The Drug Titration Paradox: Correlation of More Drug With Less Effect in Clinical Data.

While analyzing clinical data where an anesthetic was titrated based on an objective measure of drug effect, we observed paradoxically that greater effect was associated with lesser dose. With this study we sought to find a mathematical explanation for this negative correlation between dose and effect, to confirm its existence with additional clinical data, and to explore it further with Monte Carlo simulations. Automatically recorded dosing and effect data from more than 9,000 patients was available for the analysis. The anesthetics propofol and sevoflurane and the catecholamine norepinephrine were titrated to defined effect targets, i.e., the processed electroencephalogram (Bispectral Index, BIS) and the blood pressure. A proportional control titration algorithm was developed for the simulations. We prove by deduction that the average dose-effect relationship during titration to the targeted effect will associate lower doses with greater effects. The finding of negative correlations between propofol and BIS, sevoflurane and BIS, and norepinephrine and mean arterial pressure confirmed the titration paradox. Monte Carlo simulations revealed two additional factors that contribute to the paradox. During stepwise titration toward a target effect, the slope of the dose-effect data for the population will be "reversed," i.e., the correlation between dose and effect will not be positive, but will be negative, and will be "horizontal" when the titration is "perfect." The titration paradox must be considered whenever data from clinical titration (flexible dose) studies are interpreted. Such data should not be used naively for the development of dosing guidelines.

European Society of Anaesthesiology Task Force on Nitrous Oxide: a narrative review of its role in clinical practice.

Nitrous oxide (N2O) is one of the oldest drugs still in use in medicine. Despite its superior pharmacokinetic properties, controversy remains over its continued use in clinical practice, reflecting in part significant improvements in the pharmacology of other anaesthetic agents and developing awareness of its shortcomings. This narrative review describes current knowledge regarding the clinical use of N2O based on a systematic and critical analysis of the available scientific literature. The pharmacological properties of N2O are reviewed in detail along with current evidence for the indications and contraindications of this drug in specific settings, both in perioperative care and in procedural sedation. Novel potential applications for N2O for the prevention or treatment of chronic pain and depression are also discussed. In view of the available evidence, we recommend that the supply of N2O in hospitals be maintained while encouraging its economic delivery using modern low flow delivery systems. Future research into its potential novel applications in prevention or treatment of chronic conditions should be pursued to better identify its role place in the developing era of precision medicine.

Experimental assessment of a myocyte-based multiscale model of cardiac contractile dysfunction.

Cardiac contractile dysfunction (CD) is a multifactorial syndrome caused by different acute or progressive diseases which hamper assessing the role of the underlying mechanisms characterizing a defined pathological condition. Mathematical modeling can help to understand the processes involved in CD and analyze their relative impact in the overall response. The aim of this study was thus to use a myocyte-based multiscale model of the circulatory system to simulate the effects of halothane, a volatile anesthetic which at high doses elicits significant acute CD both in isolated myocytes and intact animals. Ventricular chambers built using a human myocyte model were incorporated into a whole circulatory system represented by resistances and capacitances. Halothane-induced decreased sarco(endo)plasmic reticulum Ca2+ (SERCA2a) reuptake pump, transient outward K+ (Ito), Na+-Ca2+ exchanger (INCX) and L-type Ca2+ channel (ICaL) currents, together with ryanodine receptor (RyR2) increased open probability (Po) and reduced myofilament Ca2+ sensitivity, reproduced equivalent decreased action potential duration at 90% repolarization and intracellular Ca2+ concentration at the myocyte level reported in the literature. In the whole circulatory system, model reduction in mean arterial pressure, cardiac output and regional wall thickening fraction was similar to experimental results in open-chest sheep subjected to acute halothane overdose. Effective model performance indicates that the model structure could be used to study other changes in myocyte targets eliciting CD.

Voltage modulates halothane-triggered Ca2+ release in malignant hyperthermia-susceptible muscle.

Malignant hyperthermia (MH) is a fatal hypermetabolic state that may occur during general anesthesia in susceptible individuals. It is often caused by mutations in the ryanodine receptor RyR1 that favor drug-induced release of Ca2+ from the sarcoplasmic reticulum. Here, knowing that membrane depolarization triggers Ca2+ release in normal muscle function, we study the cross-influence of membrane potential and anesthetic drugs on Ca2+ release. We used short single muscle fibers of knock-in mice heterozygous for the RyR1 mutation Y524S combined with microfluorimetry to measure intracellular Ca2+ signals. Halothane, a volatile anesthetic used in contracture testing for MH susceptibility, was equilibrated with the solution superfusing the cells by means of a vaporizer system. In the range 0.2 to 3%, the drug causes significantly larger elevations of free myoplasmic [Ca2+] in mutant (YS) compared with wild-type (WT) fibers. Action potential-induced Ca2+ signals exhibit a slowing of their time course of relaxation that can be attributed to a component of delayed Ca2+ release turnoff. In further experiments, we applied halothane to single fibers that were voltage-clamped using two intracellular microelectrodes and studied the effect of small (10-mV) deviations from the holding potential (-80 mV). Untreated WT fibers show essentially no changes in [Ca2+], whereas the Ca2+ level of YS fibers increases and decreases on depolarization and hyperpolarization, respectively. The drug causes a significant enhancement of this response. Depolarizing pulses reveal a substantial negative shift in the voltage dependence of activation of Ca2+ release. This behavior likely results from the allosteric coupling between RyR1 and its transverse tubular voltage sensor. We conclude that the binding of halothane to RyR1 alters the voltage dependence of Ca2+ release in MH-susceptible muscle fibers such that the resting membrane potential becomes a decisive factor for the efficiency of the drug to trigger Ca2+ release.

Isoflurane inhalation anesthesia should be a new requirement in intracavernosal pressure detection-the gold standard of erectile function assessment.

Intracavernosal pressure (ICP) is gold standard for the detection of erectile function in animals, but no consensus has yet been achieved on what kind of anesthetic protocol should be applied. A total of 16 adult male Sprague-Dawley rats were randomized into two groups. In group A, chloral hydrate was injected intraperitoneally. Rats in group B were induced in 5% isoflurane for 3 min and then maintained in 1.0-1.5% isoflurane. Mean arterial pressure (MAP), respiratory rate (RR) and heart rate were monitored during all experiments. After ICP detection, tail vein and carotid artery blood were collected. The maximum ICP value, MAP and ICP/MAP ratio in group B was significantly higher than in that of group A. The RR in group A was lower than in that of group B, but the heart rate in group A was higher than in group B. There were no significant differences in both pO2 and pCO2 between groups. While the data showed that animals in group A were relatively hypoxemic. Isoflurane inhalation anesthesia in detection of erectile function could offer a relatively more stable physical state than in that under the effect of chloral hydrate intraperitoneal anesthesia. Isoflurane inhalation anesthesia is more suitable for ICP test.

COMPARISON OF ISOFLURANE AND SEVOFLURANE FOR SHORT-TERM ANESTHESIA IN MEERKATS (SURICATA SURICATTA)-ARE THERE BENEFITS THAT OUTWEIGH COSTS?

Meerkats ( Suricata suricatta ) are routinely anesthetized with isoflurane in zoo and field settings. Twenty healthy adult meerkats of mixed age and sex held in the Zoological Society of London's collection were anesthetized with 4% isoflurane by face mask for routine health examinations. The procedure was repeated 5 mo later in the same group of animals utilizing sevoflurane at 5% for induction, and again 3 mo later with sevoflurane at 6.5% for induction to approximate equipotency with isoflurane. The speed and quality of induction and recovery were compared between the two volatile anesthetic agents. There was no statistically significant difference in the speed of induction across any of the anesthetic regimes. There was a significant difference in recovery times between isoflurane and 6.5% sevoflurane (427 ± 218 and 253 ± 65 sec, respectively [mean ± SD]). Under the conditions of this study, sevoflurane at 6.5% induction dose resulted in better quality induction and recovery than sevoflurane at 5% induction or isoflurane. The mean heart and respiratory rates during anesthesia were higher using 5% sevoflurane for induction but there was no significant difference in either rate between isoflurane and sevoflurane used at a 6.5% induction dose. This study suggests that sevoflurane at a dose of 6.5% for induction and 4% for maintenance is a safe and effective anesthetic agent in healthy adult meerkats. Rapid return to normal behavior after anesthesia is important in all zoo species but particularly so in animals with a complex social and hierarchical structure such as meerkats. For this species, the advantage afforded by the speed of recovery with sevoflurane may offset the cost in certain circumstances.

Quantitative assessment of brain glucose metabolic rates using in vivo deuterium magnetic resonance spectroscopy.

Quantitative assessment of cerebral glucose consumption rate (CMRglc) and tricarboxylic acid cycle flux (VTCA) is crucial for understanding neuroenergetics under physiopathological conditions. In this study, we report a novel in vivo Deuterium (2H) MRS (DMRS) approach for simultaneously measuring and quantifying CMRglc and VTCA in rat brains at 16.4 Tesla. Following a brief infusion of deuterated glucose, dynamic changes of isotope-labeled glucose, glutamate/glutamine (Glx) and water contents in the brain can be robustly monitored from their well-resolved 2H resonances. Dynamic DMRS glucose and Glx data were employed to determine CMRglc and VTCA concurrently. To test the sensitivity of this method in response to altered glucose metabolism, two brain conditions with different anesthetics were investigated. Increased CMRglc (0.46 vs. 0.28 µmol/g/min) and VTCA (0.96 vs. 0.6 µmol/g/min) were found in rats under morphine as compared to deeper anesthesia using 2% isoflurane. This study demonstrates the feasibility and new utility of the in vivo DMRS approach to assess cerebral glucose metabolic rates at high/ultrahigh field. It provides an alternative MRS tool for in vivo study of metabolic coupling relationship between aerobic and anaerobic glucose metabolisms in brain under physiopathological states.

Effect of Inhalational Anesthetics and Positive-pressure Ventilation on Ultrasound Assessment of the Great Vessels: A Prospective Study at a Children's Hospital.

BACKGROUND: Bedside ultrasound has emerged as a rapid, noninvasive tool for assessment and monitoring of fluid status in children. The inferior vena cava (IVC) varies in size with changes in blood volume and intrathoracic pressure, but the magnitude of change to the IVC with inhalational anesthetic and positive-pressure ventilation (PPV) is unknown. METHODS: Prospective observational study of 24 healthy children aged 1 to 12 yr scheduled for elective surgery. Ultrasound images of the IVC and aorta were recorded at five time points: awake; spontaneous ventilation with sevoflurane by mask; intubated with peak inspiratory pressure/positive end-expiratory pressure of 15/0, 20/5, and 25/10 cm H2O. A blinded investigator measured IVC/aorta ratios (IVC/Ao) and changes in IVC diameter due to respiratory variation (IVC-RV) from the recorded videos. RESULTS: Inhalational anesthetic decreased IVC/Ao (1.1 ± 0.3 vs. 0.6 ± 0.2; P < 0.001) but did not change IVC-RV (median, 43%; interquartile range [IQR], 36 to 58% vs. 46%; IQR, 36 to 66%; P > 0.99). The initiation of PPV increased IVC/Ao (0.64 ± 0.21 vs. 1.16 ± 0.27; P < 0.001) and decreased IVC-RV (median, 46%; IQR, 36 to 66% vs. 9%; IQR, 4 to 14%; P < 0.001). There was no change in either IVC/Ao or IVC-RV with subsequent incremental increases in peak inspiratory pressure/positive end-expiratory pressure (P > 0.99 for both). CONCLUSIONS: Addition of inhalational anesthetic affects IVC/Ao but not IVC-RV, and significant changes in IVC/Ao and IVC-RV occur with initiation of PPV in healthy children. Clinicians should be aware of these expected vascular changes when managing patients. Establishing these IVC parameters will enable future studies to better evaluate these measurements as tools for diagnosing hypovolemia or predicting fluid responsiveness.

CARDIAC ASSESSMENT OF ZOO-KEPT, BLACK-TAILED PRAIRIE DOGS (CYNOMYS LUDOVICIANUS) ANESTHETIZED WITH ISOFLURANE.

Cardiomyopathy is suggested to be a relatively common disease condition in prairie dogs; however, there are no reports of normal cardiac echosonography and radiology in the prairie dog ( Cynomys spp.). The objective of this study was to report the ultrasonographic and radiographic measurements of the heart, and plasma troponin concentration in captive healthy anesthetized black-tailed prairie dogs ( Cynomys ludovicianus ). Zoo-kept prairie dogs with no signs of cardiac disease (n = 17) were evaluated. Each animal was anesthetized with isoflurane via face mask and a complete clinical assessment was performed, including complete blood cell count and plasma biochemistry, urinalysis, blood gasses, plasma troponin concentration, three-view whole body radiography, and echocardiogram. Standard measurements were taken. Few trivial findings were identified on echocardiographic evaluation. Further research with a larger sample size is needed to determine if these variations are normal, or represent early or mild cardiac disease. The data presented here can aid, with the necessary caution, in evaluating prairie dogs with possible cardiac disease, potentially resulting in earlier diagnosis and more successful treatment.

[Xenon and sevoflurane anti stress activity comparative assessment during elective anaesthesia in pediatric patients].

UNLABELLED: Research objective was to compare Xenon and Sevoflurane anti stress activities during elective anaesthesia in Pediatric patients. MATERIAL AND METHODS: The results of anaesthesia in 42 patients in age from 1 to 18 years were analyzed. The clinical sings, BIS-index, Somatotropinum hormone and Cortisol levels in patient's blood were studied. RESULTS: Xenon and Sevoflurane provide sufficient level of sedation, analgesia and do not cause Somatotropinum hormone and Cortisol levels increase. CONCLUSION: Xenon and Sevoflurane have the same high anti stress activity However Xenon anaesthesia is characterized by more stable haemodynamics.

In vitro muscle contracture investigations on the malignant hyperthermia like episodes in myotonia congenita.

BACKGROUND: A common form of congenital myotonia, myotonia congenita (MC), is caused by mutations in the skeletal muscle Cl(-) channel gene type 1 (CLCN1). Due to the reduced Cl(-) conductance of the mutated channels, the patients may develop generalized muscle rigidity and hypermetabolism during general anaesthesia. The clinical symptoms resemble malignant hyperthermia (MH), which may lead to mistreatment of the patient. METHODS: Muscle specimens of ADR mice (an animal model of MC) as well as of human individuals were used and exposed to potent ryanodine receptor type 1 (RyR1) activators and increasing K(+) concentration. Muscle force was monitored by a standardized diagnostic method for MH, the so-called in vitro contracture test. RESULTS: Neither muscle of ADR mice nor MC muscle (murine and human myotonic muscle) showed pathological contractures after exposure to the potent RyR1 agonists caffeine and halothane. Increasing concentrations of K(+) had a dose-dependent preventive effect on myotonic stiffness. CONCLUSION: We conclude that the adverse anaesthetic MH-like episodes observed in MC patients do not primarily originate from an altered Ca(2+) release in skeletal muscle. In MC muscle, this hypermetabolism is facilitated by a (pharmacologically induced) sustained depolarization due to an instable membrane potential. The in vitro results suggest that these patients benefit from tight K(+) monitoring because of the membrane potential stabilizing effect of K(+) .

Effects of anesthetic isoflurane and desflurane on human cerebrospinal fluid Aß and τ level.

BACKGROUND: Accumulation of ß-amyloid protein (Aß) and tau protein is the main feature of Alzheimer disease neuropathogenesis. Anesthetic isoflurane, but not desflurane, may increase Aß levels in vitro and in animals. Therefore, we set out to determine the effects of isoflurane and desflurane on cerebrospinal fluid (CSF) levels of Aß and tau in humans. METHODS: The participants were assigned into spinal anesthesia (N=35), spinal plus desflurane anesthesia (N=33), or spinal plus isoflurane anesthesia (N=38) group by randomization using computer-generated lists. Pre- and postoperative human CSF samples were obtained through an inserted spinal catheter. The levels of Aß (Aß40 and Aß42) and total tau in the CSF were determined. RESULTS: Here, we show that isoflurane, but not desflurane, was associated with an increase in human CSF Aß40 levels (from 10.90 to 12.41 ng/ml) 24 h after the surgery under anesthesia compared to spinal anesthesia (from 11.59 to 11.08 ng/ml), P=0.022. Desflurane, but not isoflurane, was associated with a decrease in Aß42 levels 2 h after the surgery under anesthesia (from 0.39 to 0.35 ng/ml) compared to spinal anesthesia (from 0.43 to 0.44 ng/ml), P=0.006. Isoflurane and desflurane did not significantly affect the tau levels in human CSF. CONCLUSIONS: These studies have established a system to study the effects of anesthetics on human biomarkers associated with Alzheimer disease and cognitive dysfunction. These findings have suggested that isoflurane and desflurane may have different effects on human CSF Aß levels.

Desflurane: a clinical update of a third-generation inhaled anaesthetic.

Available volatile anaesthetics are safe and efficacious; however, their varying pharmacology provides small but potentially clinically important differences. Desflurane is one of the third-generation inhaled anaesthetics. It is the halogenated inhaled anaesthetic with the lowest blood and tissue solubilities, which promotes its rapid equilibration and its rapid elimination following cessation of administration at the end of anaesthesia. The low fat solubility of desflurane provides pharmacological benefits, especially in overweight patients and in longer procedures by reducing slow compartment accumulation. A decade of clinical use has provided evidence for desflurane's safe and efficacious use as a general anaesthetic. Its benefits include rapid and predictable emergence, and early recovery. In addition, the use of desflurane promotes early and predictable extubation, and the ability to rapidly transfer patients from the operating theatre to the recovery area, which has a positive impact on patient turnover. Desflurane also increases the likelihood of patients, including obese patients, recovering their protective airway reflexes and awakening to a degree sufficient to minimise the stay in the high dependency recovery area. The potential impact of the rapid early recovery from desflurane anaesthesia on intermediate and late recovery and resumption of activities of daily living requires further study.

Behavioral and activity assessment of laboratory mice (Mus musculus) after tail biopsy under isoflurane anesthesia.

Contemporary laboratory animal guidance suggests that tail biopsy of laboratory mice can be performed before 21 d of age without anesthesia, whereas older mice must receive anesthesia before biopsy. Our objective was to determine whether administration of isoflurane anesthesia before tail biopsy produced a measurable effect on the behavior of mice (n = 196). We evaluated C57BL/6 and BALB/c mice at 21 to 24 (weaning), 28 to 31 (delayed weaning), and 42 to 45 (adult) d of age. Mice were observed at the time of biopsy and then twice within the first hour after a sham or tail biopsy. Anxiety-like responses were assessed by using an elevated plus-maze. Activity was evaluated remotely for 120 min. Isoflurane did not diminish acute responses to tail biopsy in mice 31 d or younger compared with sham-biopsied animals but had a significant effect in C57BL/6 biopsied adult mice. In addition, mice of all ages and strains that received anesthesia, regardless of biopsy, spent more time in the enclosed maze arms and had decreased activity up to 5 h after isoflurane exposure. Although tail biopsy should be performed in young mice to avoid transection of distal mature vertebrae, our experimental paradigm indicates that isoflurane anesthesia does not appreciably enhance wellbeing over that of mice biopsied without anesthesia at weaning ages. The influence of inhaled isoflurane was demonstrable and indicated that acute and prolonged alterations in anxiety and activity must be considered when interpreting the impact of anesthesia on tail biopsy across various ages and strains of laboratory mice.

Effects of heart rate and anesthetic timing on high-resolution echocardiographic assessment under isoflurane anesthesia in mice.

OBJECTIVE: Anesthesia provides sedation and immobility, facilitating echocardiography in mice, but it influences cardiovascular function and therefore outcomes of measurement. This study aimed to determine the effect of the optimal heart rate (HR) and anesthetic timing on echocardiographic reproducibility under isoflurane anesthesia. METHODS: Male C57BL/6J mice underwent high-resolution echocardiography with relative fixed HRs and anesthetic timing. The same experiment was repeated once again after 1 week. RESULTS: Echocardiography was highly reproducible in repeated measurements under low-HR (350-400 beats per minute [bpm]) and high-HR (475-525 bpm) conditions except some M-mode parameters under low-HR conditions. With similar anesthetic timing, mice with a high HR had decreased preload indices and increased ejection phase and Doppler indices. Inversely, when the HR was similar, the echocardiographic results of mice under short anesthetic timing showed little difference from the ones under long anesthetic timing. CONCLUSIONS: This study shows that echocardiographic assessment is greatly reproducible under a high HR. The HR is more important than anesthetic timing for echocardiographic evaluation in mice.

Xenon as an anesthetic agent.

Discovered in 1898 by British chemists, xenon is a rare gas belonging to the noble gases of the periodic table. Xenon is used in many different ways, from high-intensity lamps to jet propellant, and in 1939, its anesthetic properties were discovered. Xenon exerts its anesthetic properties, in part, through the noncompetitive inhibition of N-methyl-D-aspartate receptors. Currently, xenon is being used primarily throughout Europe; however, the high price of manufacturing and scavenging the noble gas has discouraged more widespread use. As technology in anesthetic delivery improves, xenon is being investigated further as a possible replacement for nitrous oxide as an inhalational agent. This article reviews the anesthetic properties of xenon and current and potential research about the gas.

Should sevoflurane be used in the electrophysiology assessment of accessory pathways?

Sevoflurane has been shown to significantly prolong the action potential duration and the QTc interval. Despite this, clinical studies have shown only minor clinical effects on accessory pathway properties under general anaesthesia with sevoflurane compared with conscious sedation with midazolam. This case demonstrates significant prolongation of accessory pathway effective refractory period (APERP) under general anaesthetic with sevoflurane compared with propofol.

Sevoflurane modulation of Ca2+ regulation in skeletal muscle sarcoplasmic reticulum vesicles from young and mature rabbits.

INTRODUCTION: Developmental differences in splice variants of the two key sarcoplasmic reticulum (SR) calcium regulatory proteins, ryanodine (RyR1), and sarcoendoplasmic reticulum calcium pump (SERCA1) have been linked to various neuromuscular disorders, but not malignant hyperthermia (MH). However, it is unclear whether an age-related difference in volatile anesthetic-mediated SR calcium function exists that could add to our current understanding of the clinical presentation of MH syndrome and provide insight into molecular mechanisms for general anesthesia that may have other physiologic and/or pathophysiologic significance. Therefore, the effects of sevoflurane on intracellular calcium regulation in isolated SR membrane vesicles from the skeletal muscle of healthy young rabbits were compared to their adult counterpart using an established in vitro model with the assumption that exposure to sevoflurane would elicit a weaker response in the young SR. METHODS: Through dual wavelength spectroscopy of Ca(2+): Arsenazo III difference absorbance, the effects of sevoflurane on SR Ca(2+) uptake rate and release in heavy and light fraction SR membrane vesicles isolated from the white muscle of anesthetized, postweaned (age = 6 weeks, n = 5) and adult (age = 6 months, n = 5) male New Zealand rabbits were examined. RESULTS: The adult group showed a 50% increase in Ca(2+) uptake rate from control at both subclinical and clinically relevant anesthetic concentrations, whereas in the SR from the younger animals, Ca(2+) uptake rate was not altered by any concentration of sevoflurane. The sensitivity of both the low and high affinity Ca(2+)-binding sites on RyR1 was increased by sevoflurane to the same extent in the SR vesicles from the young and mature adult rabbits. Interestingly, a greater potency of sevoflurane for the high affinity-binding site was identified, and this was independent of age. CONCLUSIONS: These findings suggest that the sensitivity of the SR to sevoflurane-mediated Ca(2+) uptake may be increased with maturity, while an analogous developmental effect on RyR1 is less probable. Nonetheless, this study shows for the first time that a potent inhalational agent such as sevoflurane can influence the high affinity SR calcium-binding site by lowering the extraluminal concentration of calcium necessary to trigger calcium release. While this may not be of consequence when inhaled anesthetics are administered to normal children or adults, it may have life-threatening consequences in carriers of RyR1 mutations.