternal uncle's cooperatives. Charles was educated at Oldershaw Grammar School, Wallasey, and the University of Liverpool, where he obtained a first class honours degree in chemistry (1942). With this qualification he was directed to carry out national service in the chemical industry at ICI in Widnes and was subsequently able to obtain a scholarship to work towards a PhD at the University of Liverpool (1949), which he was awarded for the structural elucidation of the natural product santal, by classical organic chemical methods. The project leading to the discovery of halothane was begun in 1951 at ICI's Widnes Laboratory and was one of the first examples of rational drug design; halothane reached clinical practice in 1956. This and other industrial research innovations were recognized by his election to the Fellowship of the Royal Society in 1978. Charles’s career at ICI took him into both scientific and commercial management roles, including chairman of Paints Division and general manager of Research and Technology, a company-wide brief at head office, Millbank. After retiring from ICI (1982) he undertook many public service and charitable tasks, including membership of the Royal Commission on Environmental Pollution, for which he was awarded the CBE, and positions on the councils of the Royal College of Anaesthetists and Royal College of Art and Design. Charles retired from professional life fully in 2001. In 1946 he married Eleanor Margaret Watterson; their family comprised twin sons, both of whom became professional scientists, and a daughter, who became a medical doctor. Charles died at Knebworth, Hertfordshire, in 2013.

Use of microminipigs for unveiling unknown mechanisms of azithromycin-induced cardiovascular death

Although azithromycin can suppress cardiac INa, IKr, IKs, ICa,L and IK1, its onset mechanisms for cardiovascular death have not been fully investigated. We examined electropharmacological effects of azithromycin in intravenous doses of 0.3, 3 and 30 mg/kg using microminipigs under the halothane anesthesia (n = 4), which provided plasma concentrations of 3.1, 11.2 and 120.4 μg/mL, respectively. The low dose did not alter any of the cardiohemodynamic or electrocardiographic variables. The middle dose significantly shortened QT interval for 10–20 min and QTc for 10–30 min. The high dose significantly decreased mean blood pressure for 5–60 min, prolonged QRS width at 20 min, but shortened QT interval for 15–20 min and QTc for 15–30 min (n = 3). Cardiohemodynamic collapse occurred in 1 animal after the start of the high dose infusion, which might be associated with the cardiovascular death in patients with vasomotor dysfunction. Prolongation of QRS width indicates that azithromycin may suppress ventricular INa in vivo, which may unmask latent type of Brugada electrocardiographic genotype. Meanwhile, abbreviation of the QTc might cause potentially lethal, short QT-related, cardiac arrhythmia syndrome. These findings with microminipigs suggest the possible entry point for analyzing the mechanisms of cardiovascular death clinically seen with this antibiotic.

Comparison of effects of serine racemase knockout on nociceptive behavior among different models of neuropathic and inflammatory pain

Peripheral nerve injury and tissue inflammation often induce abnormal pain. The activation of N‐methyl‐D‐aspartate (NMDA) receptors mediates the development and maintenance of such abnormal pain. D‐serine co‐localizes with NMDA receptors and acts as an endogenous co‐agonist of the NMDA receptor at the glycine binding site. D‐serine is synthesized from L‐serine by serine racemase (SR), which is an enzyme that is abundant in the central nervous system. It remains unclear how alterations in SR activity are involved in modulation of neuropathic and inflammatory pain behavior. In the present investigation, we compared pain behaviors in SR knockout (KO) mice and wild‐type (WT) mice after subjection to a chronic constriction injury (CCI model of Bennett), partial sciatic nerve ligation (PSL model of Seltzer), spinal nerve ligation (SNL model of Chung), and an inflammatory pain model that was induced by subcutaneous formalin.Seven‐ to nine‐week‐old male WT and SR‐KO mice were used for the experiments. Under halothane anesthesia, the mice were subjected to neuropathic surgery. Three types of nerve ligation were performed, as previously described by Bennett et al. (1988), Kim and Chung (1992), and Seltzer et al. (1990). The left sciatic nerve was tied loosely with four ligatures of chromic gut at the mid‐thigh level (Bennett model), the left L5 and L6 spinal nerves were isolated and ligated tightly with a 4‐0 silk thread (Chung model), and the dorsal one‐third to one‐half of the left sciatic nerve was tightly ligated (Seltzer model). Mechanical allodynia was assessed by measuring the frequency of withdrawal responses using von Frey filaments both before and after ligation. To induce inflammatory pain, paraformaldehyde (50 μL, 25% in distilled water) was injected subcutaneously in the dorsal surface of the left hind paw. The mice were continuously observed for 60 min after the formalin injection, and the number of flinches of the injected paw was measured during the observation period.Behavioral observations showed the following results: 1) The second phase of the formalin‐induced licking response was augmented in SR‐KO mice, while the first phase was not; 2) mechanical allodynia in the Seltzer model was quite similar between SR‐KO mice and WT mice; 3) mechanical allodynia in both the Chung and Bennett models was significantly augmented in SR‐KO mice compared with WT mice.The mechanisms of the presently observed different effects of SR knockout on different pain models are unclear. We are currently investigating how differently synaptic circuit activity in the spinal dorsal horn is affected by SR knockout in different pain models.Support or Funding InformationDokkyo Med Univ Mutual FundThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Antinociceptive effects of epidural tramadol administration in dogs as an anlagesic for experimental stifle surgery

Tramadol is a centrally acting analgesic with m -opioid and monoaminergic agonist effect. Ten healthy adult dogs were studied (mean ± SEM body weight 17.3 ± 3.8 kg), premedicated with acepromazine (0.05 mg/kg, IM), induced with thiopental (10 mg/kg, IV) and maintained under anesthesia with halothane in oxygen. Twenty minutes after starting halothane anesthesia, tramadol (1.0 mg/kg in 0.22 ml/kg of sterile water) was administered epidurally at the lumbo-sacral space. Surgery began 15 minutes later. Pulse and respiratory rates, systolic, mean and diastolic arterial blood pressure, and pulse oximetry were measured before premedication (baseline), and at fixed intervals after anesthesia induction. Arterial pH, PaO 2 , PaCO 2 , HCO 3 - , and SaO 2 were measured at baseline, immediately before the epidural, and 60, 120, 240 and 360 minutes thereafter. Post-operative analgesia was evaluated for four hours using a scoring system. Statistically significant decrease in arterial blood pressure was observed following anesthetic induction. The PaCO 2 increased significantly from baseline at 60 minutes after epidural tramadol. The remaining variables were not significantly different from baseline values. No variables were significantly different from values obtained immediately before tramadol administration. Intraoperative antinociception was considered adequate, with satisfactory post-operative analgesia for four hours. In conclusion, epidural tramadol seems to produce satisfactory antinociception and analgesia without causing clinically significant hemodynamic and respiratory depression in healthy dogs undergoing stifle surgery.

Analysis of the analgesic effect and safety of dexmedetomidine combined with dorsal penile nerve block in children with circumcision

Objective To investigate the effect and safety of dexmedetomidine combined with dorsal penile nerve block for circumcision in children. Methods 130 children with circumcision were divided into the observation group and the control group according to the digital table, 65 cases in each group. The control group received total inhalation of seven halothane anesthesia, and the observation group received dexmedetomidine combined with dorsal penile nerve block anesthesia. The efficacy and safety of the two groups were compared. Results In the observation group after induction, the mean arterial pressure[(69.89±5.24)mmHg], awake and mean arterial pressure[(70.14±5.30)mmHg], rhythm of the heart after induction[(100.36±10.67)times/min], the rhythm of the heart when they woke up[(102.64±10.58)times/min], blood oxygen saturation after induction[(98.25±0.63)%], awake and blood oxygen saturation[(98.64±0.66)%]and other signs of vital signs had no statistically significant differences compared with the control group(F=0.130, 0.215, 0.548, 0.613, 0.106, 0.257, all P>0.05). In the observation group, the eyelash reflex disappearing time, operation time, awakening time were(23.16±2.13)s, (9.70±1.24)min, (10.03±1.27)min, respectively, which in the control group were(27.98±3.87)s, (11.88±2.87)min, (11.89±3.87)min, respectively, there were statistically significant differences between the two groups(t=8.797, 5.621, 6.633, all P<0.05). In the observation group, the postoperative agitation score, sedation score, pain score were(2.75±1.25)points, (1.11±0.13)points, (5.26±1.44)points, respectively, which in the control group were(6.78±2.89)points, (1.11±0.13)points, (8.97±3.64)points, respectively, there were statistically significant differences between the two groups(t=10.318, 17.236, 10.318, all P<0.05). Conclusion Application of dexmedetomidine combined with penile dorsal nerve block anesthesia in pediatric circumcision takes effect quickly, children with stable vital signs, less postoperative agitation, it is worthy of popularization and application in clinic. Key words: Circumcision, male; Penis; Nerve block; Dexmedetomidine; Child

Effects of halothane on the electroencephalogram of the chicken.

Little is known about the effects of inhalant anaesthetics on the avian electroencephalogram (EEG). The effects of halothane on the avian EEG are of interest, as this agent has been widely used to study nociception and analgesia in mammals. The objective of this study was to characterize the effects of halothane anaesthesia on the EEG of the chicken. Twelve female Hyline Brown chickens aged 8–10 weeks were anaesthetized with halothane in oxygen. For each bird, anaesthesia was progressively increased from 1–1.5 to 2 times the Minimum Anesthetic Concentration (MAC), then progressively decreased again. At each concentration, a sample of EEG was recorded after a 10‐min stabilization period. The mean Total Power (PTOT), Median Frequency (F50) and 95% Spectral Edge Frequency (F95) were calculated at each halothane MAC, along with the Burst Suppression Ratio (BSR). Burst suppression was rare and BSR did not differ between halothane concentrations. Increasing halothane concentration from 1 to 2 MAC resulted in a decrease in F50 and increase in PTOT, while F95 increased when MAC was reduced from 1.5 to 1. The results indicate dose‐dependent spectral EEG changes consistent with deepening anaesthesia in response to increasing halothane MAC. As burst suppression was rare, even at 1.5 or 2 times MAC, halothane may be a suitable anaesthetic agent for use in future studies exploring EEG activity in anaesthetized birds.

Regional knockdown of NDUFS4 implicates a thalamocortical circuit mediating anesthetic sensitivity.

Knockout of the mitochondrial complex I protein, NDUFS4, profoundly increases sensitivity of mice to volatile anesthetics. In mice carrying an Ndufs4lox/lox gene, adeno-associated virus expressing Cre recombinase was injected into regions of the brain postulated to affect sensitivity to volatile anesthetics. These injections generated otherwise phenotypically wild type mice with region-specific, postnatal inactivation of Ndufs4, minimizing developmental effects of gene loss. Sensitivities to the volatile anesthetics isoflurane and halothane were measured using loss of righting reflex (LORR) and movement in response to tail clamp (TC) as endpoints. Knockdown (KD) of Ndufs4 in the vestibular nucleus produced resistance to both anesthetics for movement in response to TC. Ndufs4 loss in the central and dorsal medial thalami and in the parietal association cortex increased anesthetic sensitivity to both TC and LORR. Knockdown of Ndufs4 only in the parietal association cortex produced striking hypersensitivity for both endpoints, and accounted for half the total change seen in the global KO (Ndufs4(KO)). Excitatory synaptic transmission in the parietal association cortex in slices from Ndufs4(KO) animals was hypersensitive to isoflurane compared to control slices. We identified a direct neural circuit between the parietal association cortex and the central thalamus, consistent with a model in which isoflurane sensitivity is mediated by a thalamic signal relayed through excitatory synapses to the parietal association cortex. We postulate that the thalamocortical circuit is crucial for maintenance of consciousness and is disrupted by the inhibitory effects of isoflurane/halothane on mitochondria.

Urodynamic and molecular characteristics of detrusor underactivity in a rat cryoinjury model and effects of low energy shock wave therapy.

Low energy shock wave (LESW) has been shown to facilitate tissue regeneration and reduce inflammation. We investigated the effects of LESW in an underactive (DU) model induced by cryoinjury of rat detrusor. Forty-six female Sprague-Dawley rats were divided into sham, cryoinjury with or without LESW (0.12 mJ/mm2 ; 200 pulses). Under halothane anesthesia, a low midline incision was made and a cryoinjury of detrusor was induced by placing an aluminum rod (chilled with dry ice) for 30 s on the serosal side of the bladder filled with 1 mL sterile saline bilaterally. Awake cystometrogram (CMG), molecular and histopathology studies were performed on Day 8 or 15 after cryoinjury. Significant urodynamic, histological, and molecular changes induced by cryoinjury of rat detrusor were detected on Day 8 and decrease in the contraction amplitude (54.3%), a significant increase in wet bladder weight (64.1%), edematous changes, muscle thinning and downregulation of α-SMA, IL-6, and upregulation of COX-2. LESW reversed the cryoinjury induced histological and COX-2 expression to cause a 49.0% increase in the contraction amplitude (P < 0.05). LESW induced cell proliferation was revealed by increased CD31 and Ki67 immunostaining. The effect of cryoinjury on urodynamic and histological changes was maintained till Day 15. The cryoinjury of rat detrusor models myogenic DU, which is partially reversed by LESW. LESW may afford a simple, non-invasive modality to facilitate tissue regeneration and improve voiding function in myogenic detrusor underactivity.

Resolving the contributions of anaesthesia, surgery, and nerve injury on brain derived neurotrophic factor expression in the medial prefrontal cortex of male rats in the CCI model of neuropathic pain.

The medial prefrontal cortex (mPFC) is critical for selecting and shaping complex behavioral responses. In rodent models of neuropathic pain there is evidence for both structural and functional changes in the mPFC. Brain derived neurotrophic factor (BDNF) plays a critical role in the normal functioning of the mPFC. It has been suggested that the disruption of complex behaviors and mood seen in some neuropathic pain patients is mediated in part by alterations of BDNF in this cortical region. In Sprague-Dawley rats, mPFC levels of BDNF and TrkB mRNA and protein, were quantified and compared to controls (n = 24) 6 days after either: (a) halothane (1.5%) anaesthesia (n = 12), (b) sham surgery under halothane (n = 12), (c) sciatic nerve chronic constriction injury under halothane (n = 48). The social behaviors of the rats were quantified daily during the experimental period. Halothane anaesthesia increased BDNF and TrkB mRNA bilaterally. These increases were reversed in rats that underwent sham surgical and nerve injury procedures. Further, halothane anaesthesia, surgical procedures, and nerve injury each decreased BDNF protein levels. These results reveal a marked and distinct BDNF expression profile in the mPFC of rats that have undergone each stage of the procedure to produce neuropathic pain by chronic constriction injury of the sciatic nerve. The highly sensitive nature of neurotrophic signalling to general anaesthesia in the mature neuronal circuit of the adult rat brain highlights the importance of careful evaluation and interpretation of data evaluating the effects of experimental procedures on neural substrates.

Retrograde Naso-Tracheal Intubation Using a Cook Retrograde Intubation Set: A Case Report

Endotracheal intubation in patients with limited mouth opening always remains a challenge, especially in the absence of flexible fibre optic bronchoscope. The retrograde catheter technique is an accepted option for airway management in cases where oral intubation is not possible because of limited mouth opening or not recommended because of fear of dislodgement of fracture segments or facial bones. We performed retrograde nasal intubation in a patient with complicated bilateral mandibular fracture from gunshot injury, using the Cook retrograde intubation set. This procedure was performed on a 51-year-old farmer victim of gunshot injury with communited fracture of the mandible, and consequent limited mouth opening from previous emergency surgery. Difficult airway tray, and the Cook retrograde intubation set was assembled. Retrograde nasal intubation was successfully performed under deep inhalational halothane anesthesia, with preservation of the patient’s respiratory effort, using the Cook retrograde intubation set.

Background activity and visual responsiveness of caudate nucleus neurons in halothane anesthetized and in awake, behaving cats

This study focuses on the important question whether brain activity recorded from anesthetized, paralyzed animals is comparable to that recorded from awake, behaving ones. We compared neuronal activity recorded from the caudate nucleus (CN) of two halothane-anesthetized, paralyzed and two awake, behaving cats. In both models, extracellular recordings were made from the CN during static and dynamic visual stimulation. The anesthesia was maintained during the recordings by a gaseous mixture of air and halothane (1.0%). The behaving animals were trained to perform a visual fixation task. Based on their electrophysiological properties, the recorded CN neurons were separated into three different classes: phasically active (PANs), high firing (HFNs), and tonically active (TANs) neurons. Halothane anesthesia significantly decreased the background activity of the CN neurons in all three classes. The anesthesia had the most remarkable suppressive effect on PANs, where the background activity was consistently under 1 spike/s. The analysis of these responses was almost impossible due to the extremely low activity. The evoked responses during both static and dynamic visual stimulation were obvious in the behaving cats. On the other hand, only weak visual responses were found in some neurons of halothane anesthetized cats. These results show that halothane gas anesthesia has a marked suppressive effect on the feline CN. We suggest that for the purposes of the visual and related multisensory/sensorimotor electrophysiological exploration of the CN, behaving animal models are preferable over anesthetized ones.

A combined X-ray scattering and simulation study of halothane in membranes at raised pressures

Using a combination of high pressure wide angle X-ray scattering experiments and molecular dynamics simulations, we probe the effect of the archetypal general anaesthetic halothane on the lipid hydrocarbon chain packing and ordering in model bilayers and the variation in these parameters with pressure. Incorporation of halothane into the membrane causes an expansion of the lipid hydrocarbon chain packing at all pressures. The effect of halothane incorporation on the hydrocarbon chain order parameter is significantly reduced at elevated pressure.

Pharmacological characterization of microminipig as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies.

We tried to establish the halothane-anesthetized microminipigs as an alternative animal model for non-clinical toxicity and/or safety pharmacology studies. In order to characterize the halothane-anesthetized microminipigs, we firstly clarified the effects of halothane anesthesia on their cardiovascular system (n = 5). Then, we examined the cardiovascular effects of dl-sotalol in doses of 0.1, 0.3 and 1 mg/kg, i.v. on the halothane-anesthetized microminipigs (n = 6). Induction of the halothane anesthesia by itself prolonged the QT interval as well as QTcF, suggesting that the halothane anesthesia can reduce the cardiac repolarization reserve in microminipigs like in dogs. dl-Sotalol showed more potent negative chronotropic, dromotropic and hypotensive effects together with repolarization delay in microminipigs than in dogs, although each cardiovascular response to dl-sotalol was directionally similar between them, suggesting greater basal sympathetic tone and/or smaller volume of distribution of the drug in microminipigs than in dogs. Analyses of proarrhythmic surrogate markers indicate that Tpeak-Tend and short-term variability of QT interval may be more sensitive to detect the dl-sotalol-induced direct electrophysiological changes in microminipigs than in dogs, but its reverse will be true for J-Tpeakc. Thus, these results may help better understand the drug-induced cardiovascular responses in microminipigs.

Anesthesia specific differences in a cardio-pulmonary resuscitation rat model; halothane versus sevoflurane

ObjectiveOur asphyxia cardiac arrest (ACA) rat model is well established. The original model was designed in the 1990th using halothane and nitrous oxide for pre-insult anesthesia. Because of its hepato-toxicity and its potential to induce severe liver failures, halothane is no longer used in clinical anesthesia for several years. In order to minimize the health risk for our laboratory staff as well as to keep the experimental settings of our model on a clinically oriented basis we decided to replace halothane by sevoflurane. In this study we intended to determine if the change of the narcotic gas regiment causes changes in the neurological damage and how far our model had to be adjusted. MethodsAdult rats were subjected to 5min of ACA followed by resuscitation. There were four treatment groups: ACA - halothane, ACA - sevoflurane and with halothane or sevoflurane sham operated animals. Vital and blood parameters were monitored during the 45min post-resuscitation intensive care phase. After a survival time of 7 days histological evaluation of the hippocampus was performed. ResultsWe observed that resuscitated rats anesthetized prior by sevoflurane (i) have had a lower heart rate and a higher MAP compared to halothane anesthetized animals; (ii) The neurological damaged were significantly reduced in the hippocampal CA1 region in sevoflurane treated rats. ConclusionUsing sevoflurane instead of halothane for anesthesia requires some physiological and experimental changes. However the model keeps its validity. Sevoflurane caused less pronounced neurodegeneration in the CA1 region of the hippocampus. This had to be considered in further resuscitation-studies containing sevoflurane as anesthetic.Institutional protocol number for animal studies: 42502-2-2–947 Uni MD.

Nerve growth factor release from the urothelium increases via activation of bladder C-fiber in rats with cerebral infarction.

There are some reports that bladder C-fibers are partially involved in detrusor overactivity in patients with brain lesions. We investigated the contribution of bladder C-fiber to decreased bladder capacity in rats with cerebral infarction. Cerebral infarction was induced under halothane anesthesia by left middle cerebral artery occlusion with 4-0 nylon thread in female Sprague-Dawley rats. Intramural amounts of ATP and prostaglandin E2 , in vivo and in vitro ATP, NGF, and prostaglandin E2 release from the distended bladder urothelium, and changes in mRNA expressions of sensor molecules and receptors were monitored 6 h after the occlusion. Cystometry was performed in rats with or without resiniferatoxin pretreatment. Overexpression of sensor molecule, transient receptor potential vanilloid-type channel 1, acid-sensing ion channel 2, purinergic receptors P2X3 , and M2 /M3 muscarinic receptors was found in the bladder. These changes were accompanied by increases in ATP and NGF release from the urothelium. In contrast, when bladder C-fibers were desensitized by resiniferatoxin, no increase in NGF release from the urothelium was found either in vivo or in vitro. There was no difference in the percentage decrease in bladder capacity between cerebral infarction rats pretreated with resiniferatoxin and cerebral infarction rats without pretreatment. Results indicate that expression of sensor molecules in the bladder is altered by distant infarction in the brain. ATP and NGF release from the urothelium also increased. NGF release was related to activation of bladder C-fibers. Bladder C-fibers might not contribute much to decreased bladder capacity caused by cerebral infarction.

From Bench to Bedside and Back Again: A Personal Journey with Dexmedetomidine.

Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha 2 Adrenergic Receptor. By Segal IS, Vickery RG, Walton JK, Doze VA, and Maze M. ANESTHESIOLOGY 1988; 125:590-4. Abstract reprinted with permission.The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the α2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (D-enantiomer) or levomedetomidine (L-enantiomer) 10, 30, and 100 μg/kg, or vehicle intraperitoneally. There was a dose-dependent increase in MAC with the D-, but not the L-, stereoisomer. At the highest dose of dexmedetomidine (100 μg/kg), halothane could be discontinued for up to 30 min with no response to tail clamping. To determine whether α2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10 mg/kg intraperitoneally, a highly selective α2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5 mg/kg intraperitoneally, an opiate antagonist, or 8-phenyltheophylline, 2.5 mg/kg intraperitoneally, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine or reserpine and α-methyl-para-tyrosine, and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine-depleted rats. These data indicate that the reduction of MAC caused by dexmedetomidine is mediated through α2 adrenoreceptors with no apparent involvement of either opiate or A1 adenosine receptors. Data from catecholamine-depleted rats suggest that the mediating mechanism must involve site(s) other than or in addition to the presynaptic α2 adrenergic receptors on noradrenergic neurons. The authors conclude that central postsynaptic α2 adrenergic receptors mediate a significant part of the reduction of anesthetic requirements caused by dexmedetomidine.