Population Pharmacokinetics of Single Bolus Dose Fentanyl in Obese Children.

BACKGROUND: Childhood obesity is a significant problem. Obesity may alter the pharmacokinetics (PKs) of medications. Fentanyl is commonly used for procedural sedation, but there is a paucity of bolus dose fentanyl PK data in obese children. Better understanding of fentanyl PK in obese children would facilitate dosing recommendations. We conducted a study involving children with and without obesity to assess the potential differences in bolus dose fentanyl PK between the 2 groups. METHODS: We enrolled children 2 to 12 years of age with and without obesity, defined as >95th percentile body mass index (BMI) for age and sex, undergoing elective tonsillectomy ± adenoidectomy. After induction, subjects had 2 intravenous (IV) lines placed in 2 different extremities: 1 for medications and IV fluids and 1 for obtaining blood aliquots for fentanyl concentration analysis. After administration of 1 mcg/kg of fentanyl based on total body weight (TBW), blood sample collections for fentanyl concentration analysis were attempted at 5, 15, 30, 60, 90, and 120 minutes. Five-minute fentanyl concentrations were compared between obese and nonobese cohorts. Population PK analysis to examine the differences between obese and nonobese children was performed and included various body size descriptors, such as TBW, BMI, and fat-free mass (FFM), to examine their influence on model parameters. RESULTS: Half of the 30 subjects were obese. Mean fentanyl concentrations at 5 minutes were 0.53 ng/mL for the nonobese group and 0.88 ng/mL for the obese group, difference 0.35 ng/mL (95% CI, 0.08-0.61 ng/mL; P = .01). Population PK analysis showed that FFM was a significant covariate for the central volume of distribution. The potential clinical effect of an IV bolus dose of fentanyl based on TBW versus FFM in an obese child was assessed in a simulation using our model. 1 mcg/kg fentanyl dose based on TBW resulted in an approximately 60% higher peak fentanyl effect site concentration than dosing based on FFM. CONCLUSIONS: Our data demonstrated higher peak plasma fentanyl concentrations in obese compared to nonobese subjects. Population PK analysis found that FFM was a significant covariate for the central volume of distribution. Model simulation showed dosing of fentanyl in obese children based on TBW resulted in significantly higher peak concentrations than dosing based on FFM. Based on this modeling and the known concentration-effect relationship between fentanyl and adverse effects, our results suggest that bolus dosing of fentanyl in obese children should be based on FFM rather than TBW, particularly for procedures of short duration.

Hypoxemia in School-age Children Undergoing One-lung Ventilation: A Retrospective Cohort Study from the Multicenter Perioperative Outcomes Group.

BACKGROUND: Risk factors for hypoxemia in school-age children undergoing one-lung ventilation remain poorly understood. The hypothesis was that certain modifiable and nonmodifiable factors may be associated with increased risk of hypoxemia in school-age children undergoing one-lung ventilation and thoracic surgery. METHODS: The Multicenter Perioperative Outcomes Group database was queried for children 4 to 17 yr of age undergoing one-lung ventilation. Patients undergoing vascular or cardiac procedures were excluded. The original cohort was divided into two cohorts: 4 to 9 and 10 to 17 yr of age inclusive. All records were reviewed electronically for the primary outcome of hypoxemia during one-lung ventilation, which was defined as an oxygen saturation measured by pulse oximetry (Spo2) less than 90% for 3 min or longer continuously, while severe hypoxemia was defined as Spo2 less than 90% for 5 min or longer. Potential modifiable and nonmodifiable risk factors associated with these outcomes were evaluated using separate multivariable least absolute shrinkage and selection operator regression analyses for each cohort. The covariates evaluated included age, extremes of weight, American Society of Anesthesiologists Physical Status of III or higher, duration of one-lung ventilation, preoperative Spo2 less than 98%, approach to one-lung ventilation, right operative side, video-assisted thoracoscopic surgery, lower tidal volume ventilation (defined as tidal volume of 6 ml/kg or less and positive end-expiratory pressure of 4 cm H2O or greater for more than 80% of the duration of one-lung ventilation), and procedure type. RESULTS: The prevalence of hypoxemia in the 4- to 9-yr-old cohort and the 10- to 17-yr-old cohort was 24 of 228 (10.5% [95% CI, 6.5 to 14.5%]) and 76 of 1,012 (7.5% [95% CI, 5.9 to 9.1%]), respectively. The prevalence of severe hypoxemia in both cohorts was 14 of 228 (6.1% [95% CI, 3.0 to 9.3%]) and 47 of 1,012 (4.6% [95% CI, 3.3 to 5.8%]). Initial Spo2 less than 98% was associated with hypoxemia in the 4- to 9-yr-old cohort (odds ratio, 4.20 [95% CI, 1.61 to 6.29]). Initial Spo2 less than 98% (odds ratio, 2.76 [95% CI, 1.69 to 4.48]), extremes of weight (odds ratio, 2.18 [95% CI, 1.29 to 3.61]), and right-sided cases (odds ratio, 2.33 [95% CI, 1.41 to 3.92]) were associated with an increased risk of hypoxemia in the older cohort. Increasing age (1-yr increment; odds ratio, 0.88 [95% CI, 0.80 to 0.97]) was associated with a decreased risk of hypoxemia. CONCLUSIONS: An initial room air oxygen saturation of less than 98% was associated with an increased risk of hypoxemia in all children 4 to 17 yr of age. Extremes of weight, right-sided cases, and decreasing age were associated with an increased risk of hypoxemia in children 10 to 17 yr of age.

Anesthesia for laryngotracheal reconstruction in children: A narrative review.

Laryngotracheal stenosis, congenital or acquired, is a common cause of pediatric airway obstruction. Acquired subglottic stenosis frequently results from prolonged neonatal intubation. The clinical presentation of subglottic stenosis is variable, ranging from biphasic stridor and frequent upper respiratory infections to acute airway compromise. Optimal patient care requires clinical coordination within a multidisciplinary subspecialty team. Medical management includes optimizing respiratory status, gastroesophageal reflux, speech, feeding, nutrition therapies, and providing psychosocial support. If surgical intervention is required, the otolaryngologist, anesthesiologist, and perioperative team must collaborate closely to ensure successful operative outcomes. This narrative review of laryngotracheal stenosis will discuss the pathophysiology, clinical evaluation, medical management, and surgical interventions, and focus on the perioperative anesthetic considerations for children undergoing laryngotracheal reconstruction.

Care Levels for Fetal Therapy Centers.

Fetal therapies undertaken to improve fetal outcome or to optimize transition to neonate life often entail some level of maternal, fetal, or neonatal risk. A fetal therapy center needs access to resources to carry out such therapies and to manage maternal, fetal, and neonatal complications that might arise, either related to the therapy per se or as part of the underlying fetal or maternal condition. Accordingly, a fetal therapy center requires a dedicated operational infrastructure and necessary resources to allow for appropriate oversight and monitoring of clinical performance and to facilitate multidisciplinary collaboration between the relevant specialties. Three care levels for fetal therapy centers are proposed to match the anticipated care complexity, with appropriate resources to achieve an optimal outcome at an institutional and regional level. A level I fetal therapy center should be capable of offering fetal interventions that may be associated with obstetric risks of preterm birth or membrane rupture but that would be very unlikely to require maternal medical subspecialty or intensive care, with neonatal risks not exceeding those of moderate prematurity. A level II center should have the incremental capacity to provide maternal intensive care and to manage extreme neonatal prematurity. A level III therapy center should offer the full range of fetal interventions (including open fetal surgery) and be able manage any of the associated maternal complications and comorbidities, as well as have access to neonatal and pediatric surgical intervention including indicated surgery for neonates with congenital anomalies.

The Changing Face of Cystic Fibrosis: An Update for Anesthesiologists.

Cystic fibrosis (CF) is the most common fatal genetic disease in North America. While CF is more common among Whites, it is increasingly being recognized in other races and ethnicities. Although there is no cure, life expectancy has steadily improved, with the median survival exceeding 46 years in the United States. There are now more adults than children with CF in the United States. CF is caused by mutations in a gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, expressed in many epithelial cells. More than 2100 CFTR mutations have been linked to CF, and newer CFTR modulator drugs are being used to improve the production, intracellular processing, and function of the defective CFTR protein. CF is a multisystem disease that affects primarily the lungs, pancreas, hepatobiliary system, and reproductive organs. Anesthesiologists routinely encounter CF patients for various surgical and medical procedures, depending on the age group. This review article focuses on the changing epidemiology of CF, advances in the classification of CFTR mutations, the latest innovations in CFTR modulator therapies, the impact of the coronavirus disease pandemic, and perioperative considerations that anesthesiologists must know while caring for patients with CF.

Society for Maternal-Fetal Medicine Consult Series #59: The use of analgesia and anesthesia for maternal-fetal procedures.

Pain is a complex phenomenon that involves more than a simple physical response to external stimuli. In maternal-fetal surgical procedures, fetal analgesia is used primarily to blunt fetal autonomic responses and minimize fetal movement. The purpose of this Consult is to review the literature on what is known about the potential for fetal awareness of pain and to discuss the indications for and the risk-benefit calculus involved in the use of fetal anesthesia and analgesia. The recommendations by the Society for Maternal-Fetal Medicine are as follows: (1) we suggest that fetal paralytic agents be considered in the setting of intrauterine transfusion, if needed, for the purpose of decreasing fetal movement (GRADE 2C); (2) although the fetus is unable to experience pain at the gestational age when procedures are typically performed, we suggest that opioid analgesia should be administered to the fetus during invasive fetal surgical procedures to attenuate acute autonomic responses that may be deleterious, avoid long-term consequences of nociception and physiological stress on the fetus, and decrease fetal movement to enable the safe execution of procedures (GRADE 2C); and (3) due to maternal risk and a lack of evidence supporting benefit to the fetus, we recommend against the administration of fetal analgesia at the time of pregnancy termination (GRADE 1C).

Error traps in pediatric one-lung ventilation.

With the advent of thoracoscopic surgery, the benefits of lung isolation in children have been increasingly recognized. However, because of the small airway dimensions, equipment limitations in size and maneuverability, and limited respiratory reserve, one-lung ventilation in children remains challenging. This article highlights some of the most common error traps in the management of pediatric lung isolation and focuses on practical solutions for their management. The error traps discussed are as follows: (1) the failure to take into consideration relevant aspects of tracheobronchial anatomy when selecting the size of the lung isolation device, (2) failure to execute correct placement of the device chosen for lung isolation, (3) failure to maintain lung isolation related to surgical manipulation and isolation device movement, (4) failure to select appropriate ventilator strategies during one-lung ventilation, and (5) failure to appropriately manage and treat hypoxemia in the setting of one-lung ventilation.

Society for Maternal-Fetal Medicine Consult Series #59: The use of analgesia and anesthesia for maternal-fetal procedures.

Pain is a complex phenomenon that involves more than a simple physical response to external stimuli. In maternal-fetal surgical procedures, fetal analgesia is used primarily to blunt fetal autonomic responses and minimize fetal movement. The purpose of this Consult is to review the literature on what is known about the potential for fetal awareness of pain and to discuss the indications for and the risk-benefit calculus involved in the use of fetal anesthesia and analgesia. The recommendations by the Society for Maternal-Fetal Medicine are as follows: (1) we suggest that fetal paralytic agents be considered in the setting of intrauterine transfusion, if needed, for the purpose of decreasing fetal movement (GRADE 2C); (2) although the fetus is unable to experience pain at the gestational age when procedures are typically performed, we suggest that opioid analgesia should be administered to the fetus during invasive fetal surgical procedures to attenuate acute autonomic responses that may be deleterious, avoid long-term consequences of nociception and physiological stress on the fetus, and decrease fetal movement to enable the safe execution of procedures (GRADE 2C); and (3) due to maternal risk and a lack of evidence supporting benefit to the fetus, we recommend against the administration of fetal analgesia at the time of pregnancy termination (GRADE 1C).

Anesthesia for Maternal-Fetal Interventions: A Survey of Fetal Therapy Centers in the North American Fetal Therapy Network.

INTRODUCTION: A wide range of fetal interventions are performed across fetal therapy centers (FTCs). We hypothesized that there is significant variability in anesthesia staffing and anesthetic techniques. METHODS: We conducted an online survey of anesthesiology directors at every FTC within the North American Fetal Therapy Network (NAFTNet). The survey included details of fetal interventions performed in 2018, anesthesia staffing models, anesthetic techniques, fetal monitoring, and postoperative management. RESULTS: There was a 92% response rate. Most FTCs are located within an adult hospital and employ a small team of anesthesiologists. There is heterogeneity when evaluating anesthesiology fellowship training and staffing, indicating there is a multidisciplinary specialty team-based approach even within anesthesiology. Minimally invasive fetal interventions were the most commonly performed. The majority of FTCs also performed ex utero intrapartum treatment (EXIT) and open mid-gestation procedures under general anesthesia (GA). Compared to FTCs only performing minimally invasive procedures, FTCs performing open fetal procedures were more likely to have a pediatric surgeon as director and performed more minimally invasive procedures. CONCLUSIONS: There is considerable variability in anesthesia staffing, caseload, and anesthetic techniques among FTCs in NAFTNet. Most FTCs used maternal sedation for minimally invasive procedures and GA for EXIT and open fetal surgeries.

Vaping and E-Cigarette Use in Children and Adolescents: Implications on Perioperative Care From the American Society of Anesthesiologists Committee on Pediatric Anesthesia, Society for Pediatric Anesthesia, and American Academy of Pediatrics Section on Anesthesiology and Pain Medicine.

Electronic cigarettes (e-cigarettes) or vaping use in adolescents has emerged as a public health crisis that impacts the perioperative care of this vulnerable population. E-cigarettes have become the most commonly used tobacco products among youth in the United States. Fruit and mint flavors and additives such as marijuana have enticed children and adolescents. E-cigarette, or vaping, product use-associated lung injury (EVALI) is a newly identified lung disease linked to vaping. Clinical presentation of EVALI can be varied, but most commonly includes the respiratory system, gastrointestinal (GI) tract, and constitutional symptoms. Clinical management of EVALI has consisted of vaping cessation and supportive therapy, including supplemental oxygen, noninvasive ventilation, mechanical ventilation, glucocorticoids, and empiric antibiotics, until infectious causes are eliminated, and in the most severe cases, extracorporeal membrane oxygenation (ECMO). Currently, although there is an insufficient evidence to determine the safety and the efficacy of e-cigarettes for perioperative smoking cessation, EVALI clearly places these patients at an increased risk of perioperative morbidity. Given the relatively recent introduction of e-cigarettes, the long-term impact on adolescent health is unknown. As a result, the paucity of postoperative outcomes in this potentially vulnerable population does not support evidence-based recommendations for the management of these patients. Clinicians should identify "at-risk" individuals during preanesthetic evaluations and adjust the risk stratification accordingly. Our societies encourage continued education of the public and health care providers of the risks associated with vaping and nicotine use and encourage regular preoperative screening and postoperative outcome studies of patients with regard to smoking and vaping use.

Error traps in anesthesia for fetal interventions.

A wide range of fetal interventions are being performed worldwide to save the fetus's life, prevent permanent fetal organ damage, and allow a successful transition to extrauterine life. However, these are invasive procedures and can be associated with serious complications. This article focuses on promoting a culture of safety by highlighting five common error traps while anesthetizing patients for fetal interventions. They include failure to preserve uteroplacental perfusion and gas exchange, failure to achieve adequate uterine relaxation prior to hysterotomy, failure to monitor the fetus and prepare for fetal/neonatal resuscitation, failure to prepare for maternal hemorrhage, and failure to promptly treat uterine atony. Practical tips for avoiding these serious complications will also be discussed.

An Update on One-Lung Ventilation in Children.

One-lung ventilation in children continues to present technical and sometimes physiologic challenges to the clinician. The rarity of these cases at any single institution, however, has led to very few prospective trials to guide best practices. As a result, most clinicians continue to be guided by local tradition and preference. That said, the development of new bronchial blockers such as the EZ-Blocker or blocking devices such as the Univent tube have continued to evolve the practice of lung isolation in children. Further, the development of a variety of extraluminal blocker techniques has led to innovations in practice through a relatively diverse landscape of published case series offering different approaches to one-lung ventilation during the past 15 years. The Arndt bronchial blocker continues to represent the most well documented of these devices. Additionally, recent advances have occurred in our understanding of the relevant anatomic constraints of the lower pediatric airway. This review is intended to provide a comprehensive and practical update to practicing pediatric anesthesiologists to further their understanding of the modern practice of one-lung ventilation for thoracic surgery in children.

Anesthesia for Maternal-Fetal Interventions: A Consensus Statement From the American Society of Anesthesiologists Committees on Obstetric and Pediatric Anesthesiology and the North American Fetal Therapy Network.

Maternal-fetal surgery is a rapidly evolving specialty, and significant progress has been made over the last 3 decades. A wide range of maternal-fetal interventions are being performed at different stages of pregnancy across multiple fetal therapy centers worldwide, and the anesthetic technique has evolved over the years. The American Society of Anesthesiologists (ASA) recognizes the important role of the anesthesiologist in the multidisciplinary approach to these maternal-fetal interventions and convened a collaborative workgroup with representatives from the ASA Committees of Obstetric and Pediatric Anesthesia and the Board of Directors of the North American Fetal Therapy Network. This consensus statement describes the comprehensive preoperative evaluation, intraoperative anesthetic management, and postoperative care for the different types of maternal-fetal interventions.

New Trends in Fetal Anesthesia.

Fetal anesthesia teams must understand the pathophysiology and rationale for the treatment of each disease process. Treatment can range from minimally invasive procedures to maternal laparotomy, hysterotomy, and major fetal surgery. Timing may be in early, mid-, or late gestation. Techniques continue to be refined, and the anesthetic plans must evolve to meet the needs of the procedures. Anesthetic plans range from moderate sedation to general anesthesia that includes monitoring of 2 patients simultaneously, fluid restriction, invasive blood pressure monitoring, vasopressor administration, and advanced medication choices to optimize fetal cardiac function.

Folate decorated epigallocatechin-3-gallate (EGCG) loaded PLGA nanoparticles; in-vitro and in-vivo targeting efficacy against MDA-MB-231 tumor xenograft.

Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent of green tea exhibits significant anti-cancer potential over a wide range of cancer cells. We have developed folate peptide decorated PLGA-NPs loaded with EGCG (FP-EGCG-NPs) to bind folate receptor (FR) specific breast cancer cell lines and evaluated their efficacy in pre-clinical studies. EGCG loaded PLGA nanoparticles (EGCG-NPs) were characterised for size, surface morphology, surface charge, encapsulation efficacy and in-vitro drug release kinetics. Cellular uptake and in-vitro cytotoxicities of free drug, folate peptide conjugated and unconjugated EGCG-NPs were investigated against FR positive MDA-MB-231 and MCF-7 cells. The conjugated nanoparticles exhibited promising cytotoxic potentials as well as significantly high cellular internalisation in MDA-MB-231 cells as compared to unconjugated one. It also ensured longer half life, higher plasma concentration, favourably high apoptotic potential and significantly high mitochondrial depolarization effect as compared to free EGCG. The loaded nanoparticles were radiolabeled with technetium-99m and their tumor selectivity in MDA-MB-231 tumor bearing nude mice was investigated by scintigraphic imaging study. Finally in-vivo therapeutic efficacy studies in tumor bearing nude mice were also done to evaluate the efficacy of the formulation for cancer treatment.

Indomethacin Dosing and Constriction of the Ductus Arteriosus During Open Fetal Surgery for Myelomeningocele Repair.

INTRODUCTION: The use of perioperative tocolytic agents in fetal surgery is imperative to prevent preterm labor. Indomethacin, a well-known tocolytic agent, can cause ductus arteriosus (DA) constriction. We sought to determine whether a relationship exists between preoperative indomethacin dosing and fetal DA constriction. MATERIALS AND METHODS: This is an IRB-approved, single-center retrospective observational case series of 42 pregnant mothers who underwent open fetal myelomeningocele repair. Preoperatively, mothers received either 1 (QD) or 2 (BID) indomethacin doses. Maternal anesthetic drug exposures and fetal cardiac dysfunction measures were collected from surgical and anesthesia records and intraoperative fetal echocardiography. Pulsatility Index was used to calculate DA constriction severity. Comparative testing between groups was performed using t- and chi-square testing. RESULTS: DA constriction was observed in all fetuses receiving BID indomethacin and in 71.4% of those receiving QD dosing (p = 0.0002). Severe DA constriction was observed only in the BID group (35.7%). QD indomethacin group received more intraoperative magnesium sulfate (p < 0.0001). Minimal fetal cardiac dysfunction (9.5%) and bradycardia (9.5%) were observed in all groups independent of indomethacin dosing. CONCLUSIONS: DA constriction was the most frequent and severe in the BID indomethacin group. QD indomethacin and greater magnesium sulfate dosing was associated with reduced DA constriction.

Garcinol loaded vitamin E TPGS emulsified PLGA nanoparticles: preparation, physicochemical characterization, in vitro and in vivo studies.

Garcinol (GAR) is a naturally occurring polyisoprenylated phenolic compound. It has been recently investigated for its biological activities such as antioxidant, anti-inflammatory, anti ulcer, and antiproliferative effect on a wide range of human cancer cell lines. Though the outcomes are very promising, its extreme insolubility in water remains the main obstacle for its clinical application. Herein we report the formulation of GAR entrapped PLGA nanoparticles by nanoprecipitation method using vitamin E TPGS as an emulsifier. The nanoparticles were characterized for size, surface morphology, surface charge, encapsulation efficiency and in vitro drug release kinetics. The MTT assay depicted a high amount of cytotoxicity of GAR-NPs in B16F10, HepG2 and KB cells. A considerable amount of cell apoptosis was observed in B16f10 and KB cell lines. In vivo cellular uptake of fluorescent NPs on B16F10 cells was also investigated. Finally the GAR loaded NPs were radiolabeled with technetium-99m with >95% labeling efficiency and administered to B16F10 melanoma tumor bearing mice to investigate the in vivo deposition at the tumor site by biodistribution and scintigraphic imaging study. In vitro cellular uptake studies and biological evaluation confirm the efficacy of the formulation for cancer treatment.

Anesthesia for fetal surgery.

Fetal therapy is an exciting and growing field of medicine. Advances in prenatal imaging and continued innovations in surgical and anesthetic techniques have resulted in a wide range of fetal interventions including minimally invasive, open mid-gestation, and ex-utero intrapartum treatment procedures. The potential for maternal morbidity is significant and must be carefully weighed against claimed benefits to the fetus. Appropriate patient selection is critical, and a multidisciplinary team-based approach is strongly recommended. The anesthetic management should focus on maintaining uteroplacental circulation, achieving profound uterine relaxation, optimizing surgical conditions, monitoring fetal hemodynamics, and minimizing maternal and fetal risk.