Effect of implementing an enhanced recovery protocol for pediatric colorectal surgery on complication rate, length of stay, and opioid use in children.

Introduction In the past two decades, Enhanced Recovery After Surgery (ERAS) pathways for adults have improved efficiency of care and decreased length of stay (LOS) without increasing postoperative complications. The effects of enhanced recovery pathways for children are less well known. In this retrospective cohort study, we evaluated the effects of an enhanced recovery protocol (ERP) implementation in children undergoing colorectal surgery. Methods We introduced a colorectal ERP in 2017. Children and young adults (ages 2-22 years) were divided into pre-intervention (2014-2016) and post-intervention groups (2017-2019) for analysis. We abstracted data, including demographics, primary surgery, LOS, postoperative pain scores, and postoperative complications. Results A total of 432 patients were included. Of those,148 (34%) were pre-ERP implementation and 284 (66%) were post-ERP implementation. Post-ERP patients experienced significantly shorter LOS (5.7 vs. 8.3 days, p<0.01); required less intraoperative local anesthetic (9.5% vs. 38.5%, p<0.01) because 55% of patients received an epidural and 18% received an abdominal plane block; and used less postoperative opioid (62.5% vs. 98.7%, p<0.01) than did pre-ERAS patients. After protocol implementation, average pain scores were lower on postoperative day 1 (3.6 vs. 4.5, p<0.05) and across the hospitalization (3.0 vs. 4.0, p<0.01). Conclusion Enhanced recovery pathways decrease LOS, opioid use, and postoperative pain scores for children undergoing colorectal surgery and should be considered for this patient population.

Process measures facilitate maturation of pediatric enhanced recovery protocols.

BACKGROUND/PURPOSE: The role of process measures used to predict quality in pediatric colorectal surgery enhanced recovery protocols has not been described. The purpose of this study was to demonstrate the feasibility of abstracting and monitoring process measures over protocol improvement iteration. METHODS: Patients enrolled in the Pediatric Colorectal Enhanced Recovery After Surgery pathway at our institution were grouped by stage of implementation. We used a quality improvement database to compare multistage enhanced recovery process measures and 30-day patient outcomes. RESULTS: We identified 58 surgical patients with 28(48%) cases enrolled in the pathway. There was increased use of regional anesthesia techniques in pathway patients (83% versus 20%, p < 0.001). All preoperative process measures clinically improved between early and full implementation. Improvements included a dramatic increase in formal preoperative education (56% versus 0%, p = 0.004) and administration of preoperative medication (p = 0.025). Overall, 12 (21%) patients experienced postoperative complications, which were similarly distributed between implementation groups. Readmissions were highest during the early implementation phase (40%, p = 0.029). Children in the late implementation group experienced fewer complications, which clinically correlated with process measure adherence. CONCLUSIONS: Process measures complement outcome measures in assessing quality and effectiveness of a pediatric colorectal recovery protocol. Adherence to processes may reduce complications. LEVEL OF EVIDENCE: Treatment study, Level III.

Striatal norepinephrine efflux in l-DOPA-induced dyskinesia.

l-DOPA remains the primary treatment for Parkinson's disease (PD). Unfortunately, its therapeutic benefits are compromised by the development of abnormal involuntary movements (AIMs) known as l-DOPA-induced dyskinesia (LID). The norepinephrine (NE) system originating in the locus coeruleus is profoundly affected in PD and known to influence dopamine (DA) signaling. However, the effect of noradrenergic loss on l-DOPA-induced striatal monoamine efflux and Parkinsonian motor behavior remains controversial and is frequently overlooked in traditional animal models of LID. Thus, the current study sought to determine whether degeneration of the DA and/or NE system(s) altered l-DOPA-induced striatal monoamine efflux in hemiparkinsonian rats with additional NE loss induced by the potent NE-toxin α DA beta hydroxylase (DBH)-saporin. Sham-, DA-, NE-, and dual DA + NE-lesioned rats were treated with l-DOPA (6 mg/kg, s.c.) for 2 weeks. Thereafter, l-DOPA-mediated striatal monoamine efflux was measured with in vivo microdialysis, and concurrent AIMs testing occurred to determine responsiveness to l-DOPA. Noradrenergic lesions exacerbated parkinsonian motor deficits but did not significantly alter LID expression or corresponding l-DOPA-induced striatal monoamine efflux. Interestingly, l-DOPA-induced striatal NE efflux rather than DA efflux, corresponded more closely with dyskinesia severity. Moreover, marked reductions in striatal NE tissue concentration did not appear to impact l-DOPA-induced striatal NE efflux. The current study implicates l-DOPA-induced striatal NE as an important factor in LID expression and demonstrates the importance of developing treatment strategies that co-modulate the NE and DA systems.

Review of the enhanced recovery pathway for children: perioperative anesthetic considerations.

PURPOSE: Enhanced recovery after surgery (ERAS) pathways have been used for two decades to improve perioperative recovery in adults. Nevertheless, little is known about their effectiveness in children. The purpose of this review was to consider pediatric ERAS pathways, review the literature concerned with their potential benefit, and compare them with adult ERAS pathways. SOURCE: A PubMed literature search was performed for articles that included the terms enhanced recovery and/or fast track in the pediatric perioperative period. Pediatric patients included those from the neonatal period through teenagers and/or youths. PRINCIPAL FINDINGS: The literature search revealed a paucity of articles about pediatric ERAS. This lack of academic investigation is likely due in part to the delayed acceptance of ERAS in the pediatric surgical arena. Several pediatric studies examined individual components of adult-based ERAS pathways, but the overall study of a comprehensive multidisciplinary ERAS protocol in pediatric patients is lacking. CONCLUSION: Although adult ERAS pathways have been successful at reducing patient morbidity, the translation, creation, and utility of instituting pediatric ERAS pathways have yet to be realized.

Opioid Prescribing for the Treatment of Acute Pain in Children on Hospital Discharge.

BACKGROUND: The epidemic of nonmedical use of prescription opioids has been fueled by the availability of legitimately prescribed unconsumed opioids. The aim of this study was to better understand the contribution of prescriptions written for pediatric patients to this problem by quantifying how much opioid is dispensed and consumed to manage pain after hospital discharge, and whether leftover opioid is appropriately disposed of. Our secondary aim was to explore the association of patient factors with opioid dispensing, consumption, and medication remaining on completion of therapy. METHODS: Using a scripted 10-minute interview, parents of 343 pediatric inpatients (98% postoperative) treated at a university children's hospital were questioned within 48 hours and 10 to 14 days after discharge to determine amount of opioid prescribed and consumed, duration of treatment, and disposition of unconsumed opioid. Multivariable linear regression was used to examine predictors of opioid prescribing, consumption, and doses remaining. RESULTS: Median number of opioid doses dispensed was 43 (interquartile range, 30-85 doses), and median duration of therapy was 4 days (interquartile range, 1-8 days). Children who underwent orthopedic or Nuss surgery consumed 25.42 (95% confidence interval, 19.16-31.68) more doses than those who underwent other types of surgery (P < .001), and number of doses consumed was positively associated with higher discharge pain scores (P = .032). Overall, 58% (95% confidence interval, 54%-63%) of doses dispensed were not consumed, and the strongest predictor of number of doses remaining was doses dispensed (P < .001). Nineteen percent of families were informed how to dispose of leftover opioid, but only 4% (8 of 211) did so. CONCLUSIONS: Pediatric providers frequently prescribed more opioid than needed to treat pain. This unconsumed opioid may contribute to the epidemic of nonmedical use of prescription opioids. Our findings underscore the need for further research to develop evidence-based opioid prescribing guidelines for physicians treating acute pain in children.

The Role of Primary Motor Cortex (M1) Glutamate and GABA Signaling in l-DOPA-Induced Dyskinesia in Parkinsonian Rats.

UNLABELLED: Long-term treatment of Parkinson's disease with l-DOPA almost always leads to the development of involuntary movements termed l-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by l-DOPA. Among sham-lesioned rats, l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, l-DOPA given acutely (1 d) or chronically (14-16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that l-DOPA-induced dyskinesia was reduced by M1 infusion of a D1 antagonist, an AMPA antagonist, or a GABAA agonist. Overall, the present study demonstrates that l-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy. SIGNIFICANCE STATEMENT: Most Parkinson's disease patients will receive l-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigating in vivo neurotransmitter release in M1 during dyskinesia. In parkinsonian rats, l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAA receptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias.

Preparing enhanced recovery after surgery for implementation in pediatric populations.

Standardization in perioperative care has led to major improvements in surgical outcomes during the last two decades. Enhanced recovery after surgery (ERAS) programs are one example of a clinical pathway impacting both surgical outcomes and efficiency of care, but these programs have not yet been widely adapted for surgery in children. In adults, ERAS pathways have been shown to reduce length of stay, reduce complication rates, and improve patient satisfaction. These pathways improve outcomes through standardization of existing evidence-based best practices. Currently, the direct evidence for adapting ERAS pathways to pediatric surgery patients is limited. Challenges for implementation of ERAS programs for children include lack of direct translatability of adult evidence as well as varying levels acceptability of ERAS principles among pediatric providers and patients' families. We describe our newly implemented ERAS program for pediatric colorectal surgery patients in an era of limited direct evidence and discuss what further issues need to be addressed for broader implementation of pediatric ERAS pathways. LEVEL OF EVIDENCE: Level 5.

An Analysis of 34,218 Pediatric Outpatient Controlled Substance Prescriptions.

BACKGROUND: Prescription errors are among the most common types of iatrogenic errors. Because of a previously reported 82% error rate in handwritten discharge narcotic prescriptions, we developed a computerized, web-based, controlled substance prescription writer that includes weight-based dosing logic and alerts to reduce the error rate to (virtually) zero. Over the past 7 years, >34,000 prescriptions have been created by hospital providers using this platform. We sought to determine the ongoing efficacy of the program in prescription error reduction and the patterns with which providers prescribe controlled substances for children and young adults (ages 0-21 years) at hospital discharge. METHODS: We examined a database of 34,218 controlled substance discharge prescriptions written by our institutional providers from January 1, 2007 to February 14, 2014, for demographic information, including age and weight, type of medication prescribed based on patient age, formulation of dispensed medication, and amount of drug to be dispensed at hospital discharge. In addition, we randomly regenerated 2% (700) of prescriptions based on stored data and analyzed them for errors using previously established error criteria. Weights that were manually entered into the prescription writer by the prescriber were compared with the patient's weight in the hospital's electronic medical record. RESULTS: Patients in the database averaged 9 ± 6.1 (range, 0-21) years of age and 36.7 ± 24.9 (1-195) kg. Regardless of age, the most commonly prescribed opioid was oxycodone (73%), which was prescribed as a single agent uncombined with acetaminophen. Codeine was prescribed to 7% of patients and always in a formulation containing acetaminophen. Liquid formulations were prescribed to 98% of children <6 years of age and to 16% of children >12 years of age (the remaining 84% received tablet formulations). Regardless of opioid prescribed, the amount of liquid dispensed averaged 106 ± 125 (range, 2-3240) mL, and the number of tablets dispensed averaged 51 ± 51 (range, 1-1080). Of the subset of 700 regenerated prescriptions, all were legible (drug, amount dispensed, dose, patient demographics, and provider name) and used best prescribing practice (e.g., no trailing zero after a decimal point, leading zero for doses <1). Twenty-five of the 700 (3.6%) had incorrectly entered weights compared with the most recent weight in the chart. Of these, 14 varied by 10% or less and only 2 varied by >15%. Of these, 1 resulted in underdosing (true weight 80 kg prescribed for a weight of 50 kg) and the other in overdosing (true weight 10 kg prescribed for a weight of 30 kg). CONCLUSIONS: A computerized prescription writer eliminated most but not all the errors common to handwritten prescriptions. Oxycodone has supplanted codeine as the most commonly prescribed oral opioid in current pediatric pain practice and, independent of formulation, is dispensed in large quantities. This study underscores the need for liquid opioid formulations in the pediatric population and, because of their abuse potential, the urgent need to determine how much of the prescribed medication is actually used by patients.

Effects of the beta-adrenergic receptor antagonist Propranolol on dyskinesia and L-DOPA-induced striatal DA efflux in the hemi-parkinsonian rat.

Dopamine (DA) replacement therapy with L-DOPA continues to be the primary treatment of Parkinson's disease; however, long-term therapy is accompanied by L-DOPA-induced dyskinesias (LID). Several experimental and clinical studies have established that Propranolol, a ß-adrenergic receptor antagonist, reduces LID without affecting L-DOPA's efficacy. However, the exact mechanisms underlying these effects remain to be elucidated. The aim of this study was to evaluate the anti-dyskinetic profile of Propranolol against a panel of DA replacement strategies, as well as elucidate the underlying neurochemical mechanisms. Results indicated that Propranolol, in a dose-dependent manner, reduced LID, without affecting motor performance. Propranolol failed to alter dyskinesia produced by the D1 receptor agonist, SKF81297 (0.08 mg/kg, sc), or the D2 receptor agonist, Quinpirole (0.05 mg/kg, sc). These findings suggested a pre-synaptic mechanism for Propranolol's anti-dyskinetic effects, possibly through modulating L-DOPA-mediated DA efflux. To evaluate this possibility, microdialysis studies were carried out in the DA-lesioned striatum of dyskinetic rats and results indicated that co-administration of Propranolol (20 mg/kg, ip) was able to attenuate L-DOPA- (6 mg/kg, sc) induced DA efflux. Therefore, Propranolol's anti-dyskinetic properties appear to be mediated via attenuation of L-DOPA-induced extraphysiological efflux of DA.

Modulation of L-DOPA's antiparkinsonian and dyskinetic effects by α2-noradrenergic receptors within the locus coeruleus.

Long-term l-DOPA use for Parkinson's disease (PD) is frequently complicated by the emergence of a debilitating motor side effect known as l-DOPA-induced dyskinesia (LID). Accumulating evidence has implicated the norepinephrine (NE) system in the pathogenesis of LID. Here we used the unilateral 6-hydroxydopamine rat model of PD to determine the role of the α2-adrenoceptors (α2R) in l-DOPA's therapeutic and detrimental motor-inducing effects. First, we characterized the effects of systemic α2R stimulation with clonidine, or blockade with atipamezole, on LID using the rodent abnormal involuntary movements scale, and l-DOPA's therapeutic effects using the forepaw adjusting steps test and locomotor activity chambers. The anatomical locus of action of α2R in LID was investigated by directly infusing clonidine or atipamezole into the locus coeruleus prior to systemic l-DOPA administration. Results showed systemic clonidine treatment reduced LID and locomotor activity but did not interfere with l-DOPA's antiparkinsonian benefits. Conversely, systemic atipamezole pretreatment prolonged LID and locomotor activity but did not modulate l-DOPA's antiparkinsonian benefits. Intra-LC infusions of clonidine and atipamezole mirrored systemic effects where clonidine reduced, and atipamezole increased, LID. Collectively, these results demonstrate that α2R play an important modulatory role in l-DOPA-mediated behaviors and should be further investigated as a potential therapeutic target.

Effects of 5-HT1A receptor stimulation on D1 receptor agonist-induced striatonigral activity and dyskinesia in hemiparkinsonian rats.

Accumulating evidence supports the value of 5-HT1A receptor (5-HT1AR) agonists for dyskinesias that arise with long-term L-DOPA therapy in Parkinson's disease (PD). Yet, how 5-HT1AR stimulation directly influences the dyskinetogenic D1 receptor (D1R)-expressing striatonigral pathway remains largely unknown. To directly examine this, one cohort of hemiparkinsonian rats received systemic injections of Vehicle + Vehicle, Vehicle + the D1R agonist SKF81297 (0.8 mg/kg), or the 5-HT1AR agonist ±8-OH-DPAT (1.0 mg/kg) + SKF81297. Rats were examined for changes in abnormal involuntary movements (AIMs), rotations, striatal preprodynorphin (PPD), and glutamic acid decarboxylase (GAD; 65 and 67) mRNA via RT-PCR. In the second experiment, hemiparkinsonian rats received intrastriatal pretreatments of Vehicle (aCSF), ±8-OH-DPAT (7.5 mM), or ±8-OH-DPAT + the 5-HT1AR antagonist WAY100635 (4.6 mM), followed by systemic Vehicle or SKF81297 after which AIMs, rotations, and extracellular striatal glutamate and nigral GABA efflux were measured by in vivo microdialysis. Results revealed D1R agonist-induced AIMs were reduced by systemic and intrastriatal 5-HT1AR stimulation while rotations were enhanced. Although ±8-OH-DPAT did not modify D1R agonist-induced increases in striatal PPD mRNA, the D1R/5-HT1AR agonist combination enhanced GAD65 and GAD67 mRNA. When applied locally, ±8-OH-DPAT alone diminished striatal glutamate levels while the agonist combination increased nigral GABA efflux. Thus, presynaptic 5-HT1AR stimulation may attenuate striatal glutamate levels, resulting in diminished D1R-mediated dyskinetic behaviors, but maintain or enhance striatal postsynaptic factors ultimately increasing nigral GABA levels and rotational activity. The current findings offer a novel mechanistic explanation for previous results concerning 5-HT1AR agonists for the treatment of dyskinesia.

Serotonin transporter inhibition attenuates l-DOPA-induced dyskinesia without compromising l-DOPA efficacy in hemi-parkinsonian rats.

Long-term dopamine replacement therapy with l-DOPA in Parkinson's disease often leads to the development of abnormal involuntary movements known as l-DOPA-induced dyskinesia. Growing evidence suggests that, following dopamine cell loss, serotonin neurons acting as surrogates for dopaminergic processes take up l-DOPA, convert it to dopamine and release it in an unregulated fashion that precipitates dyskinesia. Although most studies have focused on serotonin 5-HT(1) receptor stimulation as an antidyskinetic strategy, targeting the serotonin transporter modulation of dopamine activity has been overlooked. Therefore, in the current study, selective serotonin reuptake inhibitors were tested for their ability to reduce l-DOPA- and apomorphine-induced dyskinesia. In Experiments 1 and 2, hemi-parkinsonian rats were primed with l-DOPA until stable dyskinesia developed. Rats in Experiment 1 were administered the selective serotonin reuptake inhibitors paroxetine, citalopram or fluoxetine, followed by l-DOPA. Abnormal involuntary movements and forepaw adjusting steps were recorded to determine the effects of these compounds on dyskinesia and motor performance, respectively. Brains were collected on the final test day, after which striatal and raphe monoamines were examined via high-performance liquid chromatography. In Experiment 2, dyskinesias were measured after selective serotonin reuptake inhibitors and apomorphine. Serotonin reuptake inhibitors dose-dependently attenuated l-DOPA- but not apomorphine-induced dyskinesia, and preserved l-DOPA efficacy. Neurochemically, serotonin transporter inhibition enhanced striatal and raphe serotonin levels and reduced its turnover, indicating a potential mechanism of action. The present results support targeting serotonin transporters to improve Parkinson's disease treatment and provide further evidence for the role of the serotonin system in l-DOPA's effects.

The effect of intravenous opioid patient-controlled analgesia with and without background infusion on respiratory depression: a meta-analysis.

BACKGROUND: Although the addition of a background infusion for intravenous patient-controlled analgesia (IV-PCA) has been identified as a risk factor for the development of respiratory depression, this has not clearly been examined in a systematic fashion. The authors undertook a systematic review and meta-analysis of available randomized controlled trials (RCTs) to examine whether the addition of a background or continuous infusion to an IV-PCA regimen would be associated with an increased risk of respiratory depression. METHODS: Studies were identified by searching the National Library of Medicine's PubMed database (1966 to November 30, 2008). Inclusion criteria were a clearly defined analgesic technique of demand-only IV-PCA versus IV-PCA utilizing both a demand dose and background infusion, opioid medication used, and randomized trials. Data were abstracted and analyzed with the RevMan 4.2.7 (The Cochrane Collaboration, 2004). RESULTS: The search yielded 687 abstracts from which the original articles were obtained and data abstracted with a total of 14 articles analyzed. There were 402 subjects in the continuous IV-PCA with demand group versus the 394 subjects in the demand-only IV-PCA group. Addition of a background infusion to the demand dose for IV-PCA with opioids was associated with a significant increased risk for respiratory depression (odds ratio [OR] = 4.68, 95% confidence interval [CI]: 1.20-18.21). Subgroup analysis revealed that this increased risk was seen in adult but not in pediatric patients. CONCLUSIONS: Our meta-analysis indicates that the addition of a continuous or background infusion to the demand dose for IV-PCA is associated with a higher incidence of respiratory events than demand IV-PCA alone in adult but not in pediatric patients; however, our overall results should be interpreted with caution due to the relatively small sample size and the wide range of definitions for respiratory depression in studies examined.

Src tyrosine kinase as a chemotherapeutic target: is there a clinical case?

Src tyrosine kinase was the first protooncogene described. It has been found to be overexpressed and activated in a large number of different cancers. Cellular Src has been shown to activate a number of different effectors that are involved in different aspects of cancer biology such as metastasis, cell cycle regulation and cell survival. Despite this, Src inhibitors have not entered the regular arsenal of chemotherapeutics. This article reviews some of the biology, rationale, in vitro and in vivo preclinical evidence, and some very early clinical trials demonstrating efficacy of Src inhibitors.

SRC tyrosine kinase and multidrug resistance protein-1 inhibitions act independently but cooperatively to restore paclitaxel sensitivity to paclitaxel-resistant ovarian cancer cells.

Src tyrosine kinase has been found to be overexpressed in both mouse and human ovarian cancer cells as well as in human primary ovarian cancers. Furthermore, Src inhibition sensitizes ovarian cancer cells to chemotherapeutic agents such as paclitaxel and cisplatin. Interestingly, Src inhibition has also been shown to resensitize paclitaxel-resistant cells to the cytotoxic effects of paclitaxel. The current study was undertaken in an effort to determine the mechanism by which Src resensitizes drug-resistant ovarian cancer cells. The paclitaxel-resistant human (CaOV3TaxR) and mouse (ID8TaxR) ovarian cancer cell lines express large amounts of the multidrug resistance-1 (MDR-1) protein compared with the paclitaxel-sensitive parent cell lines. Src inhibition had no effect on MDR-1 protein expression. Furthermore, Src inhibition did not affect MDR-1 function as determined by rhodamine 123 and paclitaxel uptake or retention. Coinhibition of both Src and MDR-1 synergistically enhanced paclitaxel-induced cytotoxicity in paclitaxel-resistant ovarian cancer cell lines. Inhibition of Src enhanced microtubule stabilization in paclitaxel-resistant ovarian cancer cells treated with paclitaxel without affecting expression of beta-tubulin isotypes and resulted in multipolar spindle formation and apoptosis. These results show that Src inhibition restores paclitaxel sensitivity to paclitaxel-resistant ovarian cancer cells by an MDR-independent mechanism, possibly by decreasing the critical intracellular concentration at which paclitaxel induces tubulin stabilization and bundling. Src tyrosine kinase may provide a viable target for therapeutic intervention in drug-resistant ovarian cancer.