The Reducing Opioid Use in Children with Clefts Protocol: A Multidisciplinary Quality Improvement Effort to Reduce Perioperative Opioid Use in Patients Undergoing Cleft Surgery.

BACKGROUND: Cleft repair requires multiple operations from infancy through adolescence, with repeated exposure to opioids and their associated risks. The authors implemented a quality improvement project to reduce perioperative opioid exposure in their cleft lip/palate population. METHODS: After identifying key drivers of perioperative opioid administration, quality improvement interventions were developed to address these key drivers and reduce postoperative opioid administration from 0.30 mg/kg of morphine equivalents to 0.20 mg/kg of morphine equivalents. Data were retrospectively collected from January 1, 2015, until initiation of the quality improvement project (May 1, 2017), tracked over the 6-month quality improvement study period, and the subsequent 14 months. Metrics included morphine equivalents of opioids received during admission, administration of intraoperative nerve blocks, adherence to revised electronic medical record order sets, length of stay, and pain scores. RESULTS: The final sample included 624 patients. Before implementation (n =354), children received an average of 0.30 mg/kg of morphine equivalents postoperatively. After implementation (n = 270), children received an average of 0.14 mg/kg of morphine equivalents postoperatively (p < 0.001) without increased length of stay (28.3 versus 28.7 hours; p = 0.719) or pain at less than 6 hours (1.78 versus 1.74; p = 0.626) or more than 6 hours postoperatively (1.50 versus 1.49; p = 0.924). CONCLUSIONS: Perioperative opioid administration after cleft repair can be reduced in a relatively short period by identifying key drivers and addressing perioperative education, standardization of intraoperative pain control, and postoperative prioritization of nonopioid medications and nonpharmacologic pain control. The authors' quality improvement framework has promise for adaptation in future efforts to reduce opioid use in other surgical patient populations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Author Correction: WNT-activated bone grafts repair osteonecrotic lesions in aged animals.

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WNT-activated bone grafts repair osteonecrotic lesions in aged animals.

The Wnt pathway is a new target in bone therapeutic space. WNT proteins are potent stem cell activators and pro-osteogenic agents. Here, we gained insights into the molecular and cellular mechanisms responsible for liposome-reconstituted recombinant human WNT3A protein (L-WNT3A) efficacy to treat osteonecrotic defects. Skeletal injuries were coupled with cryoablation to create non-healing osteonecrotic defects in the diaphysis of the murine long bones. To replicate clinical therapy, osteonecrotic defects were treated with autologous bone graft, which were simulated by using bone graft material from syngeneic ACTB-eGFP-expressing mice. Control osteonecrotic defects received autografts alone; test sites received autografts treated ex vivo with L-WNT3A. In vivo µCT monitored healing over time and immunohistochemistry were used to track the fate of donor cells and assess their capacity to repair osteonecrotic defects according to age and WNT activation status. Collectively, analyses demonstrated that cells from the autograft directly contributed to repair of an osteonecrotic lesion, but this contribution diminished as the age of the donor increased. Pre-treating autografts from aged animals with L-WNT3A restored osteogenic capacity to autografts back to levels observed in autografts from young animals. A WNT therapeutic approach may therefore have utility in the treatment of osteonecrosis, especially in aged patients.

Safety of pediatric continuous interscalene block catheters placed under general anesthesia: a single center's experience.

BACKGROUND: The use of interscalene catheters is an effective treatment strategy for children and adolescents undergoing shoulder surgery. Although placement of interscalene catheters in the awake child is challenging, some have cautioned against performing regional anesthesia in the patient under general anesthesia. We present a case series of 154 interscalene catheters placed in pediatric patients under general anesthesia and managed in the outpatient setting. METHODS: A total of 154 interscalene catheters were placed at a single institution between April 2006 and December 2011 using a modified lateral approach. All catheters were placed with the patient under general anesthesia. The patients discharged home with the catheters were followed-up with daily phone calls until removal of the catheter. RESULTS: Of the 154 patients with an interscalene CPNB, 132 (85.7%) were discharged home with the interscalene CPNB in place. The success rate for the catheters was 92.1% (CI: 86.9-95.7%). The most common reason for catheter failure (6%) was early dislodgement (within 24 h). In addition to these 12 patients, 3 other patients had adverse events related to the interscalene CPNB. CONCLUSION: Interscalene catheter placement under general anesthesia and management on an outpatient basis is feasible in the pediatric population and is associated with a low rate of catheter-related complications.

Variation of opioid use in pediatric inpatients across hospitals in the U.S.

CONTEXT: Appropriate use of opioids is essential to manage moderate-to-severe pain in children safely and effectively, yet published guidance regarding opioid treatment for pediatric patients is limited, potentially resulting in excessive variation in opioid use in pediatric patients across hospitals in the U.S. OBJECTIVES: The aim was to evaluate hospital variation in opioid use in pediatric inpatients. METHODS: Using data from the Pediatric Health Information System and the Premier Perspective Database regarding all pediatric inpatients in 626 hospitals, we examined hospital variation in opioid use and the length of opioid use, adjusting for patient demographic and clinical characteristics and for hospital type (children's vs. general) and hospital patient volume, using multilevel generalized linear regression modeling. RESULTS: Overall, 41.2% of all pediatric hospitalizations were exposed to opioids. Among the exposed patients, the mean length of exposure was 4.6 days. Exposure proportion and exposure length varied substantially across hospitals, even after accounting for patient demographic and clinical characteristics, hospital type and hospital patient volume, especially among terminal hospitalizations. For patients discharged alive vs. died, the adjusted exposure percentage for each hospital ranged from 0.7% to 99.1% (interquartile range [IQR]: 35.3%-59.9%) vs. 0.1% to 100.0% (IQR: 29.2%-66.2%), respectively, and the adjusted exposure length ranged from 1.0 to 8.4 days (IQR: 2.2-2.7 days) vs. 0.9 to 35.2 days (IQR: 4.0-7.4 days). CONCLUSION: The substantial hospital-level variation in opioid use in pediatric inpatients suggests room for improvement in clinical practice.

Ambulatory continuous peripheral nerve blocks in children and adolescents: a longitudinal 8-year single center study.

BACKGROUND: Although the role of regional anesthesia in pediatric patients has been increasing over the last few years, there are only a few small case series that describe the use of ambulatory continuous peripheral nerve blocks (CPNBs) in this patient population. In this report, we describe our experience with the use of ambulatory CPNBs in 1285 children. METHODS: Data were collected for consecutive children who had a CPNB placed between January 2005 and December 2011 at The Children's Hospital of Philadelphia from the departmental regional anesthesia database. Data collected included demographics, the site of catheter placement and technique of nerve block, presence of sensory/motor blockade, use of perioperative opioids, and any complications related to CPNBs. RESULTS: Continuous infusions of local anesthetics were administered via the catheters in 1285 outpatients. The mean duration of the CPNB was 50.7 ± 14.4 hours (mean ± SD). Among patients discharged home with the CPNBs, 969 (75.4%) of the patients required either no supplemental opioids or oral opioids only on an "as needed" basis in the postoperative period (confidence interval, 73.0%-77.8%). Two patients were readmitted for IV pain management after they were discharged home with the CPNB catheters. No neurological deficit related to the CPNBs was identified in any of the patients at their 6-month follow-up with the orthopedic surgeon (confidence interval, 0%-0.29%). CONCLUSION: This audit of 1285 children shows ambulatory CPNBs can provide postoperative analgesia and may reduce the need for inpatient parenteral opioid therapy.

HPA axis genetic variation, cortisol and psychosis in major depression.

Genetic variation underlying hypothalamic pituitary adrenal (HPA) axis overactivity in healthy controls (HCs) and patients with severe forms of major depression has not been well explored, but could explain risk for cortisol dysregulation. In total, 95 participants were studied: 40 patients with psychotic major depression (PMD); 26 patients with non-psychotic major depression (NPMD); and 29 HCs. Collection of genetic material was added one third of the way into a larger study on cortisol, cognition and psychosis in major depression. Subjects were assessed using the Brief Psychiatric Rating Scale, the Hamilton Depression Rating Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders. Blood was collected hourly for determination of cortisol from 1800 to 0900 h and for the assessment of alleles for six genes involved in HPA axis regulation. Two of the six genes contributed significantly to cortisol levels, psychosis measures or depression severity. After accounting for age, depression and psychosis, and medication status, only allelic variation for the glucocorticoid receptor (GR) gene accounted for a significant variance for mean cortisol levels from 1800 to 0100 h (r(2)=0.288) and from 0100 to 0900 h (r(2)=0.171). In addition, GR and corticotropin-releasing hormone receptor 1 (CRHR1) genotypes contributed significantly to psychosis measures and CRHR1 contributed significantly to depression severity rating.

Hormone-sensitive lipase deficiency disturbs the fatty acid composition of mouse testis.

Hormone-sensitive lipase (HSL) is a key enzyme in the mobilization of fatty acids from intracellular stores. In mice, HSL deficiency results in male sterility caused by a major defect in spermatogenesis. The testes contain high concentrations of PUFA and specific PUFA are essential for spermatogenesis. We investigated the fatty acid composition and the mRNA levels of key enzymes involved in fatty acid metabolism in testis of HSL-knockout mice. HSL deficiency altered fatty acid composition in the testis but not in plasma. The most important changes were decreases in the essential n-6 PUFA LNA and the n-3 PUFA ALA, and an increase in the corresponding synthesis intermediates C22:4n-6 and C22:5n-3 without changes in DPAn-6 or DHA acids. Mead acid, which has been associated with an essential fatty acid deficit leading to male infertility, was increased in the testis from HSL-knockout mice. Moreover, the expression of SCD-1, FADS1, and FADS2 was increased while expression of ELOVL2, an essential enzyme for the formation of very-long PUFA in testis, was decreased. Given the indispensability of these fatty acids for spermatogenesis, the changes in fatty acid metabolism observed in testes from HSL-knockout male mice may underlie the infertility of these animals.

Effects of intrathecal morphine on transcranial electric motor-evoked potentials in adolescents undergoing posterior spinal fusion.

BACKGROUND: Intrathecal morphine (ITM) provides effective analgesia after posterior spinal fusion (PSF). Although most anesthetic drugs have well-characterized effects on evoked potentials, there is little data on the effects of ITM on transcranial electric motor-evoked potentials (tceMEPs). We performed this study to assess the effects of ITM on tceMEPs in the first 30 minutes after administration. We hypothesized that administration of ITM in doses currently used at our institution would not significantly affect mean tceMEP amplitudes and latencies of an ITM study group relative to control patients who did not receive the drug. METHODS: tceMEPs were recorded before ITM injection and 5, 10, 20, and 30 minutes after injection in 14 subjects ages 11 through 18 years undergoing PSF. These recordings were compared to an age-matched control group undergoing PSF in which ITM was not injected. The effects of ITM on tceMEP amplitude and latency were compared between the 2 groups. RESULTS: Fourteen subjects were enrolled in the ITM group and 16 served as controls. There were no significant differences in the baseline mean response amplitudes of the 2 groups for any of the 8 muscles studied. Mean response amplitudes over the 30-minute posttreatment period in the ITM group did not differ significantly from those of the control subjects. Average response amplitudes collapsed across all muscles for each subject were not significantly different during the baseline period (95% CI = -38% to 45%; P = 0.783), nor were they significantly different between the 2 groups during the posttreatment period (95% CI = -30% to 78%; P = 0.640). There also were no significant differences in the mean response latencies of the 2 groups in either the baseline or posttreatment periods. Average response latencies collapsed across all muscles for each subject were 4% larger for the ITM group than for controls during the baseline period (95% CI = -5% to 13%; P = 0.377), and 3% larger for the ITM group than for controls during the posttreatment period (95% CI = -4% to 12%; P = 0.359). CONCLUSIONS: Administration of ITM in doses currently used at our institution did not cause more than a 70% attenuation of mean tceMEP amplitudes or latency changes of an ITM study group relative to control subjects during the 30-minute period after injection. Further studies are required to determine if there are delayed effects after this initial time period.

Evidence for protein-mediated fatty acid efflux by adipocytes.

AIM: The hormonally controlled mobilization and release of fatty acids from adipocytes into the circulation is an important physiological process required for energy homeostasis. While uptake of fatty acids by adipocytes has been suggested to be predominantly protein-mediated, it is unclear whether the efflux of fatty acids also requires membrane proteins. METHODS: We used fluorescent fatty acid efflux assays and colorimetric assays for free fatty acids and glycerol to identify inhibitors with effects on fatty acid efflux, but not lipolysis, in 3T3-L1 adipocytes. We assessed the effect of these inhibitors on a fibroblast-based cell line expressing fatty acid transport protein 1, hormone-sensitive lipase and perilipin, which presumably lacks adipocyte-specific proteins for fatty acid efflux. RESULTS: We identified 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) as an inhibitor of fatty acid efflux that did not impair lipolysis or the cellular exit of glycerol but lead to an accumulation of intracellular fatty acids. In contrast, fatty acid efflux by the reconstituted cellular model for fatty acid efflux was responsive to lipolytic stimuli, but insensitive to DIDS inhibition. CONCLUSION: We propose that adipocytes specifically express an as yet unidentified DIDS-sensitive protein that enhances the efflux of fatty acids and therefore may lead to novel treatment approaches for obesity-related disorders characterized by abnormal lipid fluxes and ectopic triglyceride accumulation.

Prospective randomized observer-blinded study comparing the analgesic efficacy of ultrasound-guided rectus sheath block and local anaesthetic infiltration for umbilical hernia repair.

BACKGROUND: Umbilical hernia repair, a common day-surgery procedure in children, is associated with considerable postoperative discomfort. Possible modes of postoperative analgesia for umbilical hernia repair are rectus sheath block (RSB) and local anaesthetic infiltration of the surgical site (LAI). METHODS: We undertook an observer-blinded, randomized, prospective, observational study to compare the efficacy of ultrasound-guided RSB and LAI in providing postoperative analgesia for umbilical hernia repair. Our primary objective was to compare the use of opioid medication between patients who receive RSB and those who receive LAI. Our secondary objectives were to compare the duration of analgesia based on time to first rescue analgesic, to compare the quality of analgesia based on revised FACES scale, and to determine the incidence of side-effects. RESULTS: Fifty-two patients (26 in each group) completed the study. There was a statistically significant difference in the perioperative opioid medication consumption between the LAI group [mean: 0.13 mg kg(-1), confidence interval (0.09-0.17 mg kg⁻¹)] and the RSB group [mean: 0.07 mg kg⁻¹, confidence interval (0.05-0.09 mg kg⁻¹)] (P=0.008). When we compared the postoperative opioid consumption between the LAI group [mean: 0.1 mg kg⁻¹, 95% confidence interval (0.07-0.13 mg kg⁻¹)] and the RSB group [mean: 0.07 mg kg(-1), 95% confidence interval (0.05-0.09 mg kg⁻¹)] (P=0.09), there was a trend towards statistical significance between the two groups. The difference in time to rescue analgesic administration between the RSB group [49.7 (36.9) min] and the LAI group [32.4 (29.4) min] was not statistically significant (P=0.11). CONCLUSIONS: This study demonstrates that ultrasound-guided RSB provides superior analgesia in the perioperative period compared with infiltration of the surgical site after umbilical hernia repair. In comparing only the postoperative period, analgesia provided by an ultrasound-guided RSB showed a trend towards statistically significant improvement compared with infiltration of the surgical site.

Treatment of acute pediatric pain.

Pediatric neurologists frequently treat acute pain in children. A broad range of medication options is available including nonsteroidal anti-inflammatory drugs, opioids, and other analgesic adjuvants, such as antidepressants and antiepileptics. This article reviews the physiology underlying the experience of pain and compares the pharmacologic mechanisms and properties of these medications, providing a framework for developing effective multimodal medical treatment approaches to pain in children.

Bradycardia during induction of anesthesia with sevoflurane in children with Down syndrome.

BACKGROUND: Bradycardia is a complication associated with inhaled induction of anesthesia with halothane in children with Down syndrome. Although bradycardia has been reported after anesthetic induction with sevoflurane in these children, the incidence is unknown. OBJECTIVES: In this study we compared the incidence and characteristics of bradycardia after induction of anesthesia with sevoflurane in children with Down syndrome to healthy controls. METHODS: We reviewed electronic anesthetic records of 209 children with Down syndrome and 268 healthy control patients who had inhaled induction of anesthesia with sevoflurane over an 8-year period. Data extracted from the medical record included demographics, history of congenital heart disease, heart rate, oxyhemoglobin saturation, expired sevoflurane concentrations, arterial blood pressure, and any treatment of bradycardia during the first 360 seconds after the start of induction of anesthesia. Bradycardia and hypotension were defined as heart rate and arterial blood pressure below the critical limits recommended for activating a pediatric rapid response team to the bedside of a hospitalized child for quick intervention. Factors associated with bradycardia were identified in a univariate analysis. A step-wise backward multiple logistic regression model was used to identify independent factors. Differences between the 2 groups were computed using Fisher's exact test or χ(2) tests for categorical data and t tests for continuous data. RESULTS: Univariate analysis demonstrated that Down syndrome, low ASA physical status, congenital heart disease, and mean sevoflurane concentrations were factors associated with bradycardia. However, multivariate analysis showed that only Down syndrome and low ASA physical status remained as independent factors associated with bradycardia. CONCLUSION: Bradycardia during anesthetic induction with sevoflurane was common in children with Down syndrome, with and without a history of congenital heart disease.

Pharmacologic management of acute pediatric pain.

The accurate assessment and effective treatment of acute pain in children in the hospital setting is a high priority. During the past 2 to 3 decades, pediatric pain management has gained tremendous knowledge with respect to the understanding of developmental neurobiology, developmental pharmacology the use of analgesics in children, the use of regional techniques in children, and of the psychological needs of children in pain. A wide range of medications is available to treat a variety of pain types. This article provides an overview of the most common analgesic medications and techniques used to treat acute pain in children.

Severe remifentanil-induced acute opioid tolerance following awake craniotomy in an adolescent.

Anesthetic goals for procedures involving resections close to the motor cortex include immobility, analgesia, and a level of consciousness that allows for the ability to follow motor commands. Remifentanil as a single agent is an attractive choice, particularly when ventilation is controlled. The successful use of large-dose remifentanil infusion during an awake craniotomy in a 16 year-old man and the subsequent severe acute opioid tolerance is presented.

Hormone-sensitive lipase is reduced in the adipose tissue of patients with type 2 diabetes mellitus: influence of IL-6 infusion.

AIMS/HYPOTHESIS: Type 2 diabetes mellitus is characterised by increased plasma NEFA and IL-6 concentrations, and IL-6 increases lipolysis in healthy men. We assessed the adipose tissue hormone-sensitive lipase (HSL) mRNA expression, protein expression and HSL activity in patients with type 2 diabetes mellitus, and determined the effect of IL-6 administration on these measures. METHODS: Seven patients with type 2 diabetes mellitus (age 67+/-4 years, weight 87+/-7 kg) and six age- and weight-matched individuals visited the laboratory on two occasions. Subcutaneous adipose tissue biopsies and blood samples were obtained prior to and during 3 h of either saline or recombinant human IL-6 infusion. RESULTS: HSL mRNA was reduced (p<0.05) by approximately 40% in type 2 diabetes mellitus relative to control subjects, while HSL protein expression showed a tendency to be decreased (35%, p=0.09). HSL activity averaged 8.87+/-1.25 and 6.91+/-1.20 nmol min(-1) mg(-1) protein for control and type 2 diabetic subjects respectively (p<0.05). IL-6 administration increased (p<0.05) HSL mRNA 2-fold at 60 min in both groups, whereas HSL protein and activity were unaffected by IL-6. Plasma insulin was elevated (p<0.05) in patients with type 2 diabetes mellitus at rest and was blunted (p<0.05) during IL-6 infusion in both groups. Plasma glucagon and cortisol were elevated (p<0.05) by IL-6 in both groups. CONCLUSIONS/INTERPRETATION: Our data demonstrate that basal HSL is decreased in patients with type 2 diabetes mellitus, and this may be a consequence of elevated plasma insulin levels. We have also shown that IL-6 administration increases HSL gene expression, although it exerted no effect on HSL protein and activity. This disparity between mRNA, protein and enzyme activity may be a function either of the marked alterations in the hormonal milieu induced by IL-6 administration and/or of post-transcriptional events.