The role of cytokines in acute and chronic postsurgical pain after major musculoskeletal surgeries in a quaternary pediatric center.

STUDY OBJECTIVE: To determine if baseline cytokines/chemokines and their changes over postoperative days 0-2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery. DESIGN: Prospective, observational, longitudinal nested study. SETTING: University-affiliated quaternary children's hospital. PATIENTS: Subjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure. MEASUREMENTS: Demographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and up to two weeks after surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score > 3/10 beyond 3 months post-surgery) post-surgical pain were analyzed using univariable and multivariable regression analyses with adjustment for covariates and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes. MAIN RESULTS: Analyses included 3,164 repeated measures of 16 cytokines/chemokines from 112 subjects (median age 15.3, IQR 13.5-17.0, 54.5 % female, 59.8 % pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (ß = 0.95, SE 0.31; p = 0.003), IL-1ß (ß = 0.84, SE 0.36; p = 0.02), IL-2 (ß = 0.78, SE 0.34; p = 0.03), and IL-12 p70 (ß = 0.88, SE 0.40; p = 0.03) and longitudinal postoperative elevations in GM-CSF (ß = 1.38, SE 0.57; p = 0.03), IFNγ (ß = 1.36, SE 0.6; p = 0.03), IL-1ß (ß = 1.25, SE 0.59; p = 0.03), IL-7 (ß = 1.65, SE 0.7; p = 0.02), and IL-12 p70 (ß = 1.17, SE 0.58; p = 0.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (ß = -0.39, SE 0.17; p = 0.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (ß = -0.57, SE 0.26; p = 0.03), IL-8 (ß = -0.68, SE 0.24; p = 0.006), and IL-13 (ß = -0.48, SE 0.22; p = 0.03). Covariates female (vs. male) sex and surgery type (pectus surgery vs. spine) were associated with higher odds for CPSP in baseline adjusted cytokine-CPSP association models for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNFα, and IL-8, IL-10, respectively. CONCLUSION: We identified pro-inflammatory cytokine profiles associated with higher risk of acute postoperative pain. Interestingly, pleiotropic cytokine IL-6, chemokine IL-8 (which promotes neutrophil infiltration and monocyte differentiation), and monocyte-released anti-inflammatory cytokine IL-13, were associated with lower CPSP risk. Our results suggest heterogenous outcomes of cytokine/chemokine signaling that can both promote and protect against post-surgical pain. These may serve as predictive and prognostic biomarkers of pain outcomes following surgery.

A survey of practice in the anesthetic management of adolescent idiopathic scoliosis spine fusion by the North American Pediatric Spine Anesthesiologists Collaborative.

BACKGROUND: Adolescent Idiopathic Scoliosis (AIS) affects 2%-4% of the general pediatric population. While surgical correction remains one of the most common orthopedic procedures performed in pediatrics, limited consensus exists on the perioperative anesthetic management. AIMS: To examine the current state of anesthetic management of typical AIS spine fusions at institutions which have a dedicated pediatric orthopedic spine surgeon. METHODS: A web-based survey was sent to all members of the North American Pediatric Spine Anesthesiologists (NAPSA) Collaborative. This group included 34 anesthesiologists at 19 different institutions, each of whom has a Harms Study Group surgeon performing spine fusions at their hospital. RESULTS: Thirty-one of 34 (91.2%) anesthesiologists completed the survey, with a missing response rate from 0% to 16.1% depending on the question. Most anesthesia practices (77.4%; 95% confidence interval [CI], 67.7-93.4) do not have patients come for a preoperative visit prior to the day of surgery. Intravenous induction was the preferred method (74.2%; 95% CI 61.3-89.9), with the majority utilizing two peripheral IVs (93.5%; 95% CI 90.3-100) and an arterial line (100%; 95% CI 88.8-100). Paralytic administration for intubation and/or exposure was divided (51.6% rocuronium/vecuronium, 45.2% no paralytic, and 3.2% succinylcholine) amongst respondents. While tranexamic acid was consistently utilized for reducing blood loss, dosing regimens varied. When faced with neuromonitoring signal issues, 67.7% employ a formal protocol. Most anesthesiologists (93.5%; 95% CI 78.6-99.2) extubate immediately postoperatively with patients admitted to an inpatient floor bed (77.4%; 95% CI 67.7-93.3). CONCLUSION: Most anesthesiologists (87.1%; 95% CI 80.6-99.9) report the use of some form of an anesthesia-based protocol for AIS fusions, but our survey results show there is considerable variation in all aspects of perioperative care. Areas of agreement on management comprise the typical vascular access required, utilization of tranexamic acid, immediate extubation, and disposition to a floor bed. By recognizing the diversity of anesthetic care, we can develop areas of research and improve the perioperative management of AIS.

Error traps and preventative strategies for adolescent idiopathic scoliosis spinal surgery.

Anesthesia for posterior spinal fusion for adolescent idiopathic scoliosis remains one of the most common surgeries performed in adolescents. These procedures have the potential for significant intraprocedural and postoperative complications. The potential for pressure injuries related to prone positioning must be understood and addressed. Additionally, neuromonitoring remains a mainstay for patient care in order to adequately assess patient neurologic integrity and alert the providers to a reversible action. As such, causes of neuromonitoring signal loss must be well understood, and the provider should have a systematic approach to signal loss. Further, anesthetic design must facilitate intraoperative wake-up to allow for a definitive assessment of neurologic function. Perioperative bleeding risk is high in posterior spinal fusion due to the extensive surgical exposure and potentially lengthy operative time, so the provider should undertake strategies to reduce blood loss and avoid coagulopathy. Pain management for adolescents undergoing spinal fusion is also challenging, and inadequate analgesia can delay recovery, impede patient/family satisfaction, increase the risk of chronic postsurgical pain/disability, and lead to prolonged opioid use. Many of the significant complications associated with this procedure, however, can be avoided with intentional and evidence-based approaches covered in this review.

Timely completion of spinal fusion: A multidisciplinary quality improvement initiative to improve operating room efficiency.

BACKGROUND: Failure to complete surgery within the scheduled timeframe impairs operating room efficiency leading to patient dissatisfaction and unplanned labor costs. We sought to improve timely completion (within 30 min of scheduled time) of first-case spine fusion surgery (for idiopathic scoliosis) from a baseline of 25%-80% over 12 months. We also targeted timely completion of perioperative stages within predetermined target completion times. METHODS: The project was conducted in three overlapping phases over 16 months. A simplified process map outlining five sequential perioperative stages, preintervention baselines (N = 24) and time targets were defined. A multidisciplinary team conducted a series of tests of change addressing the aims. The key drivers included effective scheduling, team communications, family engagement, data collection veracity, standardized pathways, and situational awareness. Data collected by an independent data collector and from electronic medical records were analyzed using control charts and statistical process control methods. RESULTS: Post-intervention, timely case completion increased from 25% to 68% (N = 49) (95% CI 15.1-62.7), (p = 0.003) and was sustained (N = 14). Implementation of prediction model for case-scheduling decreased difference between scheduled and actual case end-time (33 vs. 53 min [baseline]) and variance [lower/upper control limits ([-26, 51] vs. [-109, 216] min [baseline]). Average start time delay decreased from 6 to 2 min and on-time surgical starts improved from 50% to 70% (95% CI 3.2-41.6%). Timely completion increased for anesthesia induction (60% to 85%), surgical procedure (26% to 48%) and emergence from anesthesia (44% to 80%) but not for intraoperative patient preparation (30% to 25%) perioperative stages. Families reported satisfaction with preoperative processes (N = 14), and no untoward intraoperative safety events occurred. CONCLUSIONS: Application of QI methodology reduced time variation of several tasks and improved timely completion of spine surgery. Beyond the study period, sustained team behavior, adaptive changes, and vigilant monitoring are imperative for continued success.

Fascia Iliaca Pain Block Results in Lower Overall Opioid Usage and Shorter Hospital Stays than Epidural Anesthesia After Hip Reconstruction in Children With Cerebral Palsy.

INTRODUCTION AND OBJECTIVE: Epidural anesthesia (EA) is often used for pain control in children with cerebral palsy (CP) who undergo hip reconstructions. The purpose of this study is to determine if preoperative fascia iliaca (FI) pain blocks would improve pain scores, decrease opioid use, and result in shorter hospital stays in comparison to the use of EA. METHODS: This is a nonrandomized retrospective cohort study examining 60 consecutive patients with CP who underwent hip reconstruction utilizing either a fascia iliac compartment nerve block (FICNB) (N=37) or continuous lumbar epidural (N=22) from January 2017 to March 2019. Age at surgery was 8.5±4.6 years. We recorded age, weight, operating room (OR) time, FLACC (Face, Legs, Activity, Cry, Consolability scale) scores on postoperative days (PODs) 0, 1, 2, and 3, opioid doses, overall opioid (mg) used, and length of stay. We compared pain scores, opioid usage, OR time, and lengths of stay between our 2 patient groups. RESULTS: Pain scores were similar between groups on POD #0, 2, and 3 but were statistically improved on POD #1 (1.8±1.3 vs. 3.1±1.4, P<0.001). Total number of opiod doses (7.9±4.4 vs. 10.7±2.3, P=0.004), total milligram given (18.3±11.8 vs. 24.7±12.3, P<0.05), and milligram per kilogram given (0.77±0.42 vs. 1.11 mg/kg±0.36 mg/kg, P=0.001) were less for the FI group versus the epidural group. The OR time (which includes time for blocks/epidurals) was lower in the FI group (4.6±1.2 vs. 5.7±1.1 h, P=0.0002). Overall hospital stays were lower in the FI group (3.4±1.5 vs. 4.1±1.0 d, P<0.05). CONCLUSIONS: This study demonstrates that in the setting of hip reconstruction, patients that received preoperative FI blocks used a lower amount of opioids, required fewer rescue doses and ultimately had a shorter hospital length of stay than those undergoing EA.

Tertiary Pediatric Academic Institution's Experience With Intraoperative Neuromonitoring for Nonspinal Surgery in Children With Mucopolysaccharidosis, Based on a Novel Evidence-Based Care Algorithm.

BACKGROUND: Musculoskeletal deformities in mucopolysaccharidoses (MPSs) patients pose unique challenges when patients present for surgery, especially nonspinal surgery. MPS patients have developed postsurgical neurological deficits after nonspinal surgery. While the incidence of neurological deficits after nonspinal surgery under anesthesia is unknown, accumulating evidence provides impetus to change current practice and increased neurological monitoring in these patients. Intraoperative neurophysiologic monitoring (IONM) with somatosensory evoked potentials (SSEPs) and transcranial motor evoked potentials (TcMEPs) has been implemented at select institutions with varying degree of success. This report describes our experience with IONM in the context of a multidisciplinary evidence-based care algorithm we developed at Cincinnati Children's Hospital Medical Center. METHODS: We conducted a retrospective chart review of the electronic medical record (EPIC), for data from all MPS patients at our institution undergoing nonspinal surgery between September 2016 and March 2018. Patients were identified from IONM logs, which include procedure and patient comorbidities. Data concerning demographics, morbidities, degree of kyphoscoliosis, intraoperative administered medications and vital signs, surgical procedure, the IONM data, duration of surgery, and blood loss were extracted. Descriptive analyses were generated for all variables in the data collected. In addition, any IONM changes noted during the surgeries were identified and factors contributing to the changes described. RESULTS: Thirty-eight patients with a diagnosis of MPS underwent nonspinal surgery, and of those 38, 21 received IONM based on preoperative decision-making according to our care algorithm. Of the 21 patients who received IONM, we were able to get reliable baseline potentials on all patients. Of the 21 patients, 3 had significant neurophysiologic changes necessitating surgical/anesthetic intervention. All of these changes lasted several minutes, and the real-time IONM monitoring was able to capture them as they arose. None of the patients sustained residual neurological deficits. Thus, children who did not fit the criteria for IONM (n = 13) based on our algorithm had 0% incidence of any untoward neurological deficits after surgery (97.5% confidence interval [CI], 00%-25.5%), while 14% (95% CI, 11.5%-30.1%) of children who did fit criteria for IONM and had IONM had significant IONM changes. CONCLUSIONS: Through this case series, we describe our experience with the use of IONM and a novel care algorithm for guiding the anesthetic management of MPS patients undergoing nonspinal surgery. We conclude that they can be useful tools for provision of safe anesthetic care in this high-risk cohort.

Hydromorphone population pharmacokinetics in pediatric surgical patients.

BACKGROUND: Hydromorphone is an opioid agonist used for pediatric analgesia. Due to lack of data, pediatric dosing (based on adult pharmacokinetic models) is not optimal. AIM: This study characterizes hydromorphone population pharmacokinetics in pediatric surgical patients. METHODS: In this prospective observational study, 34 children (4-18 years, bodyweight 23-89.6 kg) received multiple intravenous hydromorphone boluses followed by postoperative hydromorphone patient-controlled analgesia. Arterial blood samples were collected before and at 3, 10, 30, and 90 (and few samples at 1350) minutes after the first dose. Hydromorphone concentrations were measured by validated LC-MS/MS assay. Nonlinear mixed-effects modeling was used for pharmacokinetic model development. The final population pharmacokinetic model was evaluated by visual predictive check and bootstrap analysis. Monte Carlo simulations based on the final pharmacokinetic model determined optimal patient-controlled analgesia parameters to achieve a target of 20 ng/mL (as the median effective analgesic concentration), using minimum effective analgesic concentration of 4 ng/mL as a proxy for patient-controlled analgesia dose demand, and not exceeding the defined safe upper threshold of 40 ng/mL. RESULTS: Hydromorphone pharmacokinetic profiles were adequately described by a two-compartmental model with first-order elimination. Bodyweight was found to be a significant covariate for hydromorphone clearance. Allometrically scaledpharmacokinetic parameter estimates (per 70 kg), systemic clearance (0.748 L/min), volume of distribution (33 L), peripheral clearance (1.57 L/min), and peripheral volume of distribution (146 L) were similar to reported adult parameter estimates. Sex, race, age, and type of surgery were not identified as significant covariates. To identify optimal patient-controlled analgesia dosing parameters, we simulated several initial loading doses, demand doses, and lockout intervals. Our simulations support an initial patient-controlled analgesia loading dose of 15 µg/kg followed by a demand dose of 6 µg/kg with lockout intervals of 20 minutes. CONCLUSIONS: After intravenous hydromorphone, plasma pharmacokinetic profiles in children undergoing different surgeries were well described by a two-compartment population allometric pharmacokinetic model using bodyweight as the size descriptor. Model informed simulations identified patient-controlled analgesia parameters to inform initial settings, with adjustments as needed based on observed individual effects.

Cost-effectiveness of intravenous acetaminophen and ketorolac in adolescents undergoing idiopathic scoliosis surgery.

BACKGROUND: Enhanced recovery after surgery protocols increasingly use multimodal analgesia after major surgeries with intravenous acetaminophen and ketorolac, despite no documented cost-effectiveness of these strategies. AIMS: The goal of this prospective cohort study was to model cost-effectiveness of adding acetaminophen or acetaminophen + ketorolac to opioids for postoperative outcomes in children having scoliosis surgery. METHODS: Of 106 postsurgical children, 36 received only opioids, 26 received intravenous acetaminophen, and 44 received acetaminophen + ketorolac as analgesia adjuncts. Costs were calculated in 2015 US $. Decision analytic model was constructed with Decision Maker® software. Base-case and sensitivity analyses were performed with effectiveness defined as avoidance of opioid adverse effects. RESULTS: The groups were comparable demographically. Compared with opioids-only strategy, subjects in the intravenous acetaminophen + ketorolac strategy consumed less opioids (P = .002; difference in mean morphine consumption on postoperative days 1 and 2 was -0.44 mg/kg (95% CI -0.72 to -0.16); tolerated meals earlier (P < .001; RR 0.250 (0.112-0.556)) and had less constipation (P < .001; RR 0.226 (0.094-0.546)). Base-case analysis showed that of the 3 strategies, use of opioids alone is both most costly and least effective, opioids + intravenous acetaminophen is intermediate in both cost and effectiveness; and opioids + intravenous acetaminophen and ketorolac is the least expensive and most effective strategy. The addition of intravenous acetaminophen with or without ketorolac to an opioid-only strategy saves $510-$947 per patient undergoing spine surgery and decreases opioid side effects. CONCLUSION: Intravenous acetaminophen with or without ketorolac reduced opioid consumption, opioid-related adverse effects, length of stay, and thereby cost of care following idiopathic scoliosis in adolescents compared with opioids-alone postoperative analgesia strategy.

Codeine and opioid metabolism: implications and alternatives for pediatric pain management.

PURPOSE OF REVIEW: Use of perioperative opioids for surgical pain management of children presents clinical challenges because of concerns of serious adverse effects including life-threatening respiratory depression. This is especially true for children with history of obstructive sleep apnea. This review will explore current knowledge of clinically relevant factors and genetic polymorphisms that affect opioid metabolism and postoperative outcomes in children. RECENT FINDINGS: Within the past several years, an increasing number of case reports have illustrated clinically important respiratory depression, anoxic brain injuries and even death among children receiving appropriate weight-based dosages of codeine and other opioids for analgesia at home setting particularly following tonsillectomy. Several national and international organizations have issued advisories on use of codeine in pediatrics, based on cytochrome P450 family 2 subfamily D type 6 (CYP2D6) pharmacogenetics. We have discussed the pros and cons of alternatives to codeine for pain management. SUMMARY: Although routine preoperative genotyping to identify children at risk and personalized opioid use for pediatric perioperative pain management is still a distant reality, current known implications of CYP2D6 pharmacogenetics on codeine use shows that pharmacogenetics has the potential to guide anesthesia providers on perioperative opioid selection and dosing to maximize efficacy and safety.

Opioid-related adverse effects in children undergoing surgery: unequal burden on younger girls with higher doses of opioids.

OBJECTIVE: Unpredictable interindividual variability in response to opioids results in inadequate analgesia and opioid-related adverse effects. The effects of the child's sex on opioid response have not been well studied. The aim of this study is to determine the effects of sex on opioid-related adverse effects in children undergoing tonsillectomy. DESIGN: Prospective observational clinical study. SETTING: Outpatient pediatric surgery. SUBJECTS: Two hundred and seventy five children between 6 and 15 years of age undergoing outpatient tonsillectomy. METHODS: All children received standard perioperative care with a standard intraoperative dose of morphine. Opioid-related analgesia and safety outcomes included incidences of respiratory depression (RD), postoperative nausea and vomiting (PONV) and incidence of prolonged stay in the, post-anesthesia recovery unit (PACU) due to opioid related adverse effects. RESULTS: Given the small sample of minority population, we focused our study on 219 white children. Significant morphine effect was observed in girls but not boys for PONV (P = 0.001) and prolonged PACU stay due to PONV (P = 0.010). Although the overall incidence of RD is not statistically different between boys and girls, the incidence of RD (52% vs 32%) and PONV (43% vs 4%) tended to be more in white girls than boys as the total perioperative morphine dose increased to 0.3 mg/kg or more. CONCLUSIONS: This study demonstrates that child's sex influences morphine's dose response and adverse effects. White girls have an unequal burden with higher incidences of PONV, RD, and prolonged PACU stays following tonsillectomy from PONV and RD as total morphine doses are increased.

Population pharmacokinetic-pharmacodynamic modeling and dosing simulation of propofol maintenance anesthesia in severely obese adolescents.

BACKGROUND: Optimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model-based dosing guidelines. METHODS: A prospective PK/PD study was conducted in 26 SO children and adolescents aged 9-18 years (body mass index 31-69 kg·m(-2)), undergoing surgery with intravenous propofol anesthesia clinically titrated by providers blinded to BIS. BIS data and propofol infusion schemes were recorded. Venous blood samples collected during and after propofol infusion were assayed for propofol concentrations. A propofol PK/PD model was developed using NONMEM and model-based simulations were performed to determine propofol dosing regimens targeting BIS of 50 ± 10. RESULTS: A three-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant, adequately described the propofol concentration (n = 375) and BIS (n = 3334) data. TBW was the most predictive covariate for propofol clearance [CL (l·min(-1) ) = 1.65 × (TBW/70)(0.75)]. An effect-site propofol concentration of 3.19 µg·ml(-1) was estimated for half-maximal effect, with no identifiable predictive covariates. The proposed maintenance dosing regimen targeted to a BIS of 50 ± 10, based on our PK/PD model, was able to predict desired propofol concentrations and BIS in a representative obese teen when used in conjunction with accepted PK/PD models for children/obese adults (PK:Eleveld/PD: Cortinez), further supporting evidence for the dosing based on TBW. CONCLUSION: This is the first study to describe the PK/PD of propofol in SO adolescents. The proposed maintenance dosing regimen for propofol uses TBW in an allometric function as a dosing scalar, with an exponent of 0.75. Our results suggest no relevant effect of obesity on the propofol concentration-BIS relationship.

Risk predictors of opioid-induced critical respiratory events in children: naloxone use as a quality measure of opioid safety.

BACKGROUND: Opioid-induced respiratory depression (OIRD) is a life-threatening complication of opioid therapy in children. Naloxone administration triggered by OIRD has been used to monitor safety of opioid therapy in adults. We used this trigger as a quality measure of opioid safety in hospitalized children to identify risk predictors of OIRD. METHODS: We retrospectively reviewed medical records of 38 patients identified from the hospital risk management database as requiring naloxone for critical respiratory events between January 2010 and June 2012 for demographics, comorbidities, surgery, naloxone event details, and outcomes. These data were compared with baseline prevalence in contemporary patients followed by pain service, who did not receive naloxone, to calculate unadjusted odds ratios. Thematic classification of preventable events was undertaken based on analysis of each event. RESULTS: The incidence of naloxone use among hospital inpatients, who received opioids at-least once, was 0.06% compared with 0.23% for patients on the pain service. A majority of naloxone events occurred in postoperative patients (n = 27/38, 71.1%) within the first 24 hours of surgery (n = 20/27, 75.1%) and in the critical care unit (50%). Patients undergoing airway surgeries had higher risk for OIRD (P = 0.01). Patient risk factors for naloxone use included age <1 year (P < 0.001), obstructive sleep apnea (P < 0.001), obesity (P = 0.019), being underweight (P < 0.0001), prematurity (P < 0.001), and developmental delay (P < 0.001). Majority of events (87%) were found to be preventable, which were classified into six main themes based on type of event. CONCLUSION: OIRD is an important, albeit mostly preventable, complication of opioid therapy in children. Naloxone use can be used as a measure to track opioid safety in children, identify contributing factors, and formulate preventive strategies to reduce the risk for OIRD.

Anesthesia- and opioids-related malpractice claims following tonsillectomy in USA: LexisNexis claims database 1984-2012.

BACKGROUND: Although commonly performed, tonsillectomy is not necessarily a low-risk procedure for litigation. We have reviewed malpractice claims involving fatal and nonfatal injuries following tonsillectomy with an emphasis on anesthesia- and opioid-related claims and their characteristics. METHODS: Tonsillectomy-related malpractice claims and jury verdict reports from the United States (US) between 1984 and 2012 found in the LexisNexis MEGA™ Jury Verdicts and Settlements database were reviewed by two independent reviewers. LexisNexis database collects nationwide surgical, anesthesia, and other malpractice claims. Data including years of case and verdicts, surgical, anesthetic and postoperative opioid-related complications, details of injury, death, cause of death, litigation result, and judgment awarded were analyzed. When there were discrepancies between the two independent reviewers, a third reviewer (SS) was involved for resolution. Inflation adjusted monetary awards were based on 2013 US dollars. RESULTS: There were 242 tonsillectomy-related claim reports of which 98 were fatal claims (40.5%) and 144 nonfatal injury claims (59.5%). Verdict/settlement information was available in 72% of cases (n = 175). The median age group of patients was 8.5 years (range 9 months to 60 years). Primary causes for fatal claims were related to surgical factors (n = 39/98, 39.8%) followed by anesthesia-related (n = 36/98, 36.7%) and opioid-related factors (n = 16/98, 16.3%). Nonfatal injury claims were related to surgical (101/144, 70.1%), anesthesia (32/144, 22.2%)- and opioid-related factors (6/144, 4.2%). Sleep apnea was recorded in 17 fatal (17.4%) and 15 nonfatal claims (10.4%). Opioid-related claims had the largest median monetary awards for both fatal ($1 625 892) and nonfatal injury ($3 484 278) claims. CONCLUSIONS: Tonsillectomy carries a high risk from a medical malpractice standpoint for the anesthesiologists and otolaryngologists. Although surgery-related claims were more common, opioids- and anesthetic-related claims were associated with larger median monetary verdicts, especially those associated with anoxic, nonfatal injuries. Caution is necessary when opioids are prescribed post-tonsillectomy, especially in patients with sleep apnea.

The Role of Cytokines in Acute and Chronic Postsurgical Pain in Pediatric Patients after Major Musculoskeletal Surgeries.

Study Objective: To determine if baseline cytokines and their changes over postoperative days 0-2 (POD0-2) predict acute and chronic postsurgical pain (CPSP) after major surgery. Design: Prospective, observational, longitudinal nested study. Setting: University-affiliated quaternary children's hospital. Patients: Subjects (≥8 years old) with idiopathic scoliosis undergoing spine fusion or pectus excavatum undergoing Nuss procedure. Measurements: Demographics, surgical, psychosocial measures, pain scores, and opioid use over POD0-2 were collected. Cytokine concentrations were analyzed in serial blood samples collected before and after (up to two weeks) surgery, using Luminex bead arrays. After data preparation, relationships between pre- and post-surgical cytokine concentrations with acute (% time in moderate-severe pain over POD0-2) and chronic (pain score>3/10 beyond 3 months post-surgery) pain were analyzed. After adjusting for covariates, univariate/multivariate regression analyses were conducted to associate baseline cytokine concentrations with postoperative pain, and mixed effects models were used to associate longitudinal cytokine concentrations with pain outcomes. Main Results: Analyses included 3,164 measures of 16 cytokines from 112 subjects (median age 15.3, IQR 13.5-17.0, 54.5% female, 59.8% pectus). Acute postsurgical pain was associated with higher baseline concentrations of GM-CSF (ß=0.95, SE 0.31; p=.003), IL-1ß (ß=0.84, SE 0.36; p=.02), IL-2 (ß=0.78, SE 0.34; p=.03), and IL-12 p70 (ß=0.88, SE 0.40; p=.03) and longitudinal postoperative elevations in GM-CSF (ß=1.38, SE 0.57; p=.03), IFNγ (ß=1.36, SE 0.6; p=.03), IL-1ß (ß=1.25, SE 0.59; p=.03), IL-7 (ß=1.65, SE 0.7, p=.02), and IL-12 p70 (ß=1.17, SE 0.58; p=.04). In contrast, CPSP was associated with lower baseline concentration of IL-8 (ß= -0.39, SE 0.17; p=.02), and the risk of developing CPSP was elevated in patients with lower longitudinal postoperative concentrations of IL-6 (ß= -0.57, SE 0.26; p=.03), IL-8 (ß= -0.68, SE 0.24; p=.006), and IL-13 (ß= -0.48, SE 0.22; p=.03). Furthermore, higher odds for CPSP were found for females (vs. males) for IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, and TNFα, and for pectus (vs. spine) surgery for IL-8 and IL-10. Conclusion: We identified pro-inflammatory cytokines associated with increased acute postoperative pain and anti-inflammatory cytokines associated with lower CPSP risk, with potential to serve as predictive and prognostic biomarkers.

Multisite prospective study of perioperative pain management practices for anterior cruciate ligament reconstruction in adolescents: Society for Pediatric Anesthesia Improvement Network (SPAIN) Project Report.

INTRODUCTION: Although 200 000 adolescents undergo anterior cruciate ligament reconstruction (ACLR) surgery annually, no benchmarks for pediatric post-ACLR pain management exist. We created a multicenter, prospective, observational registry to describe pain practices, pain, and functional recovery after pediatric ACLR. METHODS: Participants (n=519; 12-17.5 years) were enrolled from 15 sites over 2 years. Data on perioperative management and surgical factors were collected. Pain/opioid use and Lysholm scores were assessed preoperatively, on postoperative day 1 (POD1), POD3, week 6, and month 6. Descriptive statistics and trends for opioid use, pain, and function are presented. RESULTS: Regional analgesia was performed in 447/519 (86%) subjects; of these, adductor canal single shot was most frequent (54%), nerve catheters placed in 24%, and perineural adjuvants used in 43%. On POD1, POD3, week 6, and month 6, survey response rates were 73%, 71%, 61%, and 45%, respectively. Over these respective time points, pain score >3/10 was reported by 64% (95% CI: 59% to 69%), 46% (95% CI: 41% to 52%), 5% (95% CI: 3% to 8%), and 3% (95% CI: 1% to 6%); the number of daily oxycodone doses used was 2.8 (SD 0.19), 1.8 (SD 0.13), 0, and 0. There was considerable variability in timing and tests for postdischarge functional assessments. Numbness and weakness were reported by 11% and 4% at week 6 (n=315) and 16% and 2% at month 6 (n=233), respectively. CONCLUSION: We found substantial variability in the use of blocks to manage post-ACLR pain in children, with a small percentage experiencing long-term pain and neurological symptoms. Studies are needed to determine best practices for regional anesthesia and functional assessments in this patient population.

A retrospective identification of gastroesophageal reflux disease as a new risk factor for surgical site infection in cerebral palsy patients after spine surgery.

BACKGROUND: Neuromuscular scoliosis is a known risk factor for surgical site infection (SSI) after spinal fusion, with reported infection rates as high as 11.2%. Although risk factors such as antibiotic timing have been previously addressed, our objective was to identify intrinsic risk factors for SSI in cerebral palsy (CP) patients with neuromuscular scoliosis. We hypothesized that CP patients who develop SSI after spine fusion would have a risk profile similar to those who develop nosocomial infection. METHODS: We retrospectively analyzed records from patients with CP who developed infections after spinal fusion from January 1998 until July 2008, who were identified by our Infection Control Officer using National Nosocomial Infection Surveillance System criteria (N = 34). Demographically and procedurally matched controls without infection were identified from our spine database (N = 37). We compared these groups for gastroesophageal reflux disease (GERD), use of gastric acid inhibitors, presence of preoperative decubitus ulcer, previous infection, and postoperative ventilation. Multivariable logistic regression was then performed to assess the relative contributions of the predictors to "deep infection" and "any infection." RESULTS: Of 30 evaluable infected patients, 70% had incisional SSI. Although many of the infections were polymicrobial, the most common pathogens identified were Gram-negative bacilli. Many significant predictors were identified by univariable logistic regression for any infection and deep infection. Multivariable logistic regression found a significant effect only for GERD (odds ratio, 6.4; 95% confidence interval, 1.9-21.3; P = 0.002) for any infection, whereas the effect of therapy with gastric acid inhibitors did not reach statistical significance (odds ratio, 6.1 [95% confidence interval, 0.84-44.6]; P = 0.07). No significant interaction between the 2 factors was detected. Among our controls and infected patients altogether, 46.3% had GERD. CONCLUSIONS: We show that GERD increases the risk for infection in CP patients after spine fusion. Prospective multicenter studies are necessary to further validate the predictive value of this risk factor.

Evaluation of propofol anesthesia in morbidly obese children and adolescents.

BACKGROUND: Poor characterization of propofol pharmacokinetics and pharmacodynamics in the morbidly obese (MO) pediatric population poses dosing challenges. This study was conducted to evaluate propofol total intravenous anesthesia (TIVA) in this population. METHODS: After IRB approval, a prospective study was conducted in 20 MO children and adolescents undergoing laparoscopic surgery under clinically titrated propofol TIVA. Propofol doses/infusion rates, hemodynamic variables, times to induction and emergence, and postoperative occurrence of respiratory adverse events (RAE) were recorded, along with intraoperative blinded Bispectral Index/BIS and postoperative Ramsay sedation scores (RSS). Study subjects completed awareness questionnaires on postoperative days 1 and 3. Propofol concentrations were obtained at predetermined intra- and post-operative time points. RESULTS: Study subjects ranged 9 - 18 years (age) and 97 - 99.9% (BMI for age percentiles). Average percentage variability of hemodynamic parameters from baseline was ≈ 20%. Patients had consistently below target BIS values (BIS < 40 for >90% of maintenance phase), delayed emergence (25.8 ± 22 minutes), increased somnolence (RSS ≥ 4) in the first 30 minutes of recovery from anesthesia and 30% incidence of postoperative RAE, the odds for which increased by 14% per unit increase in BMI (p ≤ 0.05). Mean propofol concentration was 6.2 mg/L during maintenance and 1.8 mg/L during emergence from anesthesia. CONCLUSIONS: Our findings indicate clinical overestimation of propofol requirements and highlight the challenges of clinically titrated propofol TIVA in MO adolescents. In this setting, it may be advantageous to titrate propofol to targeted BIS levels until more accurate weight-appropriate dosing regimens are developed, to minimize relative overdosing and its consequences.

Current Evidence for Biological Biomarkers and Mechanisms Underlying Acute to Chronic Pain Transition across the Pediatric Age Spectrum.

Chronic pain is highly prevalent in the pediatric population. Many factors are involved in the transition from acute to chronic pain. Currently, there are conceptual models proposed, but they lack a mechanistically sound integrated theory considering the stages of child development. Objective biomarkers are critically needed for the diagnosis, risk stratification, and prognosis of the pathological stages of pain chronification. In this article, we summarize the current evidence on mechanisms and biomarkers of acute to chronic pain transitions in infants and children through the developmental lens. The goal is to identify gaps and outline future directions for basic and clinical research toward a developmentally informed theory of pain chronification in the pediatric population. At the outset, the importance of objective biomarkers for chronification of pain in children is outlined, followed by a summary of the current evidence on the mechanisms of acute to chronic pain transition in adults, in order to contrast with the developmental mechanisms of pain chronification in the pediatric population. Evidence is presented to show that chronic pain may have its origin from insults early in life, which prime the child for the development of chronic pain in later life. Furthermore, available genetic, epigenetic, psychophysical, electrophysiological, neuroimaging, neuroimmune, and sex mechanisms are described in infants and older children. In conclusion, future directions are discussed with a focus on research gaps, translational and clinical implications. Utilization of developmental mechanisms framework to inform clinical decision-making and strategies for prevention and management of acute to chronic pain transitions in children, is highlighted.