Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids.

Opioid-induced respiratory depression (OIRD) deaths are ~80,000 a year in the US and are a major public health issue. Approximately 90% of fatal opioid-related deaths are due to synthetic opioids such as fentanyl, most of which is illicitly manufactured and distributed either on its own or as an adulterant to other drugs of abuse such as cocaine or methamphetamine. Other potent opioids such as nitazenes are also increasingly present in the illicit drug supply, and xylazine, a veterinary tranquilizer, is a prevalent additive to opioids and other drugs of abuse. Naloxone is the main treatment used to reverse OIRD and is available as nasal sprays, prefilled naloxone injection devices, and generic naloxone for injection. An overdose needs to be treated as soon as possible to avoid death, and synthetic opioids such as fentanyl are up to 50 times more potent than heroin, so the availability of new, higher-dose, 5-mg prefilled injection or 8-mg intranasal spray naloxone preparations are important additions for emergency treatment of OIRDs, especially by lay people in the community. Higher naloxone doses are expected to reverse a synthetic overdose more rapidly and the current formulations are ideal for use by untrained lay people in the community. There are potential concerns about severe withdrawal symptoms, or pulmonary edema from treatment with high-dose naloxone. However, from the perspective of first responders, the balance of risks would point to administration of naloxone at the dose required to combat the overdose where the risk of death is very high. The presence of xylazines as an adulterant complicates the treatment of OIRDs, as naloxone is probably ineffective, although it will reverse the respiratory depression due to the opioid. For these patients, hospitalization is particularly vital. Education about the benefits of naloxone remains important not only in informing people about how to treat emergency OIRDs but also how to obtain naloxone. A call to emergency services is also essential after administering naloxone because, although the patient may revive, they may overdose again later because of the short half-life of naloxone and the long-lasting potency of fentanyl and its analogs.

Multicenter Population Pharmacokinetics of Fentanyl in Neonatal Surgical Patients Using Dried Blood Spot Specimen Collection Demonstrates Maturation of Elimination Clearance.

BACKGROUND: Fentanyl is widely used for analgesia and sedation in neonates, but pharmacokinetic (PK) analysis in this population has been limited by the relatively large sample volumes required for plasma-based assays. METHODS: In this multicenter observational study of fentanyl kinetics in neonates up to 42 weeks of postmenstrual age (PMA) who received fentanyl boluses and continuous infusions, dried blood spots were used for small-volume sampling. A population PK analysis was used to describe fentanyl disposition in term and preterm neonates. Covariates for the model parameters, including body weight, PMA, birth status (preterm or term), and presence of congenital cardiac disease, were assessed in a stepwise manner. RESULTS: Clearance was estimated to be greater than adult clearance of fentanyl and varied with weight. Covariate selection did not yield a significant relationship for age as a continuous or dichotomous variable (term or preterm, the latter defined as birth with PMA of <37 weeks) and clearance. CONCLUSIONS: A supra-allometric effect on clearance was determined during covariate analyses (exponential scaling factor for body weight >0.75), as has been described in population PK models that account for maturation of intrinsic clearance (here, predominantly hepatic microsomal activity) in addition to scaling for weight, both of which impact clearance in this age group.

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.

Cannabis, e-cigarettes and anesthesia.

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.

A Sensitive LC-MS/MS Assay for the Quantification of Methadone and its Metabolites in Dried Blood Spots: Comparison With Plasma.

INTRODUCTION: Methadone, a synthetic narcotic, is widely used both in adults and children for pain control and as a replacement drug in opioid use disorder to prevent craving and withdrawal. To support clinical pharmacokinetic trials in neonates, infants, and children, the authors developed and validated a novel, automated, highly sensitive liquid chromatography-electrospray-tandem mass spectrometry ionization (LC-ESI-MS/MS) method for the quantification of methadone and its metabolites, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP), in samples collected as dried blood spots. METHODS: Blood was spiked with different concentrations of methadone, EDDP, and EMDP, and blood drops were applied to filter paper cards. Punches of 6.4 mm were removed from the cards, and 600 µL of protein precipitation solution (methanol/0.2M ZnSO4, 7:3, vol/vol) containing the internal standards (methadone-d9 and EDDP-d5) at a concentration of 1 mcg/L was added. The extracts were analyzed using LC-ESI-MS/MS in combination with online extraction. The mass spectrometer was run in the positive multiple reaction monitoring mode, and the total run time was 3.2 minutes. RESULTS: For the dried blood spots, the assay has a lower limit of quantification of 0.1 mcg/L for methadone, EDDP, and EMDP. The range of reliable response for methadone for the ion transition m/z = 310.2→265.1 was 0.1-100 mcg/L and for the ion transition m/z = 310.2→223.1 5-1000 mcg/L. For EDDP, on the range of reliable response for the ion transition, m/z = 278.2→234.3 was 0.1-100 mcg/L and for the ion transition m/z = 278.2→186.1 5-1000 mcg/L. The calibration range for EMDP was 0.1-100 mcg/L. Accuracy (85%-115%) and imprecision (<15%) met predefined acceptance criteria. DISCUSSION: This assay allows for the measurement of small volume blood samples without the need for an intravenous blood draw, and thus, it is suitable for pharmacokinetics studies and therapeutic drug monitoring in pediatric patients.

The pharmacokinetics of intravenous ketorolac in children aged 2 months to 16 years: A population analysis.

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.

Evaluation of drug use and medication compliance in adolescents admitted to a psychiatric facility from the pediatric emergency department.

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.

Personalizing pediatric pain medicine: using population-specific pharmacogenetics, genomics, and other -omics approaches to predict response.

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.

Long-term cross-validation of everolimus therapeutic drug monitoring assays: the Zortracker study.

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.

Off-label use of drugs in children.

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 500 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.

Quantification of the 5-lipoxygenase inhibitor zileuton in human plasma using high performance liquid chromatography-tandem mass spectrometry.

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 3.05-20,000ng/mL in human plasma. The calibration curves had a correlation coefficient of r(2)>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.

Comparison of the quantification of acetaminophen in plasma, cerebrospinal fluid and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry.

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.

Laryngeal view and temperature measurements while using the perilaryngeal airway (Cobra-PLUS™) in children.

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.

Etomidate for short pediatric procedures in the emergency department.

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.

Quantification of serum fentanyl concentrations from umbilical cord blood during ex utero intrapartum therapy.

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).

A low blood volume LC-MS/MS assay for the quantification of fentanyl and its major metabolites norfentanyl and despropionyl fentanyl in children.

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)>0.99) and 250 pg/mL for both DPF and norfentanyl with a range of reliable response from 0.25 to 100 ng/mL (r(2)>0.99). 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.

A sensitive assay for the quantification of morphine and its active metabolites in human plasma and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry.

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 3ß-glucuronide (M3G) and morphine 6ß-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.

Effectiveness of an anesthetic continuous-infusion device in children with cerebral palsy undergoing orthopaedic surgery.

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<0.0001). The amount of analgesic medication administered was significantly lower for the first 2 postoperative days, but there was not a significant difference between the 2 groups overall (P=0.29). Parent satisfaction with both pain management techniques was high and responses were similar between the 2 groups. CONCLUSIONS: Children with CP present unique postoperative pain management concerns that can be effectively addressed through the use of multimodal analgesic techniques. This study found that the pain pump is an effective pain management technique that significantly reduces pain intensity in children with CP after lower extremity orthopaedic procedures. LEVEL OF EVIDENCE: Therapeutic Level II.

Genetics for the pediatric anesthesiologist: a primer on congenital malformations, pharmacogenetics, and proteomics.

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.

Opioid pharmacogenomics using a twin study paradigm: methods and procedures for determining familial aggregation and heritability.

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.