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.

Perioperative Management and In-Hospital Outcomes After Minimally Invasive Repair of Pectus Excavatum: A Multicenter Registry Report From the Society for Pediatric Anesthesia Improvement Network.

BACKGROUND: There are few comparative data on the analgesic options used to manage patients undergoing minimally invasive repair of pectus excavatum (MIRPE). The Society for Pediatric Anesthesia Improvement Network was established to investigate outcomes for procedures where there is significant management variability. For our first study, we established a multicenter observational database to characterize the analgesic strategies used to manage pediatric patients undergoing MIRPE. Outcome data from the participating centers were used to assess the association between analgesic strategy and pain outcomes. METHODS: Fourteen institutions enrolled patients from June 2014 through August 2015. Network members agreed to an observational methodology where each institution managed patients based on their institutional standards and protocols. There was no requirement to standardize care. Patients were categorized based on analgesic strategy: epidural catheter (EC), paravertebral catheter (PVC), wound catheter (WC), no regional (NR) analgesia, and intrathecal morphine techniques. Primary outcomes, pain score and opioid consumption by postoperative day (POD), for each technique were compared while adjusting for confounders using multivariable modeling that included 5 covariates: age, sex, number of bars, Haller index, and use of preoperative pain medication. Pain scores were analyzed using repeated-measures analysis of variance with Bonferroni correction. Opioid consumption was analyzed using a multivariable quantile regression. RESULTS: Data were collected on 348 patients and categorized based on primary analgesic strategy: EC (122), PVC (57), WC (41), NR (120), and intrathecal morphine (8). Compared to EC, daily median pain scores were higher in patients managed with PVC (POD 0), WC (POD 0, 1, 2, 3), and NR (POD 0, 1, 2), respectively (P < .001-.024 depending on group). Daily opioid requirements were higher in patients managed with PVC (POD 0, 1), WC (POD 0, 1, 2), and NR (POD 0, 1, 2) when compared to patients managed with EC (P < .001). CONCLUSIONS: Our data indicate variation in pain management strategies for patients undergoing MIRPE within our network. The results indicate that most patients have mild-to-moderate pain postoperatively regardless of analgesic management. Patients managed with EC had lower pain scores and opioid consumption in the early recovery period compared to other treatment strategies.

Neurotoxicity, general anesthesia in young children, and a survey of current pediatric anesthesia practice at US teaching institutions.

BACKGROUND: Recent articles in both scholarly journals and the lay press about the topic of anesthetic related neurotoxicity have increased the awareness and discussion of this topic with parents and other pediatric medical specialties (i.e., surgeons, radiologists, and pediatricians). AIM: The purpose of the present study was to survey how a subset of pediatric anesthesia departments in the US have responded to the issue of anesthetic related neurotoxicity in terms of clinical practice, training and communication with other medical specialties, and the frequency and timing of discussions with families. METHODS: A survey consisting of 22 questions was sent to PALC (Pediatric Anesthesia Leadership Council) & PAPDA (Pediatric Anesthesia Program Directors Association) via SurveyMonkey. The survey was divided into sections on Anesthesia Faculty/Trainees, Parents and Non-Anesthesia Providers. Responses to the survey were solicited via email to PALC and PAPDA, and then followed up with reminders to individual emails using the mailing lists of both organizations. RESULTS: The results of this survey demonstrate that pediatric anesthesia programs around the US do not have a consistent approach in managing the topic of anesthesia-related neurotoxicity with pediatric anesthesiologists, anesthesiology residents, pediatric anesthesiology fellows and their non-anesthesia medical and surgical colleagues, as well as the discussion of this topic with parents. CONCLUSION: A significant need exists to provide information to other pediatric professionals and parents. A consistent message from all providers that includes what is known, and indeed more importantly what is not known may be a useful approach.

Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood.

IMPORTANCE: Exposure of young animals to commonly used anesthetics causes neurotoxicity including impaired neurocognitive function and abnormal behavior. The potential neurocognitive and behavioral effects of anesthesia exposure in young children are thus important to understand. OBJECTIVE: To examine if a single anesthesia exposure in otherwise healthy young children was associated with impaired neurocognitive development and abnormal behavior in later childhood. DESIGN, SETTING, AND PARTICIPANTS: Sibling-matched cohort study conducted between May 2009 and April 2015 at 4 university-based US pediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently 8 to 15 years old. The exposed siblings were healthy at surgery/anesthesia. Neurocognitive and behavior outcomes were prospectively assessed with retrospectively documented anesthesia exposure data. EXPOSURES: A single exposure to general anesthesia during inguinal hernia surgery in the exposed sibling and no anesthesia exposure in the unexposed sibling, before age 36 months. MAIN OUTCOMES AND MEASURES: The primary outcome was global cognitive function (IQ). Secondary outcomes included domain-specific neurocognitive functions and behavior. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behavior. RESULTS: Among the 105 sibling pairs, the exposed siblings (mean age, 17.3 months at surgery/anesthesia; 9.5% female) and the unexposed siblings (44% female) had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anesthetic agents, and anesthesia duration ranged from 20 to 240 minutes, with a median duration of 80 minutes. Mean IQ scores between exposed siblings (scores: full scale = 111; performance = 108; verbal = 111) and unexposed siblings (scores: full scale = 111; performance = 107; verbal = 111) were not statistically significantly different. Differences in mean IQ scores between sibling pairs were: full scale = -0.2 (95% CI, -2.6 to 2.9); performance = 0.5 (95% CI, -2.7 to 3.7); and verbal = -0.5 (95% CI, -3.2 to 2.2). No statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior. CONCLUSIONS AND RELEVANCE: Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.

A retrospective comparison of ropivacaine and 2-chloroprocaine continuous thoracic epidural analgesia for management of postthoracotomy pain in infants.

INTRODUCTION: Continuous thoracic epidural analgesia is useful in the management of infants following thoracotomy. Concerns about drug accumulation and toxicity limit the amount of amide local anesthetics that can be delivered. Continuous epidural infusions of the ester local anesthetic chloroprocaine result in little drug accumulation allowing for higher infusion rates. We retrospectively compared patients managed with 1.5% 2- chloroprocaine or 0.1% ropivacaine epidural infusions to determine if the increased infusion rate resulted in similar or improved analgesia. METHODS: This retrospective cohort comparison consisted of full term infants 6 months or younger who underwent thoracotomy for congenital lung lesion resection. Patients were included if they were managed with either a 1.5% 2-chloroprocaine (Group C) (n = 26) or 0.1% ropivacaine (Group R) (n = 28) infusion administered through a caudally placed thoracic epidural catheter. The primary outcome was morphine administration at 0-24 h. RESULTS: Patients were similar in age, weight, length of stay, epidural location and duration. There was weak evidence for a difference in morphine use in the first 24 h in Group C compared to Group R (P = 0.08) but no difference 24-48 h. Group C was more commonly managed with ketorolac at 0-24 h (P = 0.03) and 24-48 h (P =< 0.01). DISCUSSION: The use of 2-chloroprocaine for continuous epidural infusion in infants following thoracotomy was not inferior to ropivacaine and there was weak evidence for a reduction in opioid consumption in the first 24 h postoperatively. However, the 2-chloroprocaine group was more likely to receive ketorolac.

Pain care for patients with epidermolysis bullosa: best care practice guidelines.

BACKGROUND: Inherited epidermolysis bullosa (EB) comprises a group of rare disorders that have multi-system effects and patients present with a number of both acute and chronic pain care needs. Effects on quality of life are substantial. Pain and itching are burdensome daily problems. Experience with, and knowledge of, the best pain and itch care for these patients is minimal. Evidence-based best care practice guidelines are needed to establish a base of knowledge and practice for practitioners of many disciplines to improve the quality of life for both adult and pediatric patients with EB. METHODS: The process was begun at the request of Dystrophic Epidermolysis Bullosa Research Association International (DEBRA International), an organization dedicated to improvement of care, research and dissemination of knowledge for EB patients worldwide. An international panel of experts in pain and palliative care who have extensive experience caring for patients with EB was assembled. Literature was reviewed and systematically evaluated. For areas of care without direct evidence, clinically relevant literature was assessed, and rounds of consensus building were conducted. The process involved a face-to-face consensus meeting that involved a family representative and methodologist, as well as the panel of clinical experts. During development, EB family input was obtained and the document was reviewed by a wide variety of experts representing several disciplines related to the care of patients with EB. RESULTS: The first evidence-based care guidelines for the care of pain in EB were produced. The guidelines are clinically relevant for care of patients of all subtypes and ages, and apply to practitioners of all disciplines involved in the care of patients with EB. When the evidence suggests that the diagnosis or treatment of painful conditions differs between adults and children, it will be so noted. CONCLUSIONS: Evidence-based care guidelines are a means of standardizing optimal care for EB patients, whose disease is often times horrific in its effects on quality of life, and whose care is resource-intensive and difficult. The guideline development process also highlighted areas for research in order to improve further the evidence base for future care.

Pain management following major intracranial surgery in pediatric patients: a prospective cohort study in three academic children's hospitals.

INTRODUCTION: Pain management following major intracranial surgery is often limited by a presumed lack of need and a concern that opioids will adversely affect postoperative outcome and interfere with the neurologic examination. Nevertheless, evidence in adults is accumulating that these patients suffer moderate to severe pain, and this pain is often under-treated. The purpose of this prospective, clinical observational cohort study was to assess the incidence of pain, prescribed analgesics, methods of analgesic delivery, and patient/parent satisfaction in pediatric patients undergoing cranial surgery at three major university children's hospitals. METHODS: After obtaining IRB and parental consent (and when applicable, patient assent), children who underwent cranial surgery for cancer, epilepsy, vascular malformations, and craniofacial reconstruction were studied. Neither intraoperative anesthetic management nor postoperative pain management was standardized, but were based on institutional routine. Patients were evaluated daily by a study investigator and by chart review for pain scores using age appropriate, validated tools (FLACC, Faces Pain Scale-Revised, Wong-Baker Faces Scale or Self-Report on a 0-10 scale), for patient/parent satisfaction using a subset of the NRC Picker satisfaction tool and in adolescents a modified QoR-40, and for the frequency, mode of administration, and type of analgesic provided. Finally, the incidence of opioid-induced side effects, specifically nausea, vomiting, pruritus, altered level of consciousness, and need for emergency diagnostic radiologic studies for altered neurologic examination were recorded. Data are provided as mean ± SD. RESULTS: Two hundred children (98:102 M:F), averaging 7.8 ± 5.8 years old (range 2 months-18.5 years) and 32.2 ± 23.0 kg (range 4.5-111.6 kg) undergoing craniectomy (51), craniotomy (96), and craniofacial reconstruction (53) were studied. Despite considerable variation in mode and route of analgesic administration, there were no differences in average pain score, length of hospital stay, or parental satisfaction with care. Interestingly, opioid-induced side effects were not related to total daily opioid consumption, site of surgery, or method of opioid delivery. The most common side effect was vomiting. No patient developed respiratory depression or altered mental status secondary to analgesic therapy. Regardless of age or procedure, once eating, most patients were treated with oral oxycodone and/or acetaminophen. CONCLUSIONS: Despite considerable variation in modality and route of analgesic administration, there were no differences in average pain score, length of stay, or parental satisfaction with care. Pain scores were low, side effects were minimal, and parental satisfaction was high, providing equipoise for future blinded prospective randomized trials in this patient population.

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).

Perioperative management of children undergoing craniofacial reconstruction surgery: a practice survey.

OBJECTIVE/AIMS: To assess current practices in the management of children undergoing craniofacial surgery and identify areas of significant practice variability with the intent to direct future research. BACKGROUND: The perioperative management of infants and children undergoing craniofacial reconstruction surgery can be challenging because of the routine occurrence of significant blood loss with associated morbidity. A variety of techniques have been described to improve the care for these children. It is presently unknown to what extent these practices are currently employed. METHODS: A web-based survey was sent to representatives from 102 institutions. One individual per institution was surveyed to prevent larger institutions from being over-represented in the results. RESULTS: Requests to complete the survey were sent to 102 institutions; 48 surveys were completed. The survey was composed of two parts: management of infants undergoing strip craniectomies, and management of children undergoing major craniofacial reconstruction. CONCLUSIONS: Significant variability exists in the management of children undergoing these procedures; further study is required to determine the optimal management strategies. Clinical trials assessing the utility of central venous pressure and other hemodynamic monitoring modalities would enable evidence-based decision-making for monitoring in these children. The development of institutional transfusion thresholds should be encouraged, as there exists a body of evidence supporting their efficacy and safety.

Randomized Population Pharmacokinetic Analysis and Safety of Intravenous Acetaminophen for Acute Postoperative Pain in Neonates and Infants.

Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo-controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (<2 years of age) who were undergoing surgery or had experienced a traumatic injury and were expected to need pain management for at least 24 hours were enrolled. Subjects were randomly assigned to receive intravenous acetaminophen low dose, intravenous acetaminophen high dose, or placebo. A population PK model of intravenous acetaminophen was updated by combining 581 samples from the current study of 158 neonate and infant subjects with results from a previously developed model. The individual predicted-versus-observed concentrations plots showed that the structural PK model fit the blood and plasma acetaminophen concentration-versus-time profiles in the active and placebo groups. Terminal elimination half-life was prolonged in neonates and younger infants and in intermediate and older infants similar to values in adults. When compared with placebo, total rescue opioid consumption was similar and significantly fewer intravenous acetaminophen patients prematurely discontinued because of treatment-emergent adverse events (P < .01). For intravenous acetaminophen, neonates receiving 12.5 mg/kg every 6 hours had PK profiles similar to younger, intermediate, and older infants, adolescents, and adults weighing <50 kg receiving 15 mg/kg every 6 hours and adults ≥ 50 kg receiving 1000 mg every 6 hours.

Assessment of Pain in the Newborn: An Update.

Preterm and term neonate pain assessment in neonatal intensive care units is vitally important because of the prevalence of procedural and postoperative pain. Of the 40 plus tools available, a few should be chosen for different populations and contexts (2 have been validated in premature infants). Preterm neonates do not display pain behaviors and physiologic indicators as reliably and specifically as full-term infants, and are vulnerable to long-term sequelae of painful experiences. Brain-oriented approaches may become available in the future; meanwhile, neonatal pain assessment tools must be taught, implemented, and their use optimized for consistent, reproducible, safe, and effective treatment.

Emergent excision of a prenatally diagnosed sacrococcygeal teratoma.

Prenatally diagnosed sacrococcygeal teratomas (SCT) have higher mortality rates than those diagnosed in the neonatal period. Natural history of SCT varies, and management depends on pathophysiology. Treatment may be minimally invasive or require open surgery. Intervention may take place in the prenatal period, or it may occur within minutes to days after birth. Optimal care requires close follow up and communication between members of a multidisciplinary team. We present a case of prenatally diagnosed SCT and address the evaluation, anesthetic considerations, and mechanisms needed to care for this high risk population.

Use of Intravenous Acetaminophen in Children for Analgesia After Spinal Fusion Surgery: A Randomized Clinical Trial.

OBJECTIVES: Opioid pharmacotherapy is the cornerstone of postoperative analgesia. Despite its effectiveness, it has a variety of potential adverse effects. Therefore, a multimodal approach with non-opioid analgesics would be optimal. The aim of this study was to determine if intravenous (IV) acetaminophen would reduce opioid requirements and improve clinical outcomes in children after surgery. METHODS: A single-center, randomized, double-blind study was conducted in 57 children (10-18 years old) undergoing posterior spine fusion surgery between July 2011 to May 2014. All subjects received either acetaminophen or placebo at the end of surgery, followed by repeated doses every 6 hours for a total of 8 doses. RESULTS: In the first 24 postoperative hours, the average opioid consumption was lower for the active group compared with the placebo group (p = 0.02). The total unadjusted time to patient controlled analgesia (PCA) discontinuation was also longer in the placebo group than the active group (90 hours vs. 73 hours, p = 0.02); however, this was not statistically significant after normalizing for body weight. Additionally, time to first solid intake was longer without the use of acetaminophen (69 hours vs. 49 hours, p = 0.01). CONCLUSIONS: Postoperative use of IV acetaminophen was associated with earlier time to diet advancement and discontinuation of IV analgesics and may result in lower opioid consumption.

Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations.

Clinical trials to test the safety and efficacy of analgesics across all pediatric age cohorts are needed to avoid inappropriate extrapolation of adult data to children. However, the selection of acute pain models and trial design attributes to maximize assay sensitivity, by pediatric age cohort, remains problematic. Acute pain models used for drug treatment trials in adults are not directly applicable to the pediatric age cohorts-neonates, infants, toddlers, children, and adolescents. Developmental maturation of metabolic enzymes in infants and children must be taken into consideration when designing trials to test analgesic treatments for acute pain. Assessment tools based on the levels of cognitive maturation and behavioral repertoire must be selected as outcome measures. Models and designs of clinical trials of analgesic medications used in the treatment of acute pain in neonates, infants, toddlers, children, and adolescents were reviewed and discussed at an Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) Pediatric Pain Research Consortium consensus meeting. Based on extensive reviews and continuing discussions, the authors recommend a number of acute pain clinical trial models and design attributes that have the potential to improve the study of analgesic medications in pediatric populations. Recommendations are also provided regarding additional research needed to support the use of other acute pain models across pediatric age cohorts.

Pathophysiology and management of opioid-induced pruritus.

Pruritus occurs frequently following opioid use, particularly after neuraxial administration. Although not life threatening, pruritus is discomforting and may decrease patient satisfaction. Even though the mechanism of opioid-induced pruritus is not yet fully understood, there is increasing evidence of the important role played by micro opioid receptors. Animal experiments pointing to the role of the micro opioid receptor and the efficacy of micro opioid receptor antagonists for opioid adverse effect prophylaxis and treatment have been replicated in several studies. Serotonin and dopamine D(2) receptors, prostaglandins and spinal inhibitory pathways may also be involved in the genesis of pruritus. Several pharmacological agents have been used both for the treatment of established pruritus and in its prevention. Of these, micro opioid receptor antagonists have been most consistent in terms of attenuating opioid-induced pruritus but present problems in dose and administration. Other drugs, including mixed opioid receptor agonist-antagonists, serotonin 5-HT(3) receptor antagonists, propofol, NSAIDs and D(2) receptor antagonists, have also been demonstrated to be useful. This review summarises the current understanding of the mechanisms causing opioid-induced pruritus and the pharmacological therapies available to prevent and/or manage this disorder.

Continuous peripheral nerve blockade for inpatient and outpatient postoperative analgesia in children.

BACKGROUND: This is an audit of the continuous peripheral nerve blockade (CPNB) program that was implemented at our institution to provide postoperative analgesia after orthopedic procedures in children. METHODS: We reviewed the departmental regional anesthesia registry and the medical records of consecutive children who received CPNB for postoperative analgesia at The Children's Hospital of Philadelphia between February 2003 and July 2006. Patients were prospectively followed until cessation of the effects of CPNB and/or resolution of any related complications. Data collected contemporaneously included presence of sensory and motor blockade, pain scores in inpatients, opioid administration, and complications related to CPNB. RESULTS: A total of 226 peripheral nerve catheters were placed in 217 patients. One hundred eight patients (112 catheters) were discharged home with CPNB. The ages ranged from 4 to 18 yr (13.7 +/- 3.4). Local anesthetic solution (0.125% bupivacaine [n = 164], 0.1% ropivacaine [n = 12], or 0.15% ropivacaine [n = 27]) was infused at an initial rate of 2-12 mL/h based on patients' weights and locations of catheters. The mean duration of local anesthetic infusion was 48.4 +/- 29.3 h (range 0-160 h). The percentage of patients who did not require any opioids in the first 8, 24, and 48 h after surgery was 56%, 26%, and 21%, respectively. The incidence of nausea and vomiting was 14% (13% in outpatients, 15% in inpatients). Complications were noted in 2.8% of patients. Three patients had prolonged numbness (>24 h) that resolved spontaneously; one developed superficial cellulitis that resolved with a course of antibiotics; one had difficulty removing the catheter at home and one developed tinnitus 24 h after starting CPNB that resolved quickly after clamping of the catheter followed by removal. CONCLUSION: It is feasible to implement a CPNB program to provide an alternative method of inpatient and outpatient postoperative analgesia after orthopedic surgery in children when appropriate expertise is available. Patient and family education along with frequent follow-up are crucial to detect and address adverse events promptly.