Best Practices for the Care of Breastfeeding Patients Requiring Local or General Anesthesia.

The care of breastfeeding patients who require anesthesia presents unique challenges; therefore, caregivers must be knowledgeable regarding drugs' pharmacodynamic and pharmacokinetic profiles to ensure the safety of the breastfed infant. Although most anesthetic drugs are compatible with breastfeeding, health care providers continue to advise patients to "pump and dump." This advice can lead to undesirable outcomes, including interruption or cessation of breastfeeding, creating possible physical and psychological challenges for parents and their neonates. This article outlines best practices for the care of breastfeeding patients receiving anesthesia.

Alfaxalone population pharmacokinetics in the rat: Model application for pharmacokinetic and pharmacodynamic design in inbred and outbred strains and sexes.

The translation of new injectable anesthetic drugs from rodent to humans remains slow, despite the realization that reliance on the volatile agents is unsustainable from an environmental perspective. The aim of this study was to investigate the influence of rat sex and strain on the PK and PD of the anesthetic neurosteroid alfaxalone. Forty rats had cannulas inserted under isoflurane anesthesia for drug administration and sampling. Carotid artery blood samples were collected for blood gas analysis, hematology, biochemistry, and plasma concentrations of alfaxalone. Plasma samples were assayed using liquid chromatography-mass spectrometry. Compartmental non-linear mixed effects methods (NLME) models were applied to two rat populations to determine whether body weight, sex, and strain influenced PK parameters. There were significant differences between the sexes for plasma clearance, half-life and mean residence time in Lewis rats, and mean arterial blood pressure was significantly lower in the female rats at 120 min. An initial NLME PK population model was used to design an adjusted alfaxalone infusion for SD females matching plasma concentrations in males and minimizing cardiopulmonary depression but maintaining an appropriate hypnotic effect. A final NLME population model showed that alfaxalone clearance was dependent on both bodyweight and sex, whereas volume of distribution was influenced by strain. NLME PK models offer the advantage of having a single model that describes a population and therefore shares data interpretation between animals unlike the standard deterministic PK approach. This approach can be used to propose bespoke dosing regimens for optimal use of alfaxalone.

Repetitive Treatment with Volatile Anesthetics Does Not Affect the In Vivo Plasma Concentration and Composition of Extracellular Vesicles in Rats.

BACKGROUND: Anesthetic-induced preconditioning (AIP) with volatile anesthetics is a well-known experimental technique to protect tissues from ischemic injury or oxidative stress. Additionally, plasmatic extracellular vesicle (EV) populations and their cargo are known to be affected by AIP in vitro, and to provide organ protective properties via their cargo. We investigated whether AIP would affect the generation of EVs in an in vivo rat model. METHODS: Twenty male Sprague Dawley rats received a repetitive treatment with either isoflurane or with sevoflurane for a duration of 4 or 8 weeks. EVs from blood plasma were characterized by nanoparticle tracking analysis, transmission electron microscopy (TEM) and Western blot. A scratch assay (H9C2 cardiomyoblast cell line) was performed to investigate the protective capabilities of the isolated EVs. RESULTS: TEM images as well as Western blot analysis indicated that EVs were successfully isolated. The AIP changed the flotillin and CD63 expression on the EV surface, but not the EV concentration. The scratch assay did not show increased cell migration and/or proliferation after EV treatment. CONCLUSION: AIP in rats changed the cargo of EVs but had no effect on EV concentration or cell migration/proliferation. Future studies are needed to investigate the cargo on a miRNA level and to investigate the properties of these EVs in additional functional experiments.

Drug-drug interaction between diclofenac and gamma-hydroxybutyric acid.

Gamma hydroxybutyric acid (GHB) has been approved clinically to treat excessive daytime sleepiness and cataplexy in patients with narcolepsy, alcohol and opioid withdrawal, and as an anesthetic. The use of GHB clinically is limited due to its high abuse potential. The absorption, clearance and tissue uptake of GHB is mediated by proton-dependent and sodium-coupled monocarboxylate transporters (MCTs and SMCTs) and inhibition of these transporters may result in a change in GHB pharmacokinetics and pharmacodynamics. Previous studies have reported that non-steroidal anti-inflammatory drugs (NSAIDs) may inhibit these monocarboxylate transporters. Therefore, the purpose of this work was to analyze the interaction between GHB (at a dose of 600 mg/kg i. v.) and the NSAID, diclofenac, by examining the effects of this drug on the in vivo pharmacokinetics and pharmacodynamics in rat studies. The pharmacodynamic effect evaluated was respiratory depression, a measure of toxicity observed by GHB at this dose. There was an improvement in the respiratory rate with diclofenac administration suggesting an effect of diclofenac on GHB toxicity. In vitro studies with rat blood brain endothelial cells (RBE4) that express MCT1 indicated that diclofenac can inhibit GHB transport with an IC50 of 10.6 µM at pH 7.4. In vivo studies found a decrease in brain GHB concentrations and a decrease in the brain-to-plasma concentration ratio following diclofenac treatment. With this study we can conclude that diclofenac and potentially other NSAIDs can inhibit the transport of GHB into the brain, therefore decreasing GHB's pharmacodynamic effects and toxicity.

Explaining anaesthetic hysteresis with effect-site equilibration.

BACKGROUND: Anaesthetic induction occurs at higher plasma drug concentrations than emergence in animal studies. Some studies find evidence for such anaesthetic hysteresis in humans, whereas others do not. Traditional thinking attributes hysteresis to drug equilibration between plasma and the effect site. Indeed, a key difference between human studies showing anaesthetic hysteresis and those that do not is in how effect-site equilibration was modelled. However, the effect-site is a theoretical compartment in which drug concentration cannot be measured experimentally. Thus, it is not clear whether drug equilibration models with experimentally intractable compartments are sufficiently constrained to unequivocally establish evidence for the presence or absence of anaesthetic hysteresis. METHODS: We constructed several models. One lacked hysteresis beyond effect-site equilibration. In another, neuronal dynamics contributed to hysteresis. We attempted to distinguish between these two systems using drug equilibration models. RESULTS: Our modelling studies showed that one can always construct an effect-site equilibration model such that hysteresis collapses. So long as the concentration in the effect-site cannot be measured directly, the correct effect-site equilibration model and the one that erroneously collapses hysteresis are experimentally indistinguishable. We also found that hysteresis can naturally arise even in a simple network of neurones independently of drug equilibration. CONCLUSIONS: Effect-site equilibration models can readily collapse hysteresis. However, this does not imply that hysteresis is solely attributable to the kinetics of drug equilibration.

The role of pharmacokinetics and pharmacodynamics in clinical anaesthesia practice.

PURPOSE OF REVIEW: Growing concerns about the environmental effects of volatile anaesthetics are likely to lead to increased use of intravenous anaesthetic drugs. Pharmacokinetic/pharmacodynamic (PKPD) models can increase the accuracy of intravenous drug titration, especially in populations that differ from the 'average.' However, with a growing number of PKPD models, and other technology available to date, it can be hard to see the wood for the trees. This review attempts to guide the reader through the PKPD jungle. RECENT FINDINGS: General purpose PKPD models for propofol and remifentanil designed to apply to a broader population, including children, the elderly and the obese, reduce the need for population-specific models. PKPD models for drugs such as dexmedetomidine and antimicrobial agents may be useful for procedural sedation or in the ICU. Technological advances such as Bayesian model adjustment based on point-of-care plasma concentration measurements, closed-loop drug delivery and artificial intelligence may improve the ease of use of the anaesthetic drugs and increase the accuracy of titration. SUMMARY: Newer and more complex modelling techniques and technological advancements can help to deliver anaesthetic drugs, sedatives and other drugs in a more stable and thereby safer way.

AANA Journal Course: Update for Nurse Anesthetists-Enterohepatic Recirculation: From Death by Mushroom to Perioperative Pharmacokinetics.

Enterohepatic recirculation (EHRC) is a multistaged process with the following sequence: liver metabolism, bile secretion, gut metabolism, and reabsorption from the gut back to the systemic circulation. Enterohepatic recirculation prolongs drug half-lives and may be associated with the generation of 1 or more secondary plasma peaks. For EHRC to occur, there is substantial dependence on the flora residing in the gastrointestinal (GI) tract. The role of gut microflora is so essential to our overall homeostasis that it is referred to by some authorities as an endocrine organ or "a second brain." Hepatic metabolism plays the dominant role in the fate of drugs and other xenobiotics that we encounter. The liver is rich in a host of chemical manipulators that can hydrolyze, reduce, oxidize, and conjugate xenobiotics. Many drugs, morphine being a good example, are inactivated by glucuronide or sulfate conjugation, with subsequent movement into the bile and eventual emptying into the GI tract. Once in the GI tract, enzymes produced by gut flora can hydrolyze conjugated drugs in the small and large intestine, resulting in the active form reemerging, with reabsorption likely. The clinical relevance of EHRC is discussed with its major implications for efficacy and safety.

Pharmacokinetics and sedative effects of alfaxalone with or without dexmedetomidine in rabbits.

This study aimed to investigate the specific pharmacokinetic profile and effects of alfaxalone after intravenous (IV) and intramuscular (IM) administration to rabbits and evaluate the potential interaction with dexmedetomidine. The study design was a blinded, randomized crossover with a washout period of 2 weeks. Five New Zealand white rabbits were used. Each animal received single IV and IM injections of alfaxalone at a single dose of 5 mg/kg, and single IV and IM injections of alfaxalone (5 mg/kg) combined with dexmedetomidine (100 µg/kg) administered intramuscularly. Blood samples were collected at predetermined times and analysed by high-performance liquid chromatography. The plasma concentration-time curves were analysed by non-compartmental analysis. Sedation/anaesthesia scores were evaluated by a modified numerical rating scale. At pre-determined time points heart and respiratory rates were measured. Times to sternal recumbency and standing position during the recovery were recorded. Concentrations of alfaxalone alone were very similar (slighty smaller) to concentrations when alfaxalone was combined with dexmedetomidine, after both routes of administration. Dexmedetomidine enhanced and increase the duration of the sedative effects of alfaxalone. In conclusion, alfaxalone administered in rabbits provides rapid and smooth onset of sedation. After IV and IM injections of alfaxalone combined with dexmedetomidine, a longer MRT and a deeper and extended sedation have been obtained compared to alfaxalone alone. Consequently, alfaxalone alone or in combination with dexmedetomidine could be useful to achieve respectively moderate to deep sedation in rabbits.

Thoracic paravertebral block: comparison of different approaches and techniques. A study on 27 human cadavers.

BACKGROUND AND OBJECTIVES: The success rate and spread of thoracic paravertebral block (TPVB) are variable and difficult to predict. It is now recommended that an ultrasound guidance technique should replace the traditional landmark technique. The objective was to compare anatomical outcomes of both techniques on cadavers. METHODS: A landmark technique (loss of resistance technique [LOR]) and a USG technique (three approaches: sagittal, transversal in-plane, transverse out-of-plane) were performed on 27 thawed non-embalmed cadavers. Each of the four approaches was performed in each body (T3-T5 and T9-T11 × right and left). A coloured solution (13 mL, saline 0.9%) was injected in the targeted thoracic paravertebral space (TPVS). A successful thoracic paravertebral injection (TPVI) was defined by the presence of dye in at least one TPVS during anatomical dissection. RESULTS: In 104 TPVIs analysed, the overall success rate was 78%. Factors associated with success were: USG versus LOR technique (85% vs. 52%, P < 0.0007), sagittal versus both transversal approaches (93%/81%/83%, P < 0.0007) and right side (86% vs. 66%). The median spread was 2 TPVS (min - max 1-5) with a median cephalad-caudal spread of 5 cm (min - max 1-18). By multivariate analysis, the sagittal approach was an independent factor of success (OR 2.75). Dye spread and pleural entry were influenced by neither the approach nor the site of injection. CONCLUSIONS: Paravertebral spread of TPVI is variable. USG technique has higher anatomical success rates than the LOR technique, the sagittal USG approach being the most successful.

Pharmacokinetic and Pharmacodynamic Analysis of Alfaxalone Administered as a Bolus Intravenous Injection of Phaxan in a Phase 1 Randomized Trial.

BACKGROUND: Previous formulations of alfaxalone have shown it to be a fast-acting intravenous anesthetic with high therapeutic index. Alfaxalone has been reformulated for human use as Phaxan, an aqueous solution of 10 mg/mL of alfaxalone and 13% betadex. This study assessed the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of alfaxalone given as a bolus intravenous injection of this formulation to human male volunteers. METHODS: A dose of 0.5 mg/kg (0.42-0.55 mg/kg) of alfaxalone [mean (range)] was given by single intravenous bolus injection to 12 healthy subjects. Plasma alfaxalone concentrations and bispectral index (BIS) values were analyzed using an integrated pharmacokinetic-pharmacodynamic (PKPD) model using nonlinear mixed-effects models. Effect (BIS) was described using a sigmoidal fractional maximum effect (EMAX) model. All parameters were scaled using allometry and standardized to a 70-kg person using exponents of 0.75 for clearance parameters (CL, Q2, and Q3), 1.0 for volumes (V1, V2, and V3), and 0.25 for time-related parameters half-time keo (t1/2keo). RESULTS: A 3-compartment model used to fit PK data with an additional compartment, linked by t1/2keo to describe the effect compartment, yielded alfaxalone PK parameter estimates: CL: 1.08 L/min; 0.87-1.34 L/min (median; 95% confidence interval [CI]); central volume of distribution (V1): 0.99 L; 0.53-2.05 L (median; 95% CI); intercompartment CLs (Q2): 0.87 L/min; 0.32-1.71 L/min (median; 95% CI) and Q3: 0.46 L/min; 0.19-1.03 L/min (median; 95% CI); and peripheral volumes of distribution (V2): 6.36 L; 2.79-10.7 L (median; 95% CI) and V3: 19.1 L; 8.61-37.4 L (median; 95% CI). PD interrogation assumed a baseline BIS of 96, with an estimated EMAX: 0.94; 0.71-0.99 (median; 95% CI), a plasma concentration (Cp) for 50% effect (C50): 0.98 mg/L; 0.83-1.09 mg/L (median; 95% CI), and a Hill coefficient (γ): 12.1; 6.7-15 (median; 95% CI). The t1/2keo was 8 minutes; 4.70-12.8 minutes (median; 95% CI). The mean time to a BIS 50 was 0.94 minutes (standard deviation [SD] = 0.2 minutes). CONCLUSIONS: After a single bolus intravenous injection, alfaxalone has a high plasma CL equal to hepatic blood flow as reported for earlier studies of bolus injections of a previous formulation of alfaxalone. The plasma levels associated with BIS values of <60 are comparable to those previously reported in patients anesthetized with alfaxalone. The t1/2keo is relatively high, but the large Hill coefficient contributes to rapid onset and offset of action. This information can inform future studies of this formulation.

Understanding volume kinetics.

The distribution and elimination kinetics of the water volume in infusion fluids can be studied by volume kinetics. The approach is a modification of drug pharmacokinetics and uses repeated measurements of blood hemoglobin and urinary excretion as input variables in (usually) a two-compartment model with expandable walls. Study results show that crystalloid fluid has a distribution phase that gives these fluids a plasma volume expansion amounting to 50%-60% of the infused volume as long as the infusion lasts, while the fraction is reduced to 15%-20% within 30 minutes after the infusion ends. Small volumes of crystalloid barely distribute to the interstitium, whereas rapid infusions tend to cause edema. Fluid elimination is very slow during general anesthesia due to the vasodilatation-induced reduction of the arterial pressure, whereas elimination is less affected by hemorrhage. The half-life is twice as long for saline than for Ringer solutions. Elimination is slower in conscious males than conscious females, and high red blood cell and thrombocyte counts retard both distribution and re-distribution. Children have faster turnover than adults. Plasma volume expansions are similar for glucose solutions and Ringer's, but the expansion duration is shorter for glucose. Concentrated urine before and during infusion slows down the elimination of crystalloid fluid. Colloid fluids have no distribution phase, an intravascular persistence half-life of 2-3 hours, and-at least for hydroxyethyl starch-the ability to reduce the effect of subsequently infused crystalloids. Accelerated distribution due to degradation of the endothelial glycocalyx layer has not yet been demonstrated.

Pharmacodynamics and pharmacokinetics in older adults.

PURPOSE OF REVIEW: With the growing of the aging population, increased and new methods of anesthesia and surgery allow for surgery and other interventions in older adults.Pharmacokinetics and pharmacodynamics of drugs in older adults differ from those in younger and middle-aged adults. However, the geriatric population is frequently neglected in the context of clinical trials. The present review focuses on the consequences of multimorbidity and pharmacokinetic and pharmacodynamic alterations and their implications on anesthesia. RECENT FINDINGS: Physiologically based pharmacokinetic and pharmacodynamic modeling may serve as an option to better understand the influence of age on drugs used for anesthesia. However, difficulties to adequately characterize geriatric patients are described. SUMMARY: Further research of drug effects in the aging population may include physiologically based pharmacokinetic and pharmacodynamic complex models and randomized controlled trials with thoroughly conducted geriatric assessments.

Adaptive optimal target controlled infusion algorithm to prevent hypotension associated with labor epidural: An adaptive dynamic programming approach.

Patients receiving labor epidurals commonly experience arterial hypotension as a complication of neuraxial block. The purpose of this study was to design an adaptive optimal controller for an infusion system to regulate mean arterial pressure. A state-space model relating mean arterial pressure to Norepinephrine (NE) infusion rate was derived for controller design. A data-driven adaptive optimal control algorithm was developed based on adaptive dynamic programming (ADP). The stability and disturbance rejection ability of the closed-loop system were tested via a simulation model calibrated using available clinical data. Simulation results indicated that the settling time was six minutes and the system showed effective disturbance rejection. The results also demonstrate that the adaptive optimal control algorithm would achieve individualized control of mean arterial pressure in pregnant patients with no prior knowledge of patient parameters.

Anatomical description of anaesthetic spread after deep erector spinae block at L-4. / Estudio anatómico de la distribución del volumen administrado tras bloqueo en el plano profundo del erector espinal a nivel lumbar.

INTRODUCTION: Thoracic erector spinae plane (ESP) block is now used for postoperative analgesia. However, although reports of lumbar ESP have been published, the anesthetic spread and mechanism of action of this technique remains unclear. We describe the lumbar ESP block technique and evaluate the spread of 20ml of solution administered at the level of the transverse process of L4 in a cadaver model. METHODS: Observational study after 12 lumbar ESP blocks at L4 on a fresh cadaver model (6 bilaterally). The spread of 20ml of injected contrast solution was assessed by computed tomography in all 6 samples. Four of the samples were evaluated by anatomical study, 2 by plane dissection, and 2 others were frozen and cut into 2-2.5cm axial slices. RESULTS: The injected solution spread from L2 to L5 in a cranio-caudal direction in the erector spinae muscle, reaching the facet joints medially and the thoracolumbar fascia laterally. In 33% of cases the solution did not spread anterior to the transverse process; in 51%, spread was minimal and did not affect the corresponding spinal nerves, and in 2 samples (16%), spread was extensive and reached the corresponding spinal nerves. CONCLUSIONS: Lumbar ESP at L4 always acts on the posterior branches of the spinal nerves, but seldom spreads to the paravertebral space to block the spinal nerve.

Pharmacokinetics and pharmacodynamics of alfaxalone after a single intramuscular or intravascular injection in mallard ducks (Anas platyrhynchos).

Pharmacokinetics and pharmacodynamics of alfaxalone was performed in mallard ducks (Anas platyrhynchos) after single bolus injections of 10 mg/kg administered intramuscularly (IM; n = 10) or intravenously (IV; n = 10), in a randomized cross-over design with a washout period between doses. Mean (±SD) Cmax following IM injection was 1.6 (±0.8) µg/ml with Tmax at 15.0 (±10.5) min. Area under the curve (AUC) was 84.66 and 104.58 min*mg/ml following IV and IM administration, respectively. Volume of distribution (VD ) after IV dose was 3.0 L/kg. The mean plasma clearance after 10 mg/kg IV was 139.5 (±67.9) ml min-1  kg-1 . Elimination half-lives (mean [±SD]) were 15.0 and 16.1 (±3.0) min following IV and IM administration, respectively. Mean bioavailability at 10 mg/kg IM was 108.6%. None of the ducks achieved a sufficient anesthetic depth for invasive procedures, such as surgery, to be performed. Heart and respiratory rates measured after administration remained stable, but many ducks were hyperexcitable during recovery. Based on sedation levels and duration, alfaxalone administered at dosages of 10 mg/kg IV or IM in mallard ducks does not induce clinically acceptable anesthesia.

Mucoadhesive Electrospun Patch Delivery of Lidocaine to the Oral Mucosa and Investigation of Spatial Distribution in a Tissue Using MALDI-Mass Spectrometry Imaging.

Many oral mucosal conditions cause considerable and prolonged pain that to date has been difficult to alleviate via topical delivery, and the use of injection causes many patients dental anxiety and needle-prick pain. Therefore, developing a noninjectable drug delivery system as an alternative administration procedure may vastly improve the health and wellbeing of these patients. Recent advances in the development of mucoadhesive electrospun patches for the direct delivery of therapeutics to the oral mucosa offer a potential solution, but as yet, the release of local anesthetics from this system and their uptake by oral tissue have not been demonstrated. Here, we demonstrate the fabrication of lidocaine-loaded electrospun fiber patches, drug release, and subsequent uptake and permeation through the porcine buccal mucosa. Lidocaine HCl and lidocaine base were incorporated into the electrospun patches to evaluate the difference in drug permeation for the two drug compositions. Lidocaine released from the lidocaine HCl-containing electrospun patches was significantly quicker than from the lidocaine base patches, with double the amount of drug released from the lidocaine HCl patches in the first 15 min (0.16 ± 0.04 mg) compared to that from the lidocaine base patches (0.07 ± 0.01 mg). The permeation of lidocaine from the lidocaine HCl electrospun patches through ex vivo porcine buccal mucosa was also detected in 15 min, whereas permeation of lidocaine from the lidocaine base patch was not detected. Matrix-assisted laser desorption ionization-mass spectrometry imaging was used to investigate localization of lidocaine within the oral tissue. Lidocaine in the solution as well as from the mucoadhesive patch penetrated into the buccal mucosal tissue in a time-dependent manner and was detectable in the lamina propria after only 15 min. Moreover, the lidocaine released from lidocaine HCl electrospun patches retained biological activity, inhibiting veratridine-mediated opening of voltage-gated sodium channels in SH-SY5Y neuroblastoma cells. These data suggest that a mucoadhesive electrospun patch may be used as a vehicle for rapid uptake and sustained anesthetic drug delivery to treat or prevent oral pain.

Rapid electrophoretic monitoring of the anaesthetic ketamine and its metabolite norketamine in rat blood using a contactless conductivity detector to study the pharmacokinetics.

A method of capillary electrophoresis with contactless conductivity detection has been developed for non-enantioselective monitoring the anaesthetic ketamine and its main metabolite norketamine. The separation is performed in a 15 µm capillary with an overall length of 31.5 cm and length to detector of 18 cm; inner surface of the capillary is covered with a commercial coating solution to reduce the electroosmotic flow. In an optimised background electrolyte with composition 2 M acetic acid + 1% v/v coating solution under application of a high voltage of 30 kV, the migration time is 97.1 s for ketamine and 95.8 s for norketamine, with an electrophoretic resolution of 1.2. The attained detection limit was 83 ng/mL (0.3 µmol/L) for ketamine and 75 ng/mL (0.3 µmol/L) for norketamine; the number of theoretic plates for separation of an equimolar model mixture with a concentration of 2 µg/mL was 683 500 plates/m for ketamine and 695 400 plates/m for norketamine. Laboratory preparation of rat blood plasma is based on mixing 10 µL of plasma with 30 µL of acidified acetonitrile, followed by centrifugation. A pharmacokinetic study demonstrated an exponential decrease in the plasma concentration of ketamine after intravenous application and much slower kinetics for intraperitoneal application.

Perioperative Intravenous Lidocaine Infusion Adverse Reaction: A Case Report.

Intravenous lidocaine is increasingly being utilized as an opioid-sparing analgesic. A 55-year-old man with well-controlled human immunodeficiency virus on highly active antiretroviral therapy was prescribed a lidocaine infusion at 1 mg/kg/h for postoperative pain. On postoperative day 2, the patient experienced 4 unresponsive episodes with tachycardia, hypertension, and oxygen desaturation. Serum lidocaine level was available 2 days later (high 6.3 µg/mL, therapeutic range 2.5-3.5 µg/mL). There is significant pharmacokinetic interaction between lidocaine and this patient's human immunodeficiency virus medications. This case highlights the need for a readily accessible list of medications that caution against lidocaine. We propose in-house serum lidocaine levels to monitor patients at an increased risk for toxicity.