Search

Purpose of review Both cannabis and e-cigarette use are increasing, particularly among adolescents. The use of cannabis products may impact patients' physiology under anesthesia. Understanding the effects of cannabis and vaping are critical to the provision of safe and effective anesthetic care. Recent findings E-cigarettes have recently been implicated in a severe presentation of acute lung injury, often in association with vaporization of the cannabinoid, THC. E-cigarette use appears to be associated with other less-acute pulmonary adverse effects that are yet to be fully understood. Cannabis affects many organ systems with alterations in cardiovascular, respiratory and neurological function. Specifically, there is emerging evidence that cannabis use may reduce the efficacy of sedative agents and postoperative pain management efforts. Summary There is a very wide variety of cannabis products currently available, with respect to both route of administration as well as cannabinoid content. Patients using cannabis products prior to anesthesia may present with altered physiology that place them at increased risk for cardiovascular and respiratory complications. They may also be tolerant to the effects of propofol and opioid for pain management, thus consideration should be given to use of a multimodal regimen.

Purpose Interest in the use of artisanal cannabinoids in pediatric epilepsy has increased but safety and utility data are lacking. Our aim was to prospectively characterize the use of oral cannabis extracts (OCE) in a refractory pediatric epilepsy population. Methods Families considering the use of an OCE were enrolled in a prospective observational study. Baseline seizure frequency was assessed over a period of 4 weeks. Seizure frequency, CBD and THC-COOH levels were assessed every 4 weeks during a 12-week treatment period. Response was defined as at least a 50% reduction in seizure frequency over the final 8 weeks of the study relative to baseline. Results Consent was obtained in 32 children; 11 were excluded from analysis (3 failed to complete baseline data, 3 started OCE before completing baseline period and 5 did not start OCE) leaving 21 to be included in subsequent analyses. Median age was 10.3 years (IQR 6.8–12.6), 13 (62%) were male and median seizure frequency was 2.7 seizures/day during the baseline period. The median of the high dose of CBD that was administered during the observation period was of 0.9 (0.6–2.2) mg/kg/day. Of the 21 subjects who were included in the analysis, 5 (24%) were responders. OCE was stopped early in 3 subjects (14%) due to a perceived increase in seizures. THC-COOH and CBD blood levels did not have a significant association with response status (p = 0.95 CBD, p = 0.53 THC-COOH, N = 14). Conclusion The observed response rate in this study is similar to placebo rates in prospective randomized trials of pharmaceutical grade products and the withdrawal rate is greater than rates obtained with retrospective methods. Doses of OCE administered were lower than doses used in randomized trials.

Summary Opioids have long held a prominent role in the management of perioperative pain in adults and children. Published reports concerning the appropriate, and inappropriate, use of these medications in pediatric patients have appeared in various publications over the last 50 years. For this document, the Society for Pediatric Anesthesia appointed a taskforce to evaluate the available literature and formulate recommendations with respect to the most salient aspects of perioperative opioid administration in children. The recommendations are graded based on the strength of the available evidence, with consensus of the experts applied for those issues where evidence is not available. The goal of the recommendations was to address the most important issues concerning opioid administration to children after surgery, including appropriate assessment of pain, monitoring of patients on opioid therapy, opioid dosing considerations, side effects of opioid treatment, strategies for opioid delivery, and assessment of analgesic efficacy. Regular updates are planned with a re‐release of guidelines every 2 years.

Objectives To assess if morphine pharmacokinetics are different in children with Down syndrome when compared with children without Down syndrome. Design Prospective single-center study including subjects with Down syndrome undergoing cardiac surgery (neonate to 18 yr old) matched by age and cardiac lesion with non-Down syndrome controls. Subjects were placed on a postoperative morphine infusion that was adjusted as clinically necessary, and blood was sampled to measure morphine and its metabolites concentrations. Morphine bolus dosing was used as needed, and total dose was tracked. Infusions were continued for 24 hours or until patients were extubated, whichever came first. Postinfusion, blood samples were continued for 24 hours for further evaluation of kinetics. If patients continued to require opioid, a nonmorphine alternative was used. Morphine concentrations were determined using a unique validated liquid chromatography tandem-mass spectrometry assay using dried blood spotting as opposed to large whole blood samples. Morphine concentration versus time data was modeled using population pharmacokinetics. Setting A 16-bed cardiac ICU at an university-affiliated hospital. Patients Forty-two patients (20 Down syndrome, 22 controls) were enrolled. Interventions None. Measurements and main results The pharmacokinetics of morphine in pediatric patients with and without Down syndrome following cardiac surgery were analyzed. No significant difference was found in the patient characteristics or variables assessed including morphine total dose or time on infusion. Time mechanically ventilated was longer in children with Down syndrome, and regarding morphine pharmacokinetics, the covariates analyzed were age, weight, presence of Down syndrome, and gender. Only age was found to be significant. Conclusions This study did not detect a significant difference in morphine pharmacokinetics between Down syndrome and non-Down syndrome children with congenital heart disease.

Background Intravenous ketorolac is commonly administered to children for the control of postoperative pain. An effect site EC50 for analgesia of 0.37 mg. L-1 is described in adults. Aims The aim of this study was to review age- and weight-related effects on ketorolac pharmacokinetic parameters in children and current dosing schedules. Methods Pooled intravenous ketorolac (0.5 mg. kg-1 ) concentration-time data in children aged 2 months to 16 years were analyzed using nonlinear mixed-effects models. Allometry was used to scale to a 70 kg person. Results There were 64 children aged 2 months to 16 years (641 plasma concentrations) available for analysis. A two-compartment mammillary model was used to describe pharmacokinetics. Clearance was 2.53 (CV 45.9%) L. h-1. 70 kg-1 and intercompartment clearance was 4.43 (CV 95.6%) L. h-1. 70 kg-1 . Both central (V1) and peripheral (V2) volumes of distribution decreased with age over the first few years of postnatal life to reach V1 6.89 (CV 30.3%) L. 70 kg-1 and V2 5.53 (CV 47.6%) L. 70 kg-1 . Conclusion Clearance, expressed as L. h-1. kg-1 , decreased with age from infancy. A dosing regimen of 0.5 mg. kg-1 every 6 hours maintains a trough concentration larger than 0.37 mg. L-1 in children 9 months to 16 years of age. This dosing regimen is consistent with current recommendations.

Although, especially in the United States, there has been a recent surge of legalized cannabis for either recreational or medicinal purposes, surprisingly little is known about clinical dose-response relationships, pharmacodynamic and toxicodynamic effects of cannabinoids such as Δ9-tetrahydrocannabinol (THC). Even less is known about other active cannabinoids.To address this knowledge gap, an online extraction, high-performance liquid chromatography coupled with tandem mass spectrometry method for simultaneous quantification of 11 cannabinoids and metabolites including THC, 11-hydroxy-Δ9-tetrahydrocannabinol, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid, 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid glucuronide (THC-C-gluc), cannabinol, cannabidiol, cannabigerol, cannabidivarin, Δ9-tetrahydrocannabivarin (THCV), and 11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (THCV-COOH) was developed and validated in human urine and plasma.In contrast to atmospheric pressure chemical ionization, electrospray ionization was associated with extensive ion suppression in plasma and urine samples. Thus, the atmospheric pressure chemical ionization assay was validated showing a lower limit of quantification ranging from 0.39 to 3.91 ng/mL depending on study compound and matrix. The upper limit of quantification was 400 ng/mL except for THC-C-gluc with an upper limit of quantification of 2000 ng/mL. The linearity was r0.99 for all analyzed calibration curves. Acceptance criteria for intrabatch and interbatch accuracy (85%-115%) and imprecision (15%) were met for all compounds. In plasma, the only exceptions were THCV (75.3%-121.2% interbatch accuracy) and cannabidivarin (interbatch imprecision, 15.7%-17.2%). In urine, THCV did not meet predefined acceptance criteria for intrabatch accuracy.This assay allows for monitoring not only THC and its major metabolites but also major cannabinoids that are of interest for marijuana research and clinical practice.

Atomized intranasal midazolam is a common adjunct in pediatrics for procedural anxiolysis. There are no previous studies of validated anxiety scores with pharmacokinetic data to support optimal procedure timing.We describe the clinical and pharmacokinetic profile of atomized intranasal midazolam in children presenting for laceration repair.Children 11 months to 7 years of age and weighing26 kg received 0.4 mg/kg of atomized intranasal midazolam for simple laceration repair. Blood samples were obtained at 3 time points in each patient, and the data were fit with a 1-compartment model. Patient anxiety was rated with the Observational Scale of Behavioral Distress. Secondary outcomes included use of adjunctive medications, successful completion of procedure, and adverse events.Sixty-two subjects were enrolled, with a mean age of 3.3 years. The median time to peak midazolam concentration was 10.1 min (interquartile range 9.7-10.8 min), and the median time to the procedure was 26 min (interquartile range 21-34 min). There was a trend in higher Observational Scale of Behavioral Distress scores during the procedure. We observed a total of 2 adverse events, 1 episode of vomiting (1.6%) and 1 paradoxical reaction (1.6%). Procedural completion was successful in 97% of patients.Atomized intranasal midazolam is a safe and effective anxiolytic to facilitate laceration repair. The plasma concentration was90% of the maximum from 5 to 17 min, suggesting this as an ideal procedural timeframe after intranasal midazolam administration.

Background Obesity causes multiorgan dysfunction, specifically metabolic abnormalities in the liver. Obese patients are opioid-sensitive and have high rates of respiratory complications after surgery. Obesity also has been shown to cause resistance to leptin, an adipose-derived hormone that is key in regulating hunger, metabolism, and respiratory stimulation. We hypothesized that obesity and leptin deficiency impair opioid pharmacokinetics (PK) independently of one another. Methods Morphine PK were characterized in C57BL/6J wild-type (WT), diet-induced obese (DIO), and leptin-deficient (ob/ob) mice, and in ob/ob mice given leptin-replacement (LR) therapy. WT mice received several dosing regimens of morphine. Obese mice (30 g) received one 80 mg/kg bolus of morphine. Blood was collected at fixed times after morphine injection for quantification of plasma morphine and morphine 3-glucuronide (M3G) levels. PK parameters used to evaluate morphine metabolism included area-under the curve (AUC150), maximal morphine concentration (CMAX), and M3G-to-morphine ratio, and drug elimination was determined by clearance (Cl/F), volume of distribution, and half-life (T1/2). PK parameters were compared between mouse groups by the use of 1-way analysis of variance, with P values less than .05 considered significant. Results DIO compared with WT mice had significantly decreased morphine metabolism with lower M3G-to-morphine ratio (mean difference [MD]: -4.9; 95% confidence interval [CI]: -8.8 to -0.9) as well as a decreased Cl/F (MD: -4.0; 95% CI: -8.9 to -0.03) Ob/ob compared with WT mice had a large increase in morphine exposure with a greater AUC150 (MD: 980.4; 95% CI: 630.1-1330.6), CMAX (MD: 6.8; 95% CI: 2.7-10.9), and longer T1/2 (MD: 23.1; 95% CI: 10.5-35.6), as well as a decreased Cl/F (MD: -7.0; 95% CI: -11.6 to -2.7). Several PK parameters were significantly greater in ob/ob compared with DIO mice, including AUC150 (MD: 636.4; 95% CI: 207.4-1065.4), CMAX (MD: 5.3; 95% CI: 3.2-10.3), and T1/2 (MD: 18.3; 95% CI: 2.8-33.7). When leptin was replaced in ob/ob mice, PK parameters began to approach DIO and WT levels. LR compared with ob/ob mice had significant decreases in AUC150 (MD: -779.9; 95% CI: -1229.8 to -330), CMAX (MD: -6.1; 95% CI: -11.4 to -0.9), and T1/2 (MD: -19; 95% CI: -35.1 to -2.8). Metabolism increased with LR, with LR mice having a greater M3G-to-morphine ratio compared with DIO (MD: 5.3; 95% CI: 0.3-10.4). Conclusions Systemic effects associated with obesity decrease morphine metabolism and excretion. A previous study from our laboratory demonstrated that obesity and leptin deficiency decrease the sensitivity of central respiratory control centers to carbon dioxide. Obesity and leptin deficiency substantially decreased morphine metabolism and clearance, and replacing leptin attenuated the PK changes associated with leptin deficiency, suggesting leptin has a direct role in morphine metabolism.

The high prevalence of chronic pain conditions combined with an over-reliance on opioid prescriptions has resulted in an opioid epidemic and a desperate need for solutions. There is some debate about whether cannabis might play a role in addressing chronic pain conditions as well as the opioid epidemic. Recent surveys suggest that a large number of people are using cannabis as a treatment for pain and to reduce use of opioids, and cannabis-derived products demonstrate at least modest efficacy in the treatment of pain in randomized controlled trials. In addition, surveillance studies from countries that have approved the use of Sativex, which is a cannabis-based product, have demonstrated that a combination of Δ9-tetrahydrocannabinol and cannabidiol has low potential for harm, is well tolerated, and is helpful to patients. Given the number of people in the United States who are already using cannabis to manage pain and opioid use in state-regulated markets, it is imperative to conduct additional research in these areas, and to disseminate information on how to minimize harm and maximize any benefits of using cannabinoids to mitigate pain and reduce opioid use. The purpose of this article is to call attention to the fact that cannabis is being used in the management of chronic pain. Thus, this article also provides a set of guidelines on how to approach using cannabis to treat pain.

Opioid medications are an important tool in the management of pain and have been used in clinical practice for centuries. However, due to the highly addictive nature of this class of medications coupled with the life-threatening side effect of respiratory depression, opioid misuse has become a significant public health crisis worldwide. Children and adolescents are at risk for opioid misuse, and early detection is imperative to facilitate treatment and improve outcomes. This review will address the current state of opioid misuse and treatment in children and adolescents in the United States.

R118 is an experimental compound that completed preclinical development as a potential medical therapy for the exercise limitation in peripheral artery disease. Animal studies established that R118 provided partial and reversible mitochondrial complex I inhibition with consequent increases in adenosine monophosphate (AMP) kinase activation in liver and skeletal muscle. After demonstration of improved exercise performance in a mouse model and safety in rodent and primate models, a phase I trial was performed in 24 subjects randomized to R118 vs. placebo (5:1) in escalating doses. Plasma lactic acid levels were transiently elevated in 20% of subjects at the lowest dose and in 100% of subjects using a different formulation at the highest dose, which was associated with hospitalization in all subjects and severe metabolic acidosis requiring prolonged intubation in two subjects. Thus, inhibition of mitochondrial complex I with R118 resulted in severe lactic acidosis, representing unacceptable toxicity from this mechanism of action.

Personalized medicine is the science of individualized prevention and therapy. The notion that "one size fits all" has been replaced by the idea of patient-tailored health care. Within this paradigm, the research community has turned to examine genetic predictors of disease and treatment responses. Pain researchers have produced genetic studies over the last decade that evaluate the association of genetic variability with pain sensitivity and analgesic response. While most of these studies have been conducted among cohorts of subjects of European descent, some have included other racial and ethnic groups, providing evidence of variable responses to analgesics. Simultaneously, there is an increased recognition regarding the complexity of pain research, acknowledging the additional role of epigenetic, transcriptomic, proteomic, and metabolomic factors in the development, experience, and treatment of pain. This article provides an introduction to population-specific pharmacogenetics, proteomics and other "-omics" technologies to predict drug response to pain medications in children. It aims to provide anesthesiologists with the basic knowledge to understand the potential implications of genetic and epigenetic factors managing the pain of pediatric patients.

Background: This ongoing academic collaboration was initiated for providing support to set up, validate, and maintain everolimus therapeutic drug monitoring assays and to study long-term interlaboratory performance. Methods: This study was based on EDTA whole blood samples collected from transplant patients treated with everolimus in a prospective clinical trial. Samples were handled under controlled conditions during collection, storage and were shipped on dry ice to minimize freeze–thaw cycles. For more than 1.5 years, participating laboratories received a set of 3 blinded samples on a monthly basis. Among others, these samples included individual patient samples, patient sample pools to assess long-term performance, and patient samples pools enriched with isolated everolimus metabolites. Results: The results between liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and the everolimus Quantitative Microsphere System (QMS, Thermo Fisher) assay were comparable. The monthly interlaboratory variability (coefficient of variation %) for cross-validation samples ranged from 6.5% to 23.2% (average of 14.8%) for LC-MS/MS and 4.2% to 26.4% (average of 11.1%) for laboratories using the QMS assay. A blinded long-term pool sample was sent to the laboratories for 13 months. The result was 5.31 ± 0.86 ng/mL (range, 2.9–7.8 ng/mL) for the LC-MS/MS and 5.20 ± 0.54 ng/mL (range, 4.0–6.8 ng/mL) for QMS laboratories. Enrichment of patient sample pools with 5–25 ng/mL of purified everolimus metabolites (46-hydroxy everolimus and 39-O-desmethyl everolimus) did not affect the results of either LC-MS/MS or QMS assays. Conclusions: Both LC-MS/MS and QMS assays gave similar results and showed similar performance, albeit with a trend toward higher interlaboratory variability among laboratories using LC-MS/MS than the QMS assay.

Ondansetron is the drug of choice to prevent nausea in women undergoing cesarean surgery and can be used to prevent neonatal abstinence syndrome (NAS). The pharmacokinetics of ondansetron have not been characterized in pregnant women or in newborns. A nonlinear mixed-effects modeling approach was used to analyze plasma samples obtained from 20 nonpregnant and 40 pregnant women following a single administration of 4 or 8 mg ondansetron, from umbilical cord blood at delivery, and from neonates after birth. The analysis indicates that: ondansetron disposition is not affected by pregnancy (P > 0.05), but influenced by dose (P < 0.05), and is characterized by rapid transplacental transfer and longer elimination half-life in neonates compared to their mother. A dosing regimen for prevention of NAS was designed based on the model. The regimen involves IV administration of 4 mg to the mothers shortly before cord clamping, or oral administration of 0.07 mg/kg (or equivalently 0.04 mg/kg IV) to neonates.

Medication overdoses are a common, but preventable, problem among children. Volumetric dosing errors and the use of incorrect dosing delivery devices are 2 common sources of these preventable errors for orally administered liquid medications. To reduce errors and increase precision of drug administration, milliliter-based dosing should be used exclusively when prescribing and administering liquid medications. Teaspoon- and tablespoon-based dosing should not be used. Devices that allow for precise dose administration (preferably syringes with metric markings) should be used instead of household spoons and should be distributed with the medication.

Posterior spinal fusion for scoliosis is one of the most painful elective pediatric surgeries. Good postoperative pain control allows early ambulation and return of ability to tolerate oral intake. Options for analgesia in this patient population are suboptimal. We hypothesized that extended-release epidural morphine (EREM) would provide better pain control and less adverse effects compared to intrathecal (IT) morphine.The primary outcome was total IV morphine consumption during 0-48 hours postoperatively. Secondary outcomes included time until first patient-controlled analgesia (PCA) demand, pain scores, and adverse opioid effects. After institutional review board approval, 71 subjects undergoing posterior spinal fusion for idiopathic scoliosis completed the study. The subjects were randomly allocated to 7.5 μg/kg IT morphine or 150 μg/kg EREM. The final IT morphine and EREM groups contained 37 and 34 subjects, respectively. Postoperative pain was treated with morphine PCA, ketorolac, oral oxycodone, and acetaminophen. Morphine consumption, pain scores, nausea and vomiting, pruritus, and respiratory depression were measured every 4 hours. Parents completed a caregiver questionnaire about their child's pain control regimen after the first postoperative day.There was no difference in total morphine consumption over the first 48 hours between subjects in the EREM and IT morphine groups: median (range) 42.2 (5.5-123.0) and 34.0 (4.5-128.8) mg, respectively (P = .27). EREM and IT morphine groups had no difference in time until first PCA demand. Pain scores were no different between the groups from 8 to 24 hours after surgery. Compared to IT morphine, EREM subjects had lower pain scores from 28 to 36 hours after surgery. The reported incidence of pruritus was lower in the EREM subjects.There was no difference in total morphine consumption or time until first PCA demand between the EREM and IT morphine groups. EREM provides a longer duration of analgesia after posterior spinal fusion for scoliosis and may be associated with less opioid-induced pruritus.

Opioid-related mortality is a growing problem in the United States, and in 2015 there were over 33,000 opioid-related deaths. To combat this mortality trend, naloxone is increasingly being utilized in a pre-hospital setting by emergency personnel and prescribed to laypersons for out-of-hospital administration. With increased utilization of naloxone there has been a subsequent reduction in mortality following an opioid overdose. Reversal of opioid toxicity may precipitate an opioid-withdrawal syndrome. At the same time, there is a risk of inadequate response or re-narcotization after the administration of a single dose of naloxone in patients who have taken large doses or long-acting opioid formulations, as the duration of effect of naloxone is shorter than that of many opioid agonists. As out-of-hospital use of this medication is growing, so too is concern about effective but safe dosing.

Objectives Knowledge of drug use and medication compliance during mental health evaluation can help guide evaluation and treatment. The objective was to evaluate drug use and medication compliance in a pediatric emergency department (PED) psychiatric population by comparing medical history, standard urine drug screen (EIA), and expanded urine drug screen (HPLC-MS/MS). Methods A prospective cohort study of admitted psychiatric patients ≥13years and ≤18years in a tertiary-care children's hospital psychiatric ED from January 31, 2013 through April 16, 2014. Results 100 patients in our PED were enrolled. Marijuana was the most commonly admitted and detected substance; 43% had co-ingestions. HPLC-MS/MS revealed 36 additional substance exposures than identified by history. All substances detected by EIA were also detected by HPLC-MS/MS. Combination of history and HPLC-MS/MS revealed the most substances used. HPLC-MS/MS identified antidepressants in 76% of patients prescribed a detectable antidepressant. Conclusion Marijuana use was greater than nicotine use and was associated with concomitant polysubstance abuse. A combination of history and HPLC-MS/MS was the most thorough in obtaining history of drug use. Almost a quarter of patients did not have their prescribed antidepressant detected by HPLC-MS/MS. A rapid, affordable expanded drug screen should replace the more standard limited drug screen particularly for patients who are refractory to treatment.

The passage of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act has collectively resulted in an improvement in rational prescribing for children, including more than 800 labeling changes. However, off-label drug use remains an important public health issue for infants, children, and adolescents, because an overwhelming number of drugs still have no information in the labeling for use in pediatrics. The purpose of off-label use is to benefit the individual patient. Practitioners use their professional judgment to determine these uses. As such, the term “off-label” does not imply an improper, illegal, contraindicated, or investigational use. Therapeutic decision-making must always rely on the best available evidence and the importance of the benefit for the individual patient.

Lipoprotein (a) is a risk factor for adult cardiovascular events, in which the apolipoprotein (a) component is thought to promote atherogenesis and impair fibrinolysis. We investigated whether elevated plasma lipoprotein (a) concentration and small predominant apolipoprotein (a) isoform size (number of kringle-4 domains) are risk factors for childhood arterial ischemic stroke and correlate with plasma fibrinolytic function. Patients who had had an arterial ischemic stroke in childhood (29 days - 90th percentile of race-specific reference values and apolipoprotein (a)

Objective This study aimed to prospectively determine the etomidate dose associated with adequate sedation and few significant respiratory events for procedures of short duration in children. Methods This is a prospective cohort study in an urban pediatric emergency department of patients 4 to 18 years requiring sedation and analgesia for painful procedures of short duration. Patients received fentanyl 1 μg/kg followed by intravenously administered etomidate 0.1 to 0.2 mg/kg as a loading dose. An additional dose of etomidate 0.1 mg/kg was intravenously administered if needed. The level of sedation was determined by The Children's Hospital of Wisconsin Sedation Score. The primary outcome was to determine the etomidate dose associated with an adequate level of sedation and procedural completion. Results Sixty patients were enrolled. The most frequent procedure was fracture reduction (50/60, 83.3%). Procedures were successfully completed for 59 (98.3%) of 60 patients. The initial dose of etomidate associated with adequate sedation was 0.2 mg/kg intravenously administered for 33 (66.7%) of 50 patients requiring fracture reduction and for 6 (60.0%) of 10 patients receiving a procedure other than fracture reduction. Respiratory depression was noted in 9 (16.4%) of 55 patients, and oxygen desaturation was noted in 23 (39.0%) of 59 patients. Of 58 patients, 21 (36.2%) experienced a respiratory adverse event requiring brief intervention including oxygen supplementation, stimulation, and/or airway repositioning. No patient experienced a significant adverse respiratory event, defined as positive pressure ventilation. Median time to discharge-ready was 21 minutes. Conclusions For short-duration painful emergency department procedures, etomidate 0.2 mg/kg intravenously administered after fentanyl was associated with effective sedation, successful procedural completion, and readily managed respiratory adverse events in children.

Five recent cohort studies have shown a frequency of awareness in paediatric anaesthesia of between 0.2% and 1.2%, but they were not individually large enough to identify risk factors. This study pooled raw data from these five studies to identify factors associated with awareness in children. The outcome of awareness was taken as the cases judged to be most likely awareness cases in each study. Logistic regression was used to identify awareness-associated factors. A combined sample of 4486 anaesthetics revealed 33 cases of awareness. Unadjusted analysis demonstrated weak evidence that nitrous oxide used as an anaesthetic maintenance adjunct was associated with awareness (OR 2.04 (95% CI 0.97-4.33), p=0.06), and some evidence that use of a tracheal tube was associated with awareness (OR 2.78 (95% CI 1.11-6.94), p=0.03). Multivariable regression analysis revealed that nitrous oxide maintenance and use of a tracheal tube were independently associated with awareness (nitrous oxide, OR 2.4 (95% CI 1.08-5.32), p=0.03; tracheal tube, OR 3.0 (95% CI 1.20-7.56), p=0.02).

Opioids such as morphine are the cornerstone of pain treatment. The challenge of measuring the concentrations of morphine and its active metabolites in order to assess human pharmacokinetics and monitor therapeutic drugs in children requires assays with high sensitivity in small blood volumes. We developed and validated a semi-automated LC-MS/MS assay for the simultaneous quantification of morphine and its active metabolites morphine 3β-glucuronide (M3G) and morphine 6β-glucuronide (M6G) in human plasma and in dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the internal standards were the only manual steps. Morphine and its metabolites were separated on a Kinetex 2.6-μm PFP analytical column using an acetonitrile/0.1% formic acid gradient. The analytes were detected in the positive multiple reaction mode. In plasma, the assay had the following performance characteristics: range of reliable response of 0.25-1000 ng/mL (r(2) 0.99) for morphine, 1-1,000 ng/mL (r(2) 0.99) for M3G, and 2.5-1,000 ng/mL for M6G. In DBS, the assay had a range of reliable response of 1-1,000 ng/mL (r(2) 0.99) for morphine and M3G, and of 2.5-1,000 ng/mL for M6G. For inter-day accuracy and precision for morphine, M3G and M6G were within 15% of the nominal values in both plasma and DBS. There was no carryover, ion suppression, or matrix interferences. The assay fulfilled all predefined acceptance criteria, and its sensitivity using DBS samples was adequate for the measurement of pediatric pharmacokinetic samples using a small blood of only 20-50 μL.

Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.

Fetal surgery is a rapidly growing and evolving area. Fetal surgery is based on years of animal and clinical research. In contrast, anesthesia techniques for fetal surgery are based on clinical experience. The techniques that have emerged are safe for mother and fetus. In this review, the authors describe current techniques for anesthetic management of fetal surgery patients. General anesthesia is the primary technique used for hysterotomy based surgical correction of midgestation fetuses and ex utero interpartum corrections of end-gestation fetuses. Epidural analgesia, with general anesthesia as back-up, is the primary technique used for fetoscopic cases in which anesthetic care is required. Because of the myriad of anesthetic and surgical issues these cases generate, it is essential to have good communication and cooperation between surgeons and anesthesiologists from the preoperative period to the postoperative period. This will allow development of a cohesive anesthetic and surgical plan that can be used for the safe perioperative management of the fetal surgery patient.

Fetal IM injection of fentanyl is frequently performed during ex utero intrapartum therapy (EXIT procedure). We quantified the concentration of fentanyl in umbilical vein blood. Thirteen samples from 13 subjects were analyzed. Medians and ranges are reported as follows. Weight of the newborn at delivery was 3000 g (2020-3715 g). The dose of fentanyl was 60 μg (45-65 μg). The time between IM administration of fentanyl and collection of the sample was 37 minutes (5-86 minutes). Fentanyl was detected in all of the samples, with a median serum concentration of 14.0 ng/mL (4.3-64.0 ng/mL).

*Department of Anesthesia, Children’s Hospital, Harvard Medical School, Boston, MA,**Department of Anesthesiology and Critical Care, The Children’s Hospital of Philadelphia,University of Pennsylvania School of Medicine, Philadelphia and †Department of Anesthesia andCritical Care, The Hospital of the University of Pennsylvania, University of Pennsylvania Schoolof Medicine, Philadelphia, PA, USA

Pain during venipuncture is a major source of concern to children and their caretakers. Iontophoresis is a novel technique that uses an electrical current to facilitate movement of solute ions (lidocaine) across the stratum corneum barrier to provide dermal analgesia. In this study, we compared dermal analgesia provided by lidocaine iontophoresis and eutectic mixture of local anesthetics (EMLA). After informed consent, 26 children, aged 7-16 yr, who required venous cannulation on multiple occasions, were enrolled in this prospective, randomized, crossover study to receive EMLA and iontophoresis on separate occasions. During a third session, each subject received his or her preferred treatment. Pain during venipuncture was assessed by the subject, parent, observer, and technician performing the procedure, by use of a 100-mm visual analog scale. The observer also used the Children's Hospital of Eastern Ontario Pain Scale to rate the subject's pain. Ratings of subject satisfaction were also assessed. There were no significant differences between the two groups in the subject-rated visual analog scale or the Children's Hospital of Eastern Ontario Pain Scale scores. Eleven (50%; 95% confidence interval [CI], 31%-69%) of the 22 subjects who completed both sessions preferred iontophoresis. Five subjects (23%; 95% CI, 10%-44%), including two who did not tolerate treatment with iontophoresis, preferred EMLA, and six (27%; 95% CI, 13%-48%) had no preference for the intervention to provide dermal analgesia. We conclude that lidocaine iontophoresis provides similar pain relief for insertion of IV catheters as EMLA and is a useful noninvasive alternative to establish dermal analgesia for venous cannulation.Iontophoresis is a technique that uses an electrical current to facilitate movement of solute ions (lidocaine) across the stratum corneum barrier to provide dermal analgesia. Lidocaine iontophoresis provides similar pain relief for insertion of IV catheters as eutectic mixture of local anesthetics and is a useful noninvasive alternative to establish dermal analgesia for venous cannulation.

In this randomized, double-blinded, placebo-controlled study, we evaluated the safety and efficacy of lidocaine iontophoresis for the prevention of pain associated with venipuncture in 59 children aged 6-17 yr. Children received either lidocaine HCl 2% with epinephrine 1:100,000 (Active) or the same formulation without lidocaine (Placebo) via a 20 mA/min iontophoretic treatment. Pain during venipuncture was assessed by the subject, parent, and nurse using a 100-mm visual analog scale. Median (interquartile range) visual analog scale scores were significantly lower in the Active versus Placebo groups: subject, 7.0 (2.0-20.8) versus 31.0 (12.0-48.0), P0.001; nurse, 5.0 (2.2-10.8) versus 24.0 (9.0-47.0), P0.001; and parent, 3.0 (0.8-7.2) versus 20.0 (4.5-43.0), P0.002, respectively. Similarly, higher median satisfaction scores were given to the Active versus Placebo group by the three evaluators. Of the 59 subjects completing the study, 10 subjects experienced a total of 12 adverse events that were all graded as mild. In conclusion, lidocaine iontophoresis is safe in children, reduces discomfort associated with venipuncture, and increases satisfaction when compared with the placebo.In this randomized, double-blinded, placebo-controlled study, we found that dermal anesthesia with lidocaine HCl 2% combined with epinephrine 1:100,000 administered via iontophoresis in children is achieved in 8.8 +/- 2.1 min, reduces discomfort associated with venipuncture, is safe, and increases satisfaction when compared with the placebo.

Opioids are often prescribed to children for pain relief related to procedures, acute injuries, and chronic conditions. Round-the-clock dosing of opioids can produce opioid dependence within 5 days. According to a 2001 Consensus Paper from the American Academy of Pain Medicine, American Pain Society, and American Society of Addiction Medicine, dependence is defined as “a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.” Although the experience of many children undergoing iatrogenically induced withdrawal may be mild or goes unreported, there is currently no guidance for recognition or management of withdrawal for this population. Guidance on this subject is available only for adults and primarily for adults with substance use disorders. The guideline will summarize existing literature and provide readers with information currently not available in any single source specific for this vulnerable pediatric population.

Although former preterm birth infants are at risk for postoperative apnea after surgery, it is unclear whether the same is true of full-term birth infants. We evaluated the incidence of apnea in 60 full-term neonates and infants undergoing pyloromyotomy both before and after anesthesia. All subjects were randomized to a remifentanil- or halothane-based anesthetic. Apnea was defined by the presence of prolonged apnea (>15 s) or frequent brief apnea, as observed on the pneumocardiogram. Apnea occurred before surgery in 27% of subjects and after surgery in 16% of subjects, with no significant difference between subjects randomized to remifentanil or halothane anesthesia. This apnea was primarily central in origin, occurred throughout the recording epochs, and was associated with severe desaturation in some instances. Of the subjects with normal preoperative pneumocardiograms, new onset postoperative apnea occurred in 3 (23%) of 13 subjects who received halothane-based anesthetics versus 0 (0%) of 22 subjects who received remifentanil-based anesthetics (P = 0.04). Thus, postoperative apnea can follow anesthesia in otherwise healthy full-term infants after pyloromyotomy and is occasionally severe with desaturation. New-onset postoperative apnea was not seen with a remifentanil-based anesthetic.

Pyloric stenosis is sometimes associated with hemodynamic instability and postoperative apnea. In this multicenter study we examined the hemodynamic response and recovery profile of remifentanil and compared it with that of halothane in infants undergoing pyloromyotomy. After atropine, propofol, and succinylcholine administration and tracheal intubation, patients were randomized (2:1 ratio) to receive either remifentanil with nitrous oxide and oxygen or halothane with nitrous oxide and oxygen as the maintenance anesthetic. Pre- and postoperative pneumograms were done and evaluated by an observer blinded to the study. Intraoperative hemodynamic data and postanesthesia care unit (PACU) discharge times, PACU recovery scores, pain medications, and adverse events (vomiting, bradycardia, dysrhythmia, and hypoxemia) were recorded by the study's research nurse. There were no significant differences in patient age or weight between the two groups. There were no significant differences in hemodynamic values between the two groups at the various intraoperative stress points. The extubation times, PACU discharge times, pain medications, and adverse events were similar for both groups. No patient anesthetized with remifentanil who had a normal preoperative pneumogram had an abnormal postoperative pneumogram, whereas three patients with a normal preoperative pneumogram who were anesthetized with halothane had abnormal pneumograms after.The use of ultra-short-acting opioids may be an appropriate technique for infants less than 2 mo old when tracheal extubation after surgery is anticipated.

Summary Introduction The Cobra-PLUS™ perilaryngeal airway (CP) is a modification of the Cobra perilaryngeal airway. It has a distal curve for easier placement and a thermistor on the pharyngeal cuff. We assessed the orientation of the larynx to the CP and compared temperatures measured using CP to temporal arterial (TA) and infrared tympanic (T) thermometers. Methodology American Society of Anesthesiologists (ASA) physical status 1 and 2 children 0–18 years old undergoing general anesthesia using CP were grouped into different weight cohorts. A fiberoptic scope was inserted through the CP, and laryngeal views were recorded and graded off line. Temperatures were measured from the CP, TA, and T at 15-min intervals for four readings or until the end of surgery. The CP was removed, while the patient was deeply anesthetized. Results Eighty subjects were analyzed. 87.5% (cohort range 75–95%) had an unobstructed view of the larynx. No serious adverse effects noted. Three hundred and sixteen temperature data points were recorded for each measured site. CP temperatures were consistently lower than TA and T with a bias of 0.9 and 0.6°C, respectively. Using temperatures measured at time 0 and 15 min, CP was associated with a larger intraclass correlation coefficient and smaller repeatability coefficient when compared to TA or T (ICC 0.65, 0.46. 0.44 and RC 0.78, 1, 1.36, respectively), indicating it had a better measure and remeasure reliability. Conclusion The CP has a better orientation to the larynx compared with its previous version. It may be used to reliably trend intraoperative temperatures.

Zileuton is an orally active, selective inhibitor of 5-lipoxygenase, which catalyzes the first step in the conversion of arachadonic acid into leukotrienes. Given the important role of leukotrienes in inflammation and cell signaling, multiple studies have investigated the efficacy of zileuton in the treatment of human disease. Examples of disease targets include asthma, ulcerative colitis, rheumatoid arthritis, and more recently, acne, ischemic/reperfusion injury, inflammatory pain, and sickle cell anemia. Zileuton is currently approved for the prophylaxis and chronic treatment of asthma. We report the development and validation of a sensitive and specific liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay for the quantification of zileuton in human EDTA plasma. The range of reliable response was 3.05–20,000 ng/mL in human plasma. The calibration curves had a correlation coefficient of r2 > 0.99. The intra-day precision was 3.4–5.3%. The inter-day precision ranged from 4.5% to 7.3% and inter-day accuracy from 100% to 107%. No matrix interferences, ion suppression/enhancement, or carry-over was observed. The assay met all predefined acceptance criteria and was subsequently employed to measure plasma zileuton concentrations in a clinical trial.

Acetaminophen (paracetamol, N-(4-hydroxyphenyl) acetamide) is one of the most commonly prescribed drugs for the management of pain in children. Quantification of acetaminophen in pre-term and term neonates and small children requires the availability of highly sensitive assays in small volume blood samples. We developed and validated an LC-MS/MS assay for the quantification of acetaminophen in human plasma, cerebro-spinal fluid (CSF) and dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the deuterated internal standard were the only manual steps. Extracted samples were analyzed on a Kinetex 2.6 μm PFP column using an acetonitrile/formic acid gradient. The analytes were detected in the positive multiple reaction mode. Alternatively, DBS were automatically processed using direct desorption in a sample card and preparation (SCAP) robotic autosampler in combination with online extraction. The range of reliable response in plasma and CSF was 3.05-20,000 ng/ml (r(2)>0.99) and 27.4-20,000 ng/ml (r(2)>0.99) for DBS (manual extraction and automated direct desorption). Inter-day accuracy was always within 85-115% and inter-day precision for plasma, CSF and manually extracted DBS were less than 15%. Deming regression analysis comparing 167 matching pairs of plasma and DBS samples showed a correlation coefficient of 0.98. Bland Altman analysis indicated a 26.6% positive bias in DBS, most likely reflecting the blood: plasma distribution ratio of acetaminophen. DBS are a valid matrix for acetaminophen pharmacokinetic studies.

Maternal use of certain drugs during pregnancy can result in transient neonatal signs consistent with withdrawal or acute toxicity or cause sustained signs consistent with a lasting drug effect. In addition, hospitalized infants who are treated with opioids or benzodiazepines to provide analgesia or sedation may be at risk for manifesting signs of withdrawal. This statement updates information about the clinical presentation of infants exposed to intrauterine drugs and the therapeutic options for treatment of withdrawal and is expanded to include evidence-based approaches to the management of the hospitalized infant who requires weaning from analgesics or sedatives. Copyright © 2012 by the American Academy of Pediatrics.

Preterm and term neonates often require surgical procedures and analgesia. However, our knowledge about neonatal pharmacokinetics of fentanyl, the most commonly used drug for these procedures, and its metabolites is still incomplete. To facilitate pharmacokinetic studies of fentanyl and its metabolites in neonates and other children, we developed and validated an LC-MS/MS method based on minimally invasive, low blood volume sampling. LC-MS/MS was used for the simultaneous analysis of fentanyl, despropionyl fentanyl (DPF), and norfentanyl from dried blood samples (DBS) collected on filter paper. Positive ions were monitored using multiple reaction monitoring. Since the standard matrix for measuring fentanyl blood concentrations is plasma, the assay was developed and validated in plasma, whole blood, and then DBS. Our method was able to measure clinically relevant levels of fentanyl and its metabolites. In DBS, the lower limits of quantification were 100 pg/mL for fentanyl with a range of reliable response from 0.1 to 100 ng/mL (r 2 40.99) and 250 pg/mL for both DPF and norfentanyl with a range of reliable response from 0.25 to 100 ng/mL (r 2 40.99). In plasma and in DBS inter-day accuracy and precisions of fentanyl met predefined acceptance criteria and also indicated comparable assay performance in both matrices.

BACKGROUND Effective postoperative pain management is a vital component of orthopaedic surgical care in the pediatric population. In children with cognitive impairments pain management can be difficult, making these children vulnerable to ineffectively managed postoperative pain. This prospective, randomised study evaluated the use of a local anesthetic continuous infusion device (pain pump) to manage postoperative pain in children with cerebral palsy (CP) undergoing lower extremity orthopaedic surgical procedures. METHODS Children with a diagnosis of CP who were undergoing select orthopaedic outpatient procedures were enrolled in this study. Postoperatively, patients were randomised to receive either a pain pump in addition to oral analgesics or oral analgesics only. Patient's parents were asked to record the amount of medication administered and assess pain intensity with the use of a modified visual analogue scale for 3 days postoperatively. Parents also completed an overall pain management satisfaction questionnaire at the end of the study participation period. RESULTS Fifty-four patients were enrolled in this study and data were analyzed on 37 patients. The mean daily pain intensity in the pain pump group was significantly lower for the day of surgery and for 2 days postoperatively, and there was an overall significant difference between the groups (P

Molecular genetics is the study, at the molecular level, of how genetic information is stored, inherited, and expressed and of how it influences the structure and function of cells in health and in disease. Although molecular approaches have been used for decades in the laboratory and are at the core of modern medical education, they are only now beginning to influence clinical practice. A variety of sophisticated techniques permit rapid and affordable DNA sequencing, gene expression profiling, gene cloning, gene manipulation, gene transfer, recombinant protein production, and other technologies of enormous biomedical importance. Success in genomics has spawned additional ambitious endeavors, including proteomics, pharmacogenomics, and bioinformatics. These techniques are providing new diagnostic, prognostic, and therapeutic opportunities in all areas of medicine, including anesthesiology. With the use of molecular criteria and the diminishing cost of analytic technologies, anesthetic practice will become more individualized, and greater emphasis will be placed on the patient's genetic makeup. Both surgical and nonsurgical decisions will increasingly accommodate molecular data crucial to perioperative anesthetic management. In this article we have summarized three lectures on congenital malformations, pharmacogenetics, and proteomics presented at the 22nd Annual Meeting of the Society for Pediatric Anesthesia.

Background There is a considerable discrepancy between the reported incidences of awareness under anesthesia in children (0.2%-2.7%). In this prospective, observational, cohort study we evaluated 1) the incidence of awareness during general anesthesia in children across three settings, 2) factors contributing to awareness, and 3) short-term psychological effects of awareness. Methods Children (aged 5-15 yr) who underwent general anesthesia were included, and all perioperative data including anesthetic drugs were collected prospectively. Children were interviewed three times postoperatively using a semistructured questionnaire. All cases of possible or probable awareness were discussed with the child's care providers to confirm or refute the memories. Internal consensus among investigators across sites was reached, and these cases and a random selection of others were reviewed by three external reviewers. For the purpose of this study, possible/probable awareness was defined as cases with agreement between the internal consensus and at least two of the three external reviewers. Results One thousand seven hundred eighty-four children completed at least one interview. Thirty-two cases were coded as possible or probable awareness by at least one entity (i.e., either the internal consensus or one of the external reviewers). Fourteen of these cases met the definition for possible/probable awareness, making the incidence of awareness 0.8%. Six of the 14 children with awareness (43%) remembered feeling scared during their surgery and three (21%) reported hurting. Two children in this group (14%) said they would feel worse if they had to have surgery again, which was not significantly different from reports of children with no recall (15%). None of the children with awareness required psychological follow-up. Endoscopic procedures were associated with a higher risk for awareness (relative risk = 4.5 [confidence interval 1.5-13.6]). Conclusions Although 0.8% of children experienced possible/probable awareness in this study, none experienced short-term psychological distress.