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1.
Nature ; 619(7971): 828-836, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37438524

RESUMEN

Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder2,3, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were 'probably' or 'possibly' amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.


Asunto(s)
Ataxia Telangiectasia , Empalme del ARN , Niño , Humanos , Ataxia Telangiectasia/tratamiento farmacológico , Ataxia Telangiectasia/genética , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/uso terapéutico , Estudios Prospectivos , Empalme del ARN/efectos de los fármacos , Empalme del ARN/genética , Secuenciación Completa del Genoma , Intrones , Exones , Medicina de Precisión , Proyectos Piloto
2.
Pediatr Res ; 95(5): 1237-1245, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38114607

RESUMEN

Pediatric analgesic trials are challenging, especially in newborns and infants. Following an FDA-academic consensus meeting, we analyzed pragmatic rescue designs in postoperative trials of local anesthetics, acetaminophen, opioids, and NSAIDs involving children ages 0-2 years and assessed surgical volumes to provide trial design recommendations. Searches of PubMed, Embase, CINAHL, The Cochrane Library, and Web of Science were conducted. A scoping approach identified trends in analgesic trials with an emphasis on randomized controlled trials (RCTs) utilizing immediate rescue designs. Age-specific surgical volumes were estimated from French national databases. Of 3563 studies identified, 23 RCTs used study medication(s) of interest and immediate rescue paradigms in children ages 0-2 years. A total of 270 studies met at least one of these criteria. Add-on and head-to-head designs were common and often used sparing of non-opioid or opioid rescue medication as a primary outcome measure. According to French national data, inguinal and penile surgeries were most frequent in ages 1 month to 2 years; abdominal and thoracic surgeries comprise approximately 75% of newborn surgeries. Analgesic trials with rescue sparing paradigm are currently sparse among children ages 0-2 years. Future trials could consider age-specific surgical procedures and use of add-on or head-to-head designs. IMPACT: Clinical trials of analgesic medications have been challenging in pediatrics, especially in the group from newborns to 2 years of age. Following an FDA-academic workshop, we analyzed features of completed analgesic trials in this age group. Studies using immediate rescue in placebo control, add-on, and head-to-head trial designs are pragmatic approaches that can provide important information regarding clinical effectiveness, side effects, and safety. Using a French national dataset with a granular profile of inpatient, outpatient, and short-stay surgeries, we provide information to future investigators on relative frequencies of different operations in neonates and through the first 2 years of life.

3.
Br J Anaesth ; 130(2): e381-e390, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-35803755

RESUMEN

BACKGROUND: Spectral-based EEG is used to monitor anaesthetic state during surgical procedures in adults. Spectral EEG features that can resemble the patterns seen in adults emerge in children after the age of 10 months and cannot distinguish wakefulness and anaesthesia in the youngest children. There is a need to explore alternative EEG measures. We hypothesise that functional connectivity is one of the measures that can help distinguish between consciousness states in children. METHODS: An EEG data set of children undergoing sevoflurane general anaesthesia (age 0-3 yr) was reanalysed using debiased weighted phase lag index as a measure of functional connectivity in wakefulness (n=38) and anaesthesia (n=73). Network topology measures were compared between states in 0- to 6-, 6- to 10-, and >10-month-old children. RESULTS: Functional connectivity was reduced in anaesthesia vs wakefulness in delta band (n=cluster of 17 significant connections; P=0.013; 58% connections surviving thresholding in wakefulness and 49% in anaesthesia). Network density and node degree were lower in anaesthesia even in the youngest children (0.57 in wakefulness; 0.48 in anaesthesia; t [9]=3.39; P=0.029; G=0.98; confidence interval [CI] [0.25-1.77]). Modularity was higher in anaesthesia (0-6 months: 0.16 in wakefulness and 0.19 in anaesthesia, t [9]=-2.95, P=0.04, G=-0.85, CI [-1.60 to -0.16]; >10 months: 0.16 vs 0.21, t [13]=-6.45, P<0.001, G=-1.62, CI [-2.49 to -0.85]) and decreased with age (ρ [73]=-0.456; P<0.001). CONCLUSIONS: Anaesthesia modulates functional connectivity. Increased segregation into a more modular structure in anaesthesia decreases with age as adult-like features develop. These findings advance our understanding of the network architecture underlying the effects of anaesthesia on the developing brain.


Asunto(s)
Anestésicos por Inhalación , Niño , Adulto , Humanos , Lactante , Recién Nacido , Preescolar , Sevoflurano/farmacología , Anestésicos por Inhalación/farmacología , Electroencefalografía , Encéfalo , Anestesia General
4.
Br J Anaesth ; 130(5): 595-602, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36922266

RESUMEN

BACKGROUND: Sevoflurane-induced anaesthesia generates frontal alpha oscillations as early as 6 months of age, whereas strong delta oscillations are present at birth. In adults, delta oscillations and alpha oscillations are coupled: the phase of delta waves modulates the amplitude of alpha oscillations in a phenomenon known as phase-amplitude coupling. We hypothesise that delta-alpha phase-amplitude coupling exists in young children and is a feature of sevoflurane-based general anaesthesia distinct from emergence after anaesthesia. METHODS: Electroencephalographic data from 31 paediatric patients aged 10 months to 3 yr undergoing elective surgery with sevoflurane-based anaesthesia were analysed retrospectively. Delta-alpha phase-amplitude coupling was evaluated during maintenance of anaesthesia and during emergence. RESULTS: Delta-alpha phase-amplitude coupling was observed in the study population. Strength of phase-amplitude coupling, represented by the delta-alpha mean amplitude vector, was greater during general anaesthesia than during emergence (Wilcoxon paired signed-rank test, Z=3.107, P=0.002). Frontal alpha amplitude during anaesthesia was not uniformly distributed across all delta phases. During general anaesthesia, alpha power was restricted to the positive phase of the delta wave (omnibus circular uniformity, general anaesthesia: P<0.001, mean phase: 114º; 99% confidence interval: 90º-139º; emergence: P=0.35, mean phase 181º, 99% confidence interval: 110º-253º). CONCLUSIONS: Sevoflurane-based anaesthesia is associated with delta-alpha phase-amplitude coupling in paediatric patients. These findings improve our understanding of cortical dynamics in children undergoing general anaesthesia, which might improve paediatric intraoperative depth of anaesthesia monitoring techniques.


Asunto(s)
Anestesiología , Anestésicos por Inhalación , Adulto , Recién Nacido , Humanos , Niño , Preescolar , Sevoflurano/farmacología , Estudios Retrospectivos , Anestesia General/métodos , Electroencefalografía/métodos , Anestésicos por Inhalación/farmacología
5.
N Engl J Med ; 381(17): 1644-1652, 2019 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-31597037

RESUMEN

Genome sequencing is often pivotal in the diagnosis of rare diseases, but many of these conditions lack specific treatments. We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient. Proof-of-concept experiments in cell lines from the patient served as the basis for launching an "N-of-1" study of milasen within 1 year after first contact with the patient. There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting). This study offers a possible template for the rapid development of patient-customized treatments. (Funded by Mila's Miracle Foundation and others.).


Asunto(s)
Proteínas de Transporte de Membrana/genética , Mutagénesis Insercional , Lipofuscinosis Ceroideas Neuronales/tratamiento farmacológico , Lipofuscinosis Ceroideas Neuronales/genética , Oligonucleótidos Antisentido/uso terapéutico , Medicina de Precisión , Enfermedades Raras/tratamiento farmacológico , Biopsia , Niño , Desarrollo Infantil , Descubrimiento de Drogas , Drogas en Investigación/uso terapéutico , Electroencefalografía , Femenino , Humanos , Pruebas Neuropsicológicas , ARN Mensajero , Convulsiones/diagnóstico , Convulsiones/tratamiento farmacológico , Piel/patología , Secuenciación Completa del Genoma
6.
Paediatr Anaesth ; 31(2): 178-185, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33135307

RESUMEN

BACKGROUND: Children with cerebral palsy often suffer from increased tone, which can be treated with intrathecal baclofen via implanted pump. Additionally, they often require major orthopedic surgery for hip reconstruction; however, the presence of an intrathecal baclofen pump is a relative contraindication to regional anesthesia due to concerns about damaging the intrathecal baclofen pump system. AIMS: (a) To evaluate adverse events related to placing epidural catheters in children with intrathecal baclofen pumps and (b) describe our multidisciplinary approach to the care of these complex patients. METHODS: Children with cerebral palsy and intrathecal baclofen pump in situ who underwent hip reconstruction between 2010 and 2019 and had a perioperative epidural placed were reviewed retrospectively. Charts were assessed for adverse events or intrathecal baclofen complications. Fluoroscopic images were reviewed to evaluate the proximity between epidural and intrathecal baclofen catheters. The process of coordinating multiple services was examined. RESULTS: Sixteen children met the inclusion criteria. There were no major complications following epidural placement. Postoperative pump interrogation was normal for all patients. Fluoroscopy was utilized for 9/16 (56%) epidural procedures. Epidurogram was used to confirm 11/16 catheters (68%). Children with an intrathecal baclofen pump were identified by orthopedic surgeons at the time of surgical booking and referred to the regional anesthesia team for review. The neurosurgical, pain, and regional anesthesia teams determined the appropriateness and safety of approaching the neuraxis. Pain and/or regional anesthesiologists with competency in spine fluoroscopy were scheduled on the day of surgery for fluoroscopically guided epidural placement. Postoperatively, catheters were managed by the acute pain team. Intrathecal baclofen pumps were interrogated by the baclofen pump team prior to patient discharge. DISCUSSION: In this case series, not only was epidural placement feasible but also there were no observed complications. This work highlights the importance of a multidisciplinary approach to complex regional anesthetic techniques, as well as the importance of basic competency in spine fluoroscopy for regional anesthesiologists.


Asunto(s)
Parálisis Cerebral , Relajantes Musculares Centrales , Baclofeno , Catéteres , Parálisis Cerebral/complicaciones , Parálisis Cerebral/tratamiento farmacológico , Niño , Humanos , Bombas de Infusión Implantables , Inyecciones Espinales , Relajantes Musculares Centrales/uso terapéutico , Estudios Retrospectivos
7.
Pediatr Radiol ; 51(13): 2588-2595, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34254153

RESUMEN

BACKGROUND: Spinal administration of medications is challenging in patients with complete posterior spinal fusion. We describe percutaneous image-guided intrathecal port placement for administration of the antisense oligonucleotide nusinersen for children and young adults with spinal muscular atrophy. OBJECTIVE: To describe and present our initial experience with a new technique for administering nusinersen in patients with spinal muscular atrophy and posterior spinal fusion. MATERIALS AND METHODS: We reviewed medical records of 13 patients who received intrathecal ports using DynaCT, biplane fluoroscopy and iGuide from April 2018 through June 2019, and we describe the clinical course over 1 year. RESULTS: Image-guided catheter and port implantation was successful in all cases. Two ports were subsequently removed, one for persistent cerebrospinal fluid leak and one for superficial infection. The other 11 have functioned successfully for a minimum of 23 months. CONCLUSION: We report our experience with image-guided intrathecal port placement in children with complete posterior spine fusion. The implanted port permits dosing in an outpatient setting and avoids the need for multiple future radiologic procedures, and it reduces discomfort, procedural costs and potential risks and sequelae of multiple anesthetics and radiation exposures. Further studies are needed to define the relative risks and benefits of intrathecal ports compared to other approaches such as repeated transforaminal lumbar punctures.


Asunto(s)
Atrofia Muscular Espinal , Fusión Vertebral , Catéteres , Niño , Humanos , Inyecciones Espinales , Atrofia Muscular Espinal/diagnóstico por imagen , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos
9.
Anesthesiology ; 131(6): 1239-1253, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31567366

RESUMEN

BACKGROUND: Functional brain connectivity studies can provide important information about changes in brain-state dynamics during general anesthesia. In adults, γ-aminobutyric acid-mediated agents disrupt integration of information from local to the whole-brain scale. Beginning around 3 to 4 months postnatal age, γ-aminobutyric acid-mediated anesthetics such as sevoflurane generate α-electroencephalography oscillations. In previous studies of sevoflurane-anesthetized infants 0 to 3.9 months of age, α-oscillations were absent, and power spectra did not distinguish between anesthetized and emergence from anesthesia conditions. Few studies detailing functional connectivity during general anesthesia in infants exist. This study's aim was to identify changes in functional connectivity of the infant brain during anesthesia. METHODS: A retrospective cohort study was performed using multichannel electroencephalograph recordings of 20 infants aged 0 to 3.9 months old who underwent sevoflurane anesthesia for elective surgery. Whole-brain functional connectivity was evaluated during maintenance of a surgical state of anesthesia and during emergence from anesthesia. Functional connectivity was represented as networks, and network efficiency indices (including complexity and modularity) were computed at the sensor and source levels. RESULTS: Sevoflurane decreased functional connectivity at the δ-frequency (1 to 4 Hz) in infants 0 to 3.9 months old when comparing anesthesia with emergence. At the sensor level, complexity decreased during anesthesia, showing less whole-brain integration with prominent alterations in the connectivity of frontal and parietal sensors (median difference, 0.0293; 95% CI, -0.0016 to 0.0397). At the source level, similar results were observed (median difference, 0.0201; 95% CI, -0.0025 to 0.0482) with prominent alterations in the connectivity between default-mode and frontoparietal regions. Anesthesia resulted in fragmented modules as modularity increased at the sensor (median difference, 0.0562; 95% CI, 0.0048 to 0.1298) and source (median difference, 0.0548; 95% CI, -0.0040 to 0.1074) levels. CONCLUSIONS: Sevoflurane is associated with decreased capacity for efficient information transfer in the infant brain. Such findings strengthen the hypothesis that conscious processing relies on an efficient system of integrated information transfer across the whole brain.


Asunto(s)
Anestésicos por Inhalación/administración & dosificación , Encéfalo/efectos de los fármacos , Estado de Conciencia/efectos de los fármacos , Ritmo Delta/efectos de los fármacos , Red Nerviosa/efectos de los fármacos , Sevoflurano/administración & dosificación , Encéfalo/fisiología , Estudios de Cohortes , Estado de Conciencia/fisiología , Ritmo Delta/fisiología , Electroencefalografía/efectos de los fármacos , Electroencefalografía/métodos , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Red Nerviosa/fisiología , Estudios Retrospectivos , Inconsciencia/inducido químicamente , Inconsciencia/fisiopatología
10.
Paediatr Anaesth ; 29(8): 829-834, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31077625

RESUMEN

BACKGROUND: Adolescent and young adult patients undergoing arthroscopic hip surgery experience significant pain in the immediate postoperative period. There is a small body of evidence that indicates suprainguinal fascia iliaca blocks can improve comfort during recovery from this intervention. Our hypothesis was that patients undergoing hip surgery would consume fewer opioids and have less pain in the perioperative time frame if they received the block as part of their analgesic regimen. METHODS: In this study, we evaluated the outcomes of 716 patients, including 275 who received a suprainguinal fascia iliaca block, and 441 who did not have a block. Inclusion criteria included all age groups and American Society of Anesthesiologists, functional classes 1-2. Patients who received other concurrent procedures or those with incomplete data sets were excluded. We utilized a regional anesthesia database that combined data from various repositories into one web-based relational system. The primary outcomes were total opioid consumption and pain scores in the recovery room. Secondary outcomes included opioid side effects, block-related complications, and total recovery room time. Multivariable logistic regression analysis was used to evaluate opioid consumption, side effects, and total recovery times. Pearson chi-square was applied to assess the level of pain between the two groups. RESULTS: Total opioid consumption was significantly less in the block group compared to those not receiving a block (0.28 mg/kg vs 0.35 mg/kg, P < 0.001, 95% CI of difference in medians 0.04-0.10 mg/kg), but there was no statistical difference in pain scores. Patients with the regional block had a lower frequency of emesis in the PACU (0.7% vs 4.3%; P < 0.005, 95% CI of difference: 2-25) and shorter PACU times (93 vs 108 minutes, P < 0.001, 95% CI of difference: 8-23 minutes). CONCLUSION: Our study supports the clinical effectiveness of suprainguinal fascia iliaca blocks in young patients undergoing arthroscopic hip surgery.


Asunto(s)
Analgesia/métodos , Analgésicos Opioides/uso terapéutico , Fascia/efectos de los fármacos , Bloqueo Nervioso , Dolor Postoperatorio/tratamiento farmacológico , Analgésicos/uso terapéutico , Artroscopía , Manejo del Dolor/métodos
12.
Eur J Anaesthesiol ; 35(1): 49-59, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29120939

RESUMEN

BACKGROUND: Few studies have systematically described relationships between clinical-behavioural signs, electroencephalographic (EEG) patterns and age during emergence from anaesthesia in young children. OBJECTIVE: To identify the relationships between end-tidal sevoflurane (ETsevoflurane) concentration, age and frontal EEG spectral properties in predicting recovery of clinical-behavioural signs during emergence from sevoflurane in children 0 to 3 years of age, with and without exposure to nitrous oxide. The hypothesis was that clinical signs occur sequentially during emergence, and that for infants aged more than 3 months, changes in alpha EEG power are correlated with clinical-behavioural signs. DESIGN: An observational study. SETTING: A tertiary paediatric teaching hospital from December 2012 to August 2016. PATIENTS: Ninety-five children aged 0 to 3 years who required surgery below the neck. OUTCOME MEASURES: Time-course of, and ETsevoflurane concentrations at first gross body movement, first cough, first grimace, dysconjugate eye gaze, frontal (F7/F8) alpha EEG power (8 to 12 Hz), frontal beta EEG power (13 to 30 Hz), surgery-end. RESULTS: Clinical signs of emergence followed an orderly sequence of events across all ages. Clinical signs occurred over a narrow ETsevoflurane, independent of age [movement: 0.4% (95% confidence interval (CI), 0.3 to 0.4), cough 0.3% (95% CI, 0.3 to 0.4), grimace 0.2% (95% CI, 0 to 0.3); P > 0.5 for age vs. ETsevoflurane]. Dysconjugate eye gaze was observed between ETsevoflurane 1 to 0%. In children more than 3 months old, frontal alpha EEG oscillations were present at ETsevoflurane 2.0% and disappeared at 0.5%. Movement occurred within 5 min of alpha oscillation disappearance in 99% of patients. Nitrous oxide had no effect on the time course or ETsevoflurane at which children showed body movement, grimace or cough. CONCLUSION: Several clinical signs occur sequentially during emergence, and are independent of exposure to nitrous oxide. Eye position is poorly correlated with other clinical signs or ETsevoflurane. EEG spectral characteristics may aid prediction of clinical-behavioural signs in children more than 3 months.


Asunto(s)
Periodo de Recuperación de la Anestesia , Anestesia por Inhalación/métodos , Anestésicos por Inhalación/administración & dosificación , Ondas Encefálicas/efectos de los fármacos , Encéfalo/efectos de los fármacos , Electroencefalografía , Sevoflurano/administración & dosificación , Factores de Edad , Anestesia por Inhalación/efectos adversos , Anestésicos por Inhalación/efectos adversos , Encéfalo/fisiopatología , Preescolar , Femenino , Fijación Ocular/efectos de los fármacos , Humanos , Lactante , Conducta del Lactante/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Óxido Nitroso/administración & dosificación , Valor Predictivo de las Pruebas , Estudios Prospectivos , Recuperación de la Función , Sevoflurano/efectos adversos , Factores de Tiempo
13.
Paediatr Anaesth ; 27(3): 251-262, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28177176

RESUMEN

BACKGROUND: Deep anesthesia in adults may be associated with electroencephalographic (EEG) suppression and higher rates of postoperative complications. Little is known about the impact of anesthetic depth on short- or long-term outcomes in pediatrics. Brain activity monitoring may complement clinical signs of anesthetic depth. This prospective observational study aimed to assess the frequency and degree of profound EEG suppression using multichannel EEG in children during sevoflurane general anesthesia. METHODS: Children aged 0-40 months who required general anesthesia for elective surgery were included. Continuous EEG recordings were performed starting from when anesthesia began and until recovery. Discontinuity was defined as EEG amplitude <25 uV, lasting ≥2 s, and observed in all electrodes across the scalp. Frequency, duration, and inter-event interval of discontinuity events were measured. Relationships between discontinuity events and postnatal age, endtidal sevoflurane concentration (etSEVO), and multiple clinical parameters were analyzed. RESULTS: Discontinuity events were observed in 35/68 children, with a median duration of 10 s (95%CI: 8-12) and a median of 4 events per patient (95%CI: 2-7). Children who had discontinuity events were younger (5.5 months, 95%CI: 3.6-6.5) compared to children who did not have discontinuity events (10.2 months, 95%CI: 6.1-14); (difference between medians, 4.7 months, 95%CI: 2.3-8, P = 0.0002). Younger infants exhibited a higher number of discontinuity events, and the incidence decreased with postnatal age (r68 = -0.53, P < 0.0001). The majority of discontinuity events were observed during the first 30 min of anesthesia (66.4% total events), where etSEVO was >3%. Few discontinuity events were observed during maintenance and none during emergence. Blood pressure, heart rate, tissue oxygen saturation, and endtidal CO2 partial pressure did not change during these events. CONCLUSIONS: Electroencephalographic monitoring may complement clinical signs in providing information about brain homeostasis during general anesthesia. The impact of discontinuity events on immediate and long-term outcomes merits further study.


Asunto(s)
Anestesia General/métodos , Anestésicos por Inhalación , Electroencefalografía/efectos de los fármacos , Éteres Metílicos , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios Prospectivos , Sevoflurano , Tiempo
14.
Anesthesiology ; 122(1): 150-171, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25222831

RESUMEN

BACKGROUND: Designing analgesic clinical trials in pediatrics requires a balance between scientific, ethical, and practical concerns. A previous consensus group recommended immediate rescue designs using opioid sparing as a surrogate measure of analgesic efficacy. The authors summarize the performance of rescue analgesic designs in pediatric trials of four commonly used classes of analgesics: opioids, nonsteroidal antiinflammatory drugs, acetaminophen, and local anesthetics. METHODS: MEDLINE, Embase, CINAHL, The Cochrane Library, and Web of science were searched in April 2013. The 85 studies selected were randomized or controlled clinical trials using immediate rescue paradigms in postoperative pain settings. A random-effects meta-analysis was used to synthesize predefined outcomes using Hedges' g. Difference between the means of the treatment arms were also expressed as a percentage of the corresponding value in the placebo group (placebo-treatment/placebo). Distributions of pain scores in study and control groups and relationships between opioid sparing and pain scores were examined. RESULTS: For each of the four study drug classes, significant opioid sparing was demonstrated in a majority of studies by one or more of the following endpoints: (1) total dose (milligram per kilogram per hour), (2) percentage of children requiring rescue medication, and (3) time to first rescue medication (minutes). Pain scores averaged 2.4/10 in study groups, 3.4/10 in control groups. CONCLUSIONS: Opioid sparing is a feasible pragmatic endpoint for pediatric pain analgesic trials. This review serves to guide future research in pediatric analgesia trials, which could test whether some specific design features may improve assay sensitivity while minimizing the risk of unrelieved pain.


Asunto(s)
Analgésicos/uso terapéutico , Ensayos Clínicos como Asunto/métodos , Dolor Postoperatorio/tratamiento farmacológico , Pediatría/métodos , Acetaminofén/uso terapéutico , Analgésicos Opioides/uso terapéutico , Anestésicos Locales/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Niño , Humanos , Dimensión del Dolor/métodos , Proyectos de Investigación
15.
Anesthesiology ; 123(4): 873-85, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26275090

RESUMEN

BACKGROUND: Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker that produces prolonged local anesthesia in animals and humans. Under a Food and Drug Administration-approved phase 1 Investigational New Drug trial, the authors evaluated safety and efficacy of NeoSTX alone and combined with 0.2% bupivacaine (Bup) with and without epinephrine. METHODS: The authors conducted a double-blind, randomized, controlled trial involving healthy male volunteers aged 18 to 35 yr receiving two 10-ml subcutaneous injections. Control sites received Bup. In part 1, active sites received (1) 5 to 40 µg NeoSTX+Saline (NeoSTX-Saline), (2) 5 to 40 µg NeoSTX+Bup (NeoSTX-Bup), or (3) placebo (Saline). In part 2, active sites received 10 or 30 µg NeoSTX+Bup+Epinephrine (NeoSTX-Bup-Epi) or placebo. Primary outcome measures were safety and adverse events associated with NeoSTX. Secondary outcomes included clinical biochemistry, NeoSTX pharmacokinetics, and cutaneous hypoesthesia. RESULTS: A total of 84 subjects were randomized and completed the two-part trial with no serious adverse events or clinically significant physiologic impairments. Perioral numbness and tingling increased with NeoSTX dose for NeoSTX-Saline and NeoSTX-Bup. All symptoms resolved without intervention. NeoSTX-Bup-Epi dramatically reduced symptoms compared with other NeoSTX combinations (tingling: 0 vs. 70%, P = 0.004; numbness: 0 vs. 60%, P = 0.013) at the same dose. Mean peak plasma NeoSTX concentration for NeoSTX-Bup-Epi was reduced at least two-fold compared with NeoSTX-Saline and NeoSTX-Bup (67 ± 14, 134 ± 63, and 164 ± 81 pg/ml, respectively; P = 0.016). NeoSTX-Bup showed prolonged cutaneous block duration compared with Bup, NeoSTX-Saline, or placebo, at all doses. Median time to near-complete recovery for 10 µg NeoSTX-Bup-Epi was almost five-fold longer compared with Bup (50 vs. 10 h, P = 0.007). CONCLUSION: NeoSTX combinations have a tolerable side effect profile and appear promising for prolonged local anesthesia.


Asunto(s)
Anestesia Local/métodos , Bupivacaína/administración & dosificación , Epinefrina/administración & dosificación , Saxitoxina/análogos & derivados , Adulto , Anestesia Local/efectos adversos , Anestésicos Locales , Bupivacaína/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Epinefrina/efectos adversos , Humanos , Hipoestesia/inducido químicamente , Masculino , Dimensión del Dolor/efectos adversos , Dimensión del Dolor/métodos , Saxitoxina/administración & dosificación , Saxitoxina/efectos adversos , Adulto Joven
16.
Pain ; 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38981069

RESUMEN

ABSTRACT: Quantitative sensory testing (QST) is a set of methods for quantifying somatosensory functioning. Limitations of laboratory-based QST (LQST) include high cost, complexity in training, lack of portability, and time requirements for testing. Translating QST to a home setting could facilitate future research and clinical care. The objective of this study was to develop a home QST (HQST) tool-kit that is cost-effective, easy to use, and detects changes in sensory and pain processing. Thirty-two young healthy adults underwent sensory testing on their nondominant forearm using standard in-person LQST, followed by "simulated HQST" using video guidance in a separate room from the investigator before and after application of either a lidocaine or capsaicin cream. We observed good agreement between HQST and LQST scores, with significant correlations observed between the pinprick, pressure, cold and heat measures (|ρ| range = 0.36-0.54). The participants rated the HQST protocol as highly acceptable and safe but can be improved in future implementations. Home QST was able to detect hypoesthesia to vibration after lidocaine cream application (P = 0.024, d = 0.502) and could detect hypoalgesia and hyperalgesia to pressure and heat pain sensitivity tests after application of lidocaine and capsaicin creams, respectively (P-value range = <0.001-0.036, d-value range = 0.563-0.901). Despite limitations, HQST tool-kits may become a cost-effective, convenient, and scalable approach for improving sensory profiling in clinical care and clinical research.

17.
Neuroimage Clin ; 42: 103614, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38754325

RESUMEN

BACKGROUND: Previous studies have raised concerns regarding neurodevelopmental impacts of early exposures to general anesthesia and surgery. Electroencephalography (EEG) can be used to study ontogeny of brain networks during infancy. As a substudy of an ongoing study, we examined measures of functional connectivity in awake infants with prior early and prolonged anesthetic exposures and in control infants. METHODS: EEG functional connectivity was assessed using debiased weighted phase lag index at source and sensor levels and graph theoretical measures for resting state activity in awake infants in the early anesthesia (n = 26 at 10 month visit, median duration of anesthesia = 4 [2, 7 h]) and control (n = 38 at 10 month visit) groups at ages approximately 2, 4 and 10 months. Theta and low alpha frequency bands were of primary interest. Linear mixed models incorporated impact of age and cumulative hours of general anesthesia exposure. RESULTS: Models showed no significant impact of cumulative hours of general anesthesia exposure on debiased weighted phase lag index, characteristic path length, clustering coefficient or small-worldness (conditional R2 0.05-0.34). An effect of age was apparent in many of these measures. CONCLUSIONS: We could not demonstrate significant impact of general anesthesia in the first months of life on early development of resting state brain networks over the first postnatal year. Future studies will explore these networks as these infants grow older.


Asunto(s)
Anestesia General , Encéfalo , Electroencefalografía , Red Nerviosa , Humanos , Lactante , Masculino , Femenino , Encéfalo/crecimiento & desarrollo , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Anestesia General/efectos adversos , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/efectos de los fármacos , Red Nerviosa/crecimiento & desarrollo , Desarrollo Infantil/efectos de los fármacos , Desarrollo Infantil/fisiología
18.
Pain Res Manag ; 18(2): 87-93, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23662291

RESUMEN

BACKGROUND: Historically, in both adult and pediatric populations, a lack of knowledge regarding complex regional pain syndrome (CRPS) and absence of clear diagnostic criteria have contributed to the view that this is a primarily psychiatric condition. OBJECTIVE: To test the hypothesis that children with CRPS are more functionally disabled, have more pain and are more psychologically distressed than children with other pain conditions. METHODS: A total of 101 children evaluated in a tertiary care pediatric pain clinic who met the International Association for the Study of Pain consensus diagnostic criteria for CRPS participated in the present retrospective study. Comparison groups included 103 children with abdominal pain, 291 with headache and 119 with back pain. Children and parents completed self-report questionnaires assessing disability, somatization, pain coping, depression, anxiety and school attendance. RESULTS: Children with CRPS reported higher pain intensity and more recent onset of pain at the initial tertiary pain clinic evaluation compared with children with other chronic pain conditions. They reported greater functional disability and more somatic symptoms than children with headaches or back pain. Scores on measures of depression and anxiety were within normal limits and similar to those of children in other pain diagnostic groups. CONCLUSIONS: As a group, clinic-referred children with CRPS may be more functionally impaired and experience more somatic symptoms compared with children with other pain conditions. However, overall psychological functioning as assessed by self-report appears to be similar to that of children with other chronic pain diagnoses. Comprehensive assessment using a biopsychosocial framework is essential to understanding and appropriately treating children with symptoms of CRPS.


Asunto(s)
Síntomas Conductuales/etiología , Síndromes de Dolor Regional Complejo/complicaciones , Síndromes de Dolor Regional Complejo/psicología , Trastornos Somatomorfos/etiología , Adolescente , Factores de Edad , Análisis de Varianza , Síntomas Conductuales/diagnóstico , Distribución de Chi-Cuadrado , Niño , Síndromes de Dolor Regional Complejo/clasificación , Evaluación de la Discapacidad , Femenino , Humanos , Masculino , Dimensión del Dolor , Estudios Retrospectivos , Trastornos Somatomorfos/diagnóstico , Encuestas y Cuestionarios
19.
Children (Basel) ; 10(8)2023 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-37628281

RESUMEN

Erythromelalgia is a descriptive term for severe burning pain and erythema in the distal extremities relieved by cold and exacerbated by heat. Pediatric case series to date are relatively small. We extracted and analyzed medical record data for 42 pediatric patients to describe clinical characteristics, associated conditions, and responses to treatments. Informed consent was obtained according to an IRB-approved protocol that included gene discovery. Three patients had confirmed Nav1.7 sodium channelopathies, with six additional patients under investigation with novel gene candidates. There was a female predominance (2.5:1), and the median onset age was 12 years (IQR = 3-14). Patients saw a median of three specialists (IQR = 2-3) for a diagnosis. The majority (90%) reported bilateral symptoms. Cooling methods usually provided partial relief, while heat and exercise exacerbated pain. No medication appeared to be consistently effective; commonly prescribed medications included sodium channel blockers (n = 37), topical analgesics (n = 26), gabapentin (n = 22), and aspirin (n = 15). Based on the currently published literature, we believe this cohort is the largest pediatric study of erythromelalgia to date. Many findings are consistent with those of previously published case series. Work is in progress to establish a prospective cohort and multi-center registry.

20.
Front Neurol ; 13: 664710, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35222234

RESUMEN

Several neurological disorders may be amenable to treatment with gene-targeting therapies such as antisense oligonucleotides (ASOs) or viral vector-based gene therapy. The US FDA has approved several of these treatments; many others are in clinical trials. Preclinical toxicity studies of ASO candidates have identified dose-dependent neurotoxicity patterns. These include degeneration of dorsal root ganglia, the cell bodies of peripheral sensory neurons. Quantitative sensory testing (QST) refers to a series of standardized mechanical and/or thermal measures that complement clinical neurologic examination in detecting sensory dysfunction. QST primarily relies on patient self-report or task performance (i.e., button-pushing). This brief report illustrates individualized pragmatic approaches to QST in non-verbal subjects receiving early phase investigational intrathecal drug therapies as a component of clinical trial safety protocols. Three children with neurodevelopmental disorders that include Neuronal Ceroid Lipofuscinosis Type 7, Ataxia-Telangiectasia, and Epilepsy of Infancy with Migrating Focal Seizures are presented. These case studies discuss individualized testing protocols, accounting for disease presentation, cognitive and motor function. We outline specific considerations for developing assessments for detecting changes in sensory processing in diverse patient groups and safety monitoring trials of early phase investigational intrathecal drug therapies. QST may complement information obtained from the standard neurologic examination, electrophysiologic studies, skin biopsies, and imaging. QST has limitations and challenges, especially in non-verbal subjects, as shown in the three cases discussed in this report. Future directions call for collaborative efforts to generate sensory datasets and share data registries in the pediatric neurology field.

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