The halothane era in pediatric anesthesia: The convergence of a cardiac depressant anesthetic with the immature myocardium of infancy.

Introduced in the late 1950s, halothane became the anesthetic of choice for inhalational induction of children for over 40 years. Halothane enjoyed a generally favorable safety record during its time, but its cardiac contractility depressant effect-well tolerated by most age groups-was profoundly heightened in neonates and infants, leading to increased incidences of hypotension and cardiac arrest. The neonatal myocardium is immature and is characterized by poor ventricular compliance, poor contractility due to fewer contractile elements, immature sympathetic innervation with decreased norepinephrine stores, and immature mechanisms for storage and exchange of calcium in the sarcoplasmic reticulum. In vitro studies of myocardial contractility of mammalian fetal and adult myocardium demonstrated that the fetal heart was twice as sensitive to halothane as the adult. Clinical studies demonstrated that most neonates and infants less than 6 months of age experienced hypotension during halothane induction of anesthesia and significantly (p < .01) greater decreases in blood pressure than older children at equipotent concentrations of halothane. Intraoperative cardiac arrest during the halothane era occurred over twice as frequently in neonates aged less than 1 month than in infants aged 1-12 months and nearly 10 times more frequently than children 1-5 years of age. Halothane was associated with 66% of intraoperative drug-related cardiac arrests in children. The halothane era began to close in the late 1990s with the introduction of sevoflurane, which had a more favorable hemodynamic profile. Shortly thereafter, halothane was completely displaced from pediatric anesthesia practice in North America.

Visually evoked local field potential changes in the caudate nucleus are remarkably more frequent in awake, behaving cats than in anaesthetized animals.

Previous results show that halothane gas anaesthesia has a suppressive effect on the visually evoked single-cell activities in the feline caudate nucleus (CN). In this study, we asked whether the low-frequency neuronal signals, the local field potentials (LFP) are also suppressed in the CN of anaesthetized animals.To answer this question, we compared the LFPs recorded from the CN of two halothane-anaesthetized (1.0%), paralyzed, and two awake, behaving cats during static and dynamic visual stimulation. The behaving animals were trained to perform a visual fixation task.Our results denoted a lower proportion of significant power changes to visual stimulation in the CN of the anesthetized cats in each frequency range (from delta to beta) of the LFPs, except gamma. These differences in power changes were more obvious in static visual stimulation, but still, remarkable differences were found in dynamic stimulation, too. The largest differences were found in the alpha and beta frequency bands for static stimulation. Concerning dynamic stimulation, the differences were the biggest in the theta, alpha and beta bands.Similar to the single-cell activities, remarkable differences were found between the visually evoked LFP changes in the CN of the anaesthetized, paralyzed and awake, behaving cats. The halothane gas anaesthesia and the immobilization suppressed the significant LFP power alterations in the CN to both static and dynamic stimulation. These results suggest the priority of the application of behaving animals even in the analysis of the visually evoked low-frequency electric signals, the LFPs recorded from the CN.

A Single-Center Retrospective Review of Patients with Suspected Malignant Hyperthermia Susceptibility.

Purpose The diagnosis of malignant hyperthermia susceptibility (MHS) has significant implications for the perioperative period that may persist for generations. Anesthetic medication options are reduced, anesthetic workstations require preparation to reduce exposure to inhaled volatile anesthetics, and patients may be excluded from surgery at ambulatory centers. In this study, we sought to better characterize the etiology of MHS diagnoses in our health system and the downstream effects of this diagnosis on anesthetic care. Methods We retrospectively reviewed the electronic medical records of 55 patients with a documented concern for MHS who received care at University of Florida (UF) Health between 2014 and 2020. We characterized the etiology of the patient's MHS diagnosis, whether this diagnosis was supported by formal genetic or muscle contracture testing, and the details of the recorded anesthetics that were delivered to these patients. Results The 55 patients with suspected MHS were evenly split between those with a family history of malignant hyperthermia (MH) (28/55) and those with a concern for MHS in their personal medical history (27/55). Of the 28 patients with a family history of MH, 16 reported that the affected family member was a first-degree relative, and two of these 16 reported that the affected family member had undergone confirmatory muscle contracture testing. Of the 27 patients with a personal history suspicious for MHS, two had undergone confirmatory genetic testing, and two patients had anesthetic records available for review where intraoperative MH was suspected and treated with dantrolene. An additional four patients were told of a concern about MHS due to another underlying diagnosis. No patients with a personal history suspicious of MHS had undergone confirmatory muscle contracture testing. These 55 patients underwent 87 anesthetics, and exclusively non-triggering anesthetic techniques were utilized in nearly all cases. In pediatric patients, some perioperative challenges were identified, related to the avoidance of mask inhalational induction. Only six of these 87 anesthetics occurred at our ambulatory surgery centers, a proportion (6.9%) lower than that of the general surgical population at UF Health (20.0%). Conclusions Among patients suspected to be MH susceptible in our health system over a six-year period, a minority (8/55) were supported by clear records of a prior MH event, confirmatory genetic or muscle contracture testing, or an underlying diagnosis closely linked to MH. The vast majority had limited documentation supporting their MH risk but continued to be treated with non-triggering anesthetics and were less likely to have surgery at an ambulatory surgery center than our overall surgical population. Among pediatric patients, some anesthetic challenges related to delivering non-triggering anesthetics were identified. Improving the documentation of index cases of MH and increasing referrals to clinical geneticists and genetic testing may be a viable route to decreasing the proportion of suspected MHS patients with a poorly characterized risk profile.

On the Functional Role of Gamma Synchronization in the Retinogeniculate System of the Cat.

Fast gamma oscillations, generated within the retina, and transmitted to the cortex via the lateral geniculate nucleus (LGN), are thought to carry information about stimulus size and continuity. This hypothesis relies mainly on studies conducted under anesthesia and the extent to which it holds under more naturalistic conditions remains unclear. Using multielectrode recordings of spiking activity in the retina and the LGN of both male and female cats, we show that visually driven gamma oscillations are absent for awake states and are highly dependent on halothane (or isoflurane). Under ketamine, responses were nonoscillatory, as in the awake condition. Response entrainment to the monitor refresh was commonly observed up to 120 Hz and was superseded by the gamma oscillatory responses induced by halothane. Given that retinal gamma oscillations are contingent on halothane anesthesia and absent in the awake cat, such oscillations should be considered artifactual, thus playing no functional role in vision.SIGNIFICANCE STATEMENT Gamma rhythms have been proposed to be a robust encoding mechanism critical for visual processing. In the retinogeniculate system of the cat, many studies have shown gamma oscillations associated with responses to static stimuli. Here, we extend these observations to dynamic stimuli. An unexpected finding was that retinal gamma responses strongly depend on halothane concentration levels and are absent in the awake cat. These results weaken the notion that gamma in the retina is relevant for vision. Notably, retinal gamma shares many of the properties of cortical gamma. In this respect, oscillations induced by halothane in the retina may serve as a valuable preparation, although artificial, for studying oscillatory dynamics.

Different damaging effects of volatile anaesthetics alone or in combination with 1 and 2 Gy gamma-irradiation in vivo on mouse liver DNA: a preliminary study.

As the number of radiotherapy and radiology diagnostic procedures increases from year to year, so does the use of general volatile anaesthesia (VA). Although considered safe, VA exposure can cause different adverse effects and, in combination with ionising radiation (IR), can also cause synergistic effects. However, little is known about DNA damage incurred by this combination at doses applied in a single radiotherapy treatment. To learn more about it, we assessed DNA damage and repair response in the liver tissue of Swiss albino male mice following exposure to isoflurane (I), sevoflurane (S), or halothane (H) alone or in combination with 1 or 2 Gy irradiation using the comet assay. Samples were taken immediately (0 h) and 2, 6, and 24 h after exposure. Compared to control, the highest DNA damage was found in mice receiving halothane alone or in combination with 1 or 2 Gy IR treatments. Sevoflurane and isoflurane displayed protective effects against 1 Gy IR, while with 2 Gy IR the first adverse effects appeared at 24 h post-exposure. Although VA effects depend on liver metabolism, the detection of unrepaired DNA damage 24 h after combined exposure with 2 Gy IR indicates that we need to look further into the combined effects of VA and IR on genome stability and include a longer time frame than 24 h for single exposure as well as repeated exposure as a more realistic scenario in radiotherapy treatment.

Reactions Using Freons and Halothane as Halofluoroalkyl/Halofluoroalkenyl Building Blocks.

In recent years, hydrofluorocarbon compounds such as chlorofluorocarbons, hydrochlorofluorocarbons, and 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane) have been used as fluorine-containing building blocks to construct functional fluorine-containing compounds, e. g., polymers, liquid crystals, and medicines. Hydrofluorocarbons promote the formation of reactive fluoroalkyl or fluoroalkenyl species via anionic or radical processes, and these species can act as nucleophiles or electrophiles depending on the reaction conditions. Progress in fluorine chemistry using hydrofluorocarbons in the last 30 years is described in this review and diverse reactions are discussed, including the fluoroalkyl/alkenyl products and proposed mechanisms involved.

Predictive factors of the contracture test for diagnosing malignant hyperthermia in a Brazilian population sample: a retrospective observational study

Abstract Introduction Malignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome triggered by halogenates/succinylcholine. The In Vitro Contracture Test (IVCT) is the gold standard diagnostic test for MH, and it evaluates abnormal skeletal muscle reactions of susceptible individuals (earlier/greater contracture) when exposed to caffeine/halothane. MH susceptibility episodes and IVCT seem to be related to individual features. Objective To assess variables that correlate with IVCT in Brazilian patients referred for MH investigation due to a history of personal/family MH. Methods We examined IVCTs of 80 patients investigated for MH between 2004‒2019. We recorded clinical data (age, sex, presence of muscle weakness or myopathy with muscle biopsy showing cores, genetic evaluation, IVCT result) and IVCT features (initial and final maximum contraction, caffeine/halothane concentration triggering contracture of 0.2g, contracture at caffeine concentration of 2 and 32 mmoL and at 2% halothane, and contraction after 100 Hz stimulation). Results Mean age of the sample was 35±13.3 years, and most of the subjects were female (n=43 or 54%) and MH susceptible (60%). Of the 20 subjects undergoing genetic investigation, 65% showed variants in RYR1/CACNA1S genes. We found no difference between the positive and negative IVCT groups regarding age, sex, number of probands, presence of muscle weakness or myopathy with muscle biopsy showing cores. Regression analysis revealed that the best predictors of positive IVCT were male sex (+12%), absence of muscle weakness (+20%), and personal MH background (+17%). Conclusions Positive IVCT results have been correlated to male probands, in accordance with early publications. Furthermore, normal muscle strength has been confirmed as a significant predictor of positive IVCT while investigating suspected MH cases.

Silylated-Acetylated Cyclodextrins as Chiral Sensors for the Enantiodiscrimination of Fluorinated Anesthetics.

Silylated-acetylated cyclodextrin (CD) derivatives have recently been investigated, via nuclear magnetic resonance (NMR) spectroscopy, as chiral sensors for substrates that are endowed and devoid of fluorine atoms, and the importance of Si-F interaction in the discrimination phenomena has been assessed. Here, the contributions of both superficial interactions and inclusion processes were further evaluated by extending the records to other chiral fluorinated substrates of interest for pharmaceutical applications. Non-equivalences were measured for both the 1H and 19F resonances in equimolar mixtures with the CDs; the promising results also supported the use of chiral sensors in sub-stoichiometric amounts. Finally, the occurrence of inclusion processes was evaluated by analyzing the intermolecular dipolar interactions by means of ROESY (Rotating-frame Overhauser Enhancement Spectroscopy) experiments. The study confirmed that the γCD derivative is the best chiral solvating agent for the fluorinated substrates investigated, likely due to the higher number of silyl moieties that can be involved in Si-F interactions. The contribution of inclusion processes to the enantiodiscrimination was also confirmed by comparison with the α- and ß-analogues. Overall, the CD derivatives proved to be able to discriminate fluorinated substrates even when used in sub-stoichiometric amounts.

Mutations in Complex I of the Mitochondrial Electron-Transport Chain Sensitize the Fruit Fly (Drosophila melanogaster) to Ether and Non-Ether Volatile Anesthetics.

The mitochondrial electron transport chain (mETC) contains molecular targets of volatile general anesthetics (VGAs), which places carriers of mutations at risk for anesthetic complications. The ND-2360114 and mt:ND2del1 lines of fruit flies (Drosophila melanogaster) that carry mutations in core subunits of Complex I of the mETC replicate numerous characteristics of Leigh syndrome (LS) caused by orthologous mutations in mammals and serve as models of LS. ND-2360114 flies are behaviorally hypersensitive to volatile anesthetic ethers and develop an age- and oxygen-dependent anesthetic-induced neurotoxicity (AiN) phenotype after exposure to isoflurane but not to the related anesthetic sevoflurane. The goal of this paper was to investigate whether the alkane volatile anesthetic halothane and other mutations in Complex I and in Complexes II-V of the mETC cause AiN. We found that (i) ND-2360114 and mt:ND2del1 were susceptible to toxicity from halothane; (ii) in wild-type flies, halothane was toxic under anoxic conditions; (iii) alleles of accessory subunits of Complex I predisposed to AiN; and (iv) mutations in Complexes II-V did not result in an AiN phenotype. We conclude that AiN is neither limited to ether anesthetics nor exclusive to mutations in core subunits of Complex I.

Ractopamine does not rescue Halothane and Rendement Napole metabolism postmortem.

The objective of this study was to determine if ractopamine (RAC) impacts postmortem muscle metabolism and subsequent pork quality in Halothane (HAL) and Rendement Napole (RN) mutant pigs. All RAC fed pigs had increased (P < 0.04) L* values. HAL and RN mutants muscle had lower (P < 0.01) pH values but RAC feeding had no effect. RN mutants had higher and lower (P < 0.05) muscle pH and temperatures, respectfully at 15 min and RN mutant pigs had greater (P < 0.0001) glycogen initially but lactate levels similar to wild type (WT) pigs at 24 h. RAC lowered (P < 0.05) glycogen in RN mutants but not in HAL mutated or WT pig muscle. These data show RAC feeding changes postmortem energy metabolism but does not change pH and pork quality hallmark of two major pig gene mutations and supports our contention that ultimate meat quality traits and their biochemical drivers may be more complex than originally reasoned.

Predictive factors of the contracture test for diagnosing malignant hyperthermia in a Brazilian population sample: a retrospective observational study.

INTRODUCTION: Malignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome triggered by halogenates/succinylcholine. The In Vitro Contracture Test (IVCT) is the gold standard diagnostic test for MH, and it evaluates abnormal skeletal muscle reactions of susceptible individuals (earlier/greater contracture) when exposed to caffeine/halothane. MH susceptibility episodes and IVCT seem to be related to individual features. OBJECTIVE: To assess variables that correlate with IVCT in Brazilian patients referred for MH investigation due to a history of personal/family MH. METHODS: We examined IVCTs of 80 patients investigated for MH between 2004‒2019. We recorded clinical data (age, sex, presence of muscle weakness or myopathy with muscle biopsy showing cores, genetic evaluation, IVCT result) and IVCT features (initial and final maximum contraction, caffeine/halothane concentration triggering contracture of 0.2g, contracture at caffeine concentration of 2 and 32 mmoL and at 2% halothane, and contraction after 100 Hz stimulation). RESULTS: Mean age of the sample was 35±13.3 years, and most of the subjects were female (n=43 or 54%) and MH susceptible (60%). Of the 20 subjects undergoing genetic investigation, 65% showed variants in RYR1/CACNA1S genes. We found no difference between the positive and negative IVCT groups regarding age, sex, number of probands, presence of muscle weakness or myopathy with muscle biopsy showing cores. Regression analysis revealed that the best predictors of positive IVCT were male sex (+12%), absence of muscle weakness (+20%), and personal MH background (+17%). CONCLUSIONS: Positive IVCT results have been correlated to male probands, in accordance with early publications. Furthermore, normal muscle strength has been confirmed as a significant predictor of positive IVCT while investigating suspected MH cases.

Inhibition of mitochondrial respiration by general anesthetic drugs.

General anesthetic drugs have been associated with various unwanted effects including an interference with mitochondrial function. We had previously observed increases of lactate formation in the mouse brain during anesthesia with volatile anesthetic agents. In the present work, we used mitochondria that were freshly isolated from mouse brain to test mitochondrial respiration and ATP synthesis in the presence of six common anesthetic drugs. The volatile anesthetics isoflurane, halothane, and (to a lesser extent) sevoflurane caused an inhibition of complex I of the electron transport chain in a dose-dependent manner. Significant effects were seen at concentrations that are reached under clinical conditions (< 0.5 mM). Pentobarbital and propofol also inhibited complex I but at concentrations that were two-fold higher than clinical EC50 values. Only propofol caused an inhibition of complex II. Complex IV respiration was not affected by either agent. Ketamine did not affect mitochondrial respiration. Similarly, all anesthetic agents except ketamine suppressed ATP production at high concentrations. Only halothane increased cytochrome c release indicating damage of the mitochondrial membrane. In summary, volatile general anesthetic agents as well as pentobarbital and propofol dose-dependently inhibit mitochondrial respiration. This action may contribute to depressive actions of the drugs in the brain.

Simple synthesis of multi-halogenated alkenes from 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane).

A series of aryl fluoroalkenyl ethers that contain chlorine and bromine as well as fluorine atoms were prepared in moderate to good yields via the reactions of phenols and 2-bromo-2-chloro-1,1,1-trifluoroethane (halothane) in the presence of KOH. This simple reaction enabled the construction of highly halogenated compounds with the potential for further functionalization. The reaction involved a highly reactive difluoroethylene intermediate, which was produced by the reaction between halothane and KOH.

Case report: Isoflurane therapy in a case of status asthmaticus requiring extracorporeal membrane oxygenation.

Volatile anesthetics have been described as a rescue therapy for patients with refractory status asthmaticus (SA), and the use of isoflurane for this indication has been reported since the 1980s. Much of the literature reports good outcomes when inhaled isoflurane is used as a rescue therapy for patients for refractory SA. Venovenous (VV) extracorporeal membrane oxygenation (ECMO) is a mode of mechanical circulatory support that is usually employed as a potentially lifesaving intervention in patients who have high risk of mortality, primarily for underlying pulmonary pathology. VV ECMO is usually only considered in cases where patients gas exchange cannot be satisfactorily maintained by conventional therapy and mechanical ventilation strategies. We report the novel use of isoflurane delivered systemically as treatment for severe refractory SA in a patient on VV ECMO. A 51-year-old male with a history of asthma was transferred from another institution for management of severe SA. He was intubated at the referring hospital after failing non-invasive ventilation. Initial arterial blood gas (ABG) showed pH 7.21, partial pressure of carbon dioxide (PCO2) >95 mmHg, and partial pressure of oxygen (PaO2) 60 mmHg. VV ECMO was initiated on hospital day (HD) 1 due to refractory respiratory acidosis. After ECMO initiation, acid-base status improved, however, severe bronchospasm persisted and intrinsic positive end expiratory pressure (PEEP) was measured at 18 cm H2O. Systemic paralysis was employed, respiratory rate (RR) was reduced to 4 breaths per minute. This degree of bronchospasm did not allow for ECMO weaning. On HD 5, the patient received systemic isoflurane via the ECMO circuit for 20 h. The following morning, intrinsic PEEP was 4 cm H2O, and wheezing improved. He was decannulated from VV ECMO on HD 10 and extubated on HD 17. Inhaled isoflurane therapy in patients on VV ECMO for refractory SA has shown good results, but requires delivery of the medication via anesthesia ventilators. Our case highlights an effective alternative, systemic delivery of anesthetic via the ECMO circuit, as it is often difficult and dangerous to transport these patients to the operating room (OR) or have an intensive care unit (ICU) room adjusted to accommodate an anesthesia ventilator.

Anesthetics and Cell-Cell Communication: Potential Ca2+-Calmodulin Role in Gap Junction Channel Gating by Heptanol, Halothane and Isoflurane.

Cell-cell communication via gap junction channels is known to be inhibited by the anesthetics heptanol, halothane and isoflurane; however, despite numerous studies, the mechanism of gap junction channel gating by anesthetics is still poorly understood. In the early nineties, we reported that gating by anesthetics is strongly potentiated by caffeine and theophylline and inhibited by 4-Aminopyridine. Neither Ca2+ channel blockers nor 3-isobutyl-1-methylxanthine (IBMX), forskolin, CPT-cAMP, 8Br-cGMP, adenosine, phorbol ester or H7 had significant effects on gating by anesthetics. In our publication, we concluded that neither cytosolic Ca2+i nor pHi were involved, and suggested a direct effect of anesthetics on gap junction channel proteins. However, while a direct effect cannot be excluded, based on the potentiating effect of caffeine and theophylline added to anesthetics and data published over the past three decades, we are now reconsidering our earlier interpretation and propose an alternative hypothesis that uncoupling by heptanol, halothane and isoflurane may actually result from a rise in cytosolic Ca2+ concentration ([Ca2+]i) and consequential activation of calmodulin linked to gap junction proteins.

Management of patients susceptible to malignant hyperthermia: A surgeon's perspective.

OBJECTIVES: Malignant hyperthermia (MH) susceptibility caries broad implications for the care of pediatric surgical patients. While precautions must often be taken for only a vague family history, two options exist to assess MH-susceptibility. We evaluate the use of MH precautions and susceptibility testing at a freestanding children's hospital. METHODS: This single institution retrospective cohort study identified patients of any age who received general anesthetics utilizing MH precautions over a five-year period. The electronic medical record was further queried for patients diagnosed with MH. The indication for MH precautions and uses of susceptibility testing are assessed. Secondary outcomes included a diagnosis of bona fide MH. RESULTS: A total of 125 patients received 174 anesthetics with MH precautions at a mean age of 114 months (0-363 months). Otolaryngology was the procedural service most frequently involved in the care of the cohort (n = 45; 26%). A reported personal or family history of MH (n = 102; 59%) was the most common indication for precautions, followed by muscular dystrophy (n = 29; 17%). No MH events occurred in the cohort and further review of ICD-9 and -10 diagnosis codes found no MH diagnoses. No study subjects received muscle biopsy and contracture testing and only 5 (4%) underwent genetic testing for genomic variants known to cause MH susceptibility. A case example is given to highlight the implications of a reported MH history. CONCLUSION: Otolaryngologists should maintain a familiarity with the precautions necessary to manage patients at risk for MH and MH-like reactions. Without an accessible test to rule out susceptibility, surgeons must rely on a careful history to appropriately utilize precautions. An inappropriate label of "MH-susceptible" may result in decreased access to care and treatment delays.

Kidney cell DNA damage caused by combined exposure to volatile anaesthetics and 1 Gy or 2 Gy radiotherapy dose in vivo.

Patient immobilisation with volatile anaesthetics (VA) during radiotherapy is sometimes unavoidable. Although it is known that both VAs and ionising radiation can have nephrotoxic effects, there are no studies of their combined effects on DNA damage. The aim of this in vivo study was to address this gap by investigating whether 48 groups of healthy Swiss albino mice (totalling 240) would differ in kidney cell DNA damage response (alkaline comet assay) to isoflurane, sevoflurane, or halothane anaesthesia and exposure to 1 Gy or 2 Gy of ionising radiation. We took kidney cortex samples after 0, 2, 6, and 24 h of exposure and measured comet parameters: tail length and tail intensity. To quantify the efficiency of the cells to repair and re-join DNA strand breaks, we also calculated cellular DNA repair index. Exposure to either VA alone increased DNA damage, which was similar between sevoflurane and isoflurane, and the highest with halothane. In combined exposure (VA and irradiation with 1 Gy) DNA damage remained at similar levels for all time points or was even lower than damage caused by radiation alone. Halothane again demonstrated the highest damage. In combined exposure with irradiation of 2 Gy sevoflurane significantly elevated tail intensity over the first three time points, which decreased and was even lower on hour 24 than in samples exposed to the corresponding radiation dose alone. This study confirmed that volatile anaesthetics are capable of damaging DNA, while combined VA and 1 Gy or 2 Gy treatment did not have a synergistic damaging effect on DNA. Further studies on the mechanisms of action are needed to determine the extent of damage in kidney cells after longer periods of observation and how efficiently the cells can recover from exposure to single and multiple doses of volatile anaesthetics and radiotherapy.

Study of anesthetics for euthanasia in rats and mice: A systematic review and meta-analysis on the impact upon biological outcomes (SAFE-RM).

AIM: To summarize the knowledge on the effect of anesthetics employed right before euthanasia on biological outcomes. DATA SOURCE: A systematic review of the literature to find studies with isoflurane, ketamine, halothane, pentobarbital, or thiopental just before euthanasia of laboratory rats or mice. STUDY SELECTION: Controlled studies with quantitative data available. DATA EXTRACTION: The search, data extraction, and risk of bias (RoB) were performed independently by two reviewers using a structured form. For each outcome, an effect size (ES) was calculated relative to the control group. Meta-analysis was performed using robust variance meta-regression for hierarchical data structures, with adjustment for small samples. DATA SYNTHESIS: We included 20 studies with 407 biological outcomes (110 unique). RoB analysis indicated that 87.5% of the domains evaluated showed unclear risk, 2% high risk, and 10.5% low risk. The effect size for all anesthetics considered together was 0.99 (CI95% = 0.75-1.23; p < 0.0001). Sub-analyses indicate high effect sizes for pentobarbital (1.14; CI95% = 0.75-1.52; p < 0.0001), and isoflurane (1.01; CI95% = 0.58-1.44; p = 0.0005) but not for ketamine (1.49; CI95% = -7.95-10.9; p = 0.295). CONCLUSION: We showed that anesthetics interfere differently with the majority of the outcomes assessed. However, our data did not support the use of one anesthetic over others or even the killing without anesthetics. We conclude that outcomes cannot be compared among studies without considering the killing method. This protocol was registered at Prospero (CRD42019119520). FUNDING: There was no direct funding for this research.

DNA damage assessment in peripheral blood of Swiss albino mice after combined exposure to volatile anesthetics and 1 or 2 Gy radiotherapy in vivo.

PURPOSE: Patient immobilization by general volatile anesthesia (VA) may be necessary during medical radiology treatment, and its use has increased in recent years. Although ionizing radiation (IR) is a well-known genotoxic and cytotoxic agent, and VA exposure has caused a range of side effects among patients and occupationally exposed personnel, there are no studies to date comparing DNA damage effects from combined VA and single fractional IR dose exposure. MATERIAL AND METHODS: We investigate whether there is a difference in white blood cells DNA damage response (by the alkaline comet assay) in vivo in 185 healthy Swiss albino mice divided into 37 groups, anesthetized with isoflurane/sevoflurane/halothane and exposed to 1 or 2 Gy of IR. Blood samples were taken after 0, 2, 6 and 24 h after exposure, and comet parameters were measured: tail length, tail intensity and tail moment. The cellular DNA repair index was calculated to quantify the efficiency of cells in repairing and re-joining DNA strand breaks following different treatments. RESULTS: In combined exposures, halothane caused higher DNA damage levels that were dose-dependent; sevoflurane damage increase did not differ significantly from the initial 1 Gy dose, and isoflurane even demonstrated a protective effect, particularly in the 2 Gy dose combined exposure. Nevertheless, none of the exposures reached control levels even after 24 h. CONCLUSION: Halothane appears to increase the level of radiation-induced DNA damage, while sevoflurane and isoflurane exhibited a protective effect. DNA damage may have been even greater in target organs such as liver, kidney or even the brain, and this is proposed for future study.