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While effects of general anesthesia on neuronal activity in the human neonatal brain are incompletely understood, electroencephalography (EEG) provides some insight and may identify age-dependent differences. A systematic search (MEDLINE, Embase, PUBMED, Cochrane Library to November 2023) retrieved English language publications reporting EEG during general anesthesia for cardiac or non-cardiac surgery in term neonates (37 to 44 weeks post-menstrual age). Data were extracted and risk of bias (ROBINS-I Cochrane tool) and quality of evidence (GRADE checklist) assessed. From 1155 abstracts, nine publications (157 neonates; 55.7% male) fulfilled eligibility criteria. Data were limited and study quality was very low. The occurrence of discontinuity, a characteristic pattern of alternating higher and lower amplitude EEG segments, was reported with general anesthesia (94 of 119 neonates, six publications) and with hypothermia (23 of 23 neonates, two publications). Decreased power in the delta (0.5-4Hz) frequency range was also reported with increasing anesthetic dose (39 neonates; three publications). While evidence gaps were identified, both increasing sevoflurane concentration and decreasing temperature are associated with increasing discontinuity.
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Pharmacokinetic pharmacodynamic modeling is an important tool which uses statistical methodology to provide a better understanding of the relationship between concentration and effect of drugs such as analgesics and sedatives. Pharmacokinetic pharmacodynamic models also describe between-subject variability that allows identification of subgroups and dose adjustment for optimal pain management in individual patients. This approach is particularly useful in the pediatric population, where most drugs have received limited evaluation and dosing is extrapolated from adult practice. In children, the covariates of weight and age are used to describe size- and maturation-related changes in pharmacokinetics. It is important to consider both size and maturation in order to develop an accurate model and determine the optimal dose for different age groups. An adequate assessment of analgesic and sedative effect using pain scales or brain activity measures is essential to build reliable pharmacokinetic pharmacodynamic models. This is often challenging in children due to the multidimensional nature of pain and the limited sensitivity and specificity of some measurement tools. This review provides a summary of the pharmacokinetic and pharmacodynamic methodology used to describe the dose-concentration-effect relationship of analgesics and sedation in children, with a focus on the different pharmacodynamic endpoints and the challenges of pharmacodynamic modeling.
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Analgésicos , Hipnóticos y Sedantes , Adulto , Humanos , Niño , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/uso terapéutico , Dolor/tratamiento farmacológico , Manejo del Dolor , Dimensión del Dolor , Modelos BiológicosRESUMEN
BACKGROUND: The NEonate and Children audiT of Anaesthesia pRactice IN Europe (NECTARINE) prospective observational study reported critical events requiring intervention during 35.2% of 6542 anesthetic episodes in 5609 infants up to 60 weeks postmenstrual age. The United Kingdom (UK) was one of 31 participating countries. METHODS: Subgroup analysis of UK NECTARINE cases (12.8% of cohort) to identify perioperative critical events that triggered medical interventions. Secondary aims were to describe UK practice, identify factors more commonly associated with critical events, and compare 30-day morbidity and mortality between participating UK and nonUK centers. RESULTS: Seventeen UK centers recruited 722 patients (68.7% male, 36.1% born preterm, and 48.1% congenital anomalies) undergoing anesthesia for 876 surgical or diagnostic procedures at 25-60 weeks postmenstrual age. Repeat anesthesia/surgery was common: 17.6% patients prior to and 14.4% during the recruitment period. Perioperative critical events triggered interventions in 300/876 (34.3%) cases. Cardiovascular instability (16.9% of cases) and/or reduced oxygenation (11.4%) were more common in younger patients and those with co-morbidities or requiring preoperative intensive support. A higher proportion of UK than nonUK cases were graded as ASA-Physical Status scores >2 or requiring urgent or emergency procedures, and 39% required postoperative intensive care. Thirty-day morbidity (complications in 17.2%) and mortality (8/715, 1.1%) did not differ from nonUK participants. CONCLUSIONS: Perioperative critical events and co-morbidities are common in neonates and young infants. Thirty-day morbidity and mortality data did not demonstrate national differences in outcome. Identifying factors associated with increased risk informs preoperative assessment, resource allocation, and discussions between clinicians and families.
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Anestesia , Anestesia/efectos adversos , Niño , Europa (Continente)/epidemiología , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Morbilidad , Estudios Prospectivos , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Chemotherapy-induced oral mucositis can result in severe pain. Intravenous (IV) opioids are recommended, but management protocols vary. We systematically reviewed studies reporting IV opioid use for pain related to chemotherapy-induced severe oral mucositis in children and conducted a large single-center case series. METHODS: Ovid MEDLINE, PubMed, and Cochrane databases were searched for studies reporting IV opioid duration and/or dose requirements for severe mucositis. Secondly, our pain service database was interrogated to describe episodes of opioid administration by patient- or nurse-controlled analgesia (PCA/NCA) for children with mucositis and cancer treatment-related pain. RESULTS: Seventeen studies (six randomized trials, two prospective observational, three retrospective cohort, six retrospective case series) included IV opioid in 618 patients (age 0.3-22.3 years), but reported parameters varied. Mucositis severity and chemotherapy indication influenced IV opioid requirements, with duration ranging from 3 to 68 days and variable dose trajectories (hourly morphine or equivalent 0-97 mcg/kg/h). Our 7-year series included PCA/NCA for 364 episodes of severe mucositis (302 patients; age 0.12-17.2 years). Duration ranged from 1 to 107 days and dose requirements in the first 3 days from 1 to 110 mcg/kg/h morphine. Longer PCA/NCA duration was associated with: higher initial morphine requirements (ρ = 0.46 [95% CI 0.35, 0.57]); subsequent increased pain and need for ketamine co-analgesia (118/364 episodes with opioid/ketamine 13.9 [9.8-22.2] days vs opioid alone 6.0 [3.9-10.8] days; median [IQR]); but not with age or sex. CONCLUSIONS: Management of severe mucositis pain can require prolonged IV opioid therapy. Individual and treatment-related variability in analgesic requirements highlight the need for regular review, titration, and management by specialist services.
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Antineoplásicos , Mucositis , Adolescente , Adulto , Analgesia Controlada por el Paciente , Analgésicos Opioides/efectos adversos , Antineoplásicos/efectos adversos , Niño , Preescolar , Humanos , Lactante , Morfina/efectos adversos , Mucositis/inducido químicamente , Mucositis/tratamiento farmacológico , Estudios Observacionales como Asunto , Dolor/tratamiento farmacológico , Dimensión del Dolor , Dolor Postoperatorio/tratamiento farmacológico , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: Neonates and infants requiring anaesthesia are at risk of physiological instability and complications, but triggers for peri-anaesthetic interventions and associations with subsequent outcome are unknown. METHODS: This prospective, observational study recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. The primary aim was to identify thresholds of pre-determined physiological variables that triggered a medical intervention. The secondary aims were to evaluate morbidities, mortality at 30 and 90 days, or both, and associations with critical events. RESULTS: Infants (n=5609) born at mean (standard deviation [sd]) 36.2 (4.4) weeks postmenstrual age (35.7% preterm) underwent 6542 procedures within 63 (48) days of birth. Critical event(s) requiring intervention occurred in 35.2% of cases, mainly hypotension (>30% decrease in blood pressure) or reduced oxygenation (SpO2 <85%). Postmenstrual age influenced the incidence and thresholds for intervention. Risk of critical events was increased by prior neonatal medical conditions, congenital anomalies, or both (relative risk [RR]=1.16; 95% confidence interval [CI], 1.04-1.28) and in those requiring preoperative intensive support (RR=1.27; 95% CI, 1.15-1.41). Additional complications occurred in 16.3% of patients by 30 days, and overall 90-day mortality was 3.2% (95% CI, 2.7-3.7%). Co-occurrence of intraoperative hypotension, hypoxaemia, and anaemia was associated with increased risk of morbidity (RR=3.56; 95% CI, 1.64-7.71) and mortality (RR=19.80; 95% CI, 5.87-66.7). CONCLUSIONS: Variability in physiological thresholds that triggered an intervention, and the impact of poor tissue oxygenation on patient's outcome, highlight the need for more standardised perioperative management guidelines for neonates and infants. CLINICAL TRIAL REGISTRATION: NCT02350348.
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Anestesia/efectos adversos , Anestésicos/efectos adversos , Complicaciones Intraoperatorias/epidemiología , Complicaciones Posoperatorias/epidemiología , Procedimientos Quirúrgicos Operativos/efectos adversos , Factores de Edad , Anestesia/mortalidad , Comorbilidad , Europa (Continente)/epidemiología , Femenino , Edad Gestacional , Estado de Salud , Humanos , Incidencia , Lactante , Recién Nacido , Recien Nacido Prematuro , Complicaciones Intraoperatorias/diagnóstico , Complicaciones Intraoperatorias/mortalidad , Complicaciones Intraoperatorias/terapia , Masculino , Auditoría Médica , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/mortalidad , Complicaciones Posoperatorias/terapia , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Procedimientos Quirúrgicos Operativos/mortalidad , Factores de TiempoRESUMEN
Neonatal hindpaw incision primes developing spinal nociceptive circuitry, resulting in enhanced hyperalgesia following reinjury in adulthood. Spinal microglia contribute to this persistent effect, and microglial inhibition at the time of adult reincision blocks the enhanced hyperalgesia. Here, we pharmacologically inhibited microglial function with systemic minocycline or intrathecal SB203580 at the time of neonatal incision and evaluated sex-dependent differences following adult reincision. Incision in adult male and female rats induced equivalent hyperalgesia and spinal dorsal horn expression of genes associated with microglial proliferation (Emr1) and transformation to a reactive phenotype (Irf8). In control adults with prior neonatal incision, the enhanced degree and duration of incision-induced hyperalgesia and spinal microglial responses to reincision were equivalent in males and females. However, microglial inhibition at the time of the neonatal incision revealed sex-dependent effects: the persistent mechanical and thermal hyperalgesia following reincision in adulthood was prevented in males but unaffected in females. Similarly, reincision induced Emr1 and Irf8 gene expression was downregulated in males, but not in females, following neonatal incision with minocycline. To evaluate the distribution of reincision hyperalgesia, prior neonatal incision was performed at different body sites. Hyperalgesia was maximal when the same paw was reincised, and was increased following prior incision at ipsilateral, but not contralateral, sites, supporting a segmentally restricted spinal mechanism. These data highlight the contribution of spinal microglial mechanisms to persistent effects of early-life injury in males, and sex-dependent differences in the ability of microglial inhibition to prevent the transition to a persistent pain state span developmental stages.SIGNIFICANCE STATEMENT Following the same surgery, some patients develop persistent pain. Contributory mechanisms are not fully understood, but early-life experience and sex/gender may influence the transition to chronic pain. Surgery and painful procedural interventions in vulnerable preterm neonates are associated with long-term alterations in somatosensory function and pain that differ in males and females. Surgical injury in neonatal rodents primes the developing nociceptive system and enhances reinjury response in adulthood. Neuroimmune interactions are critical mediators of persistent pain, but sex-dependent differences in spinal neuroglial signaling influence the efficacy of microglial inhibitors following adult injury. Neonatal microglial inhibition has beneficial long-term effects on reinjury response in adult males only, emphasizing the importance of evaluating sex-dependent differences at all ages in preclinical studies.
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Hiperalgesia/fisiopatología , Microglía/metabolismo , Dolor/fisiopatología , Médula Espinal/fisiopatología , Animales , Inhibidores Enzimáticos/farmacología , Femenino , Hiperalgesia/metabolismo , Imidazoles/farmacología , Factores Reguladores del Interferón/metabolismo , Masculino , Microglía/efectos de los fármacos , Minociclina/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Dolor/metabolismo , Umbral del Dolor/fisiología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Superficie Celular/metabolismo , Factores Sexuales , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismoRESUMEN
Clinical outcomes are measurable changes in health, function, or quality of life that are important for evaluating the quality of care and comparing the efficacy of interventions. However, clinical outcomes and related measurement tools need to be well-defined, relevant, and valid. In adults, Core Outcome Measures in Effectiveness Trials (COMET) methodology has been used to develop core outcome sets for perioperative care. Systematic literature reviews identified standardized endpoints (StEP) and valid measurement tools, and consensus across a broader range of relevant stakeholders was achieved via a Delphi process to establish Core Outcome Measures in Perioperative and Anaesthetic Care (COMPAC). Core outcome sets for pediatric perioperative care cannot be directly extrapolated from adult data. The type and weighting of endpoints within particular domains can be influenced by age-dependent differences in the indications for and/or nature of surgery and medical comorbidities, and the validity and utility of many measurement tools vary significantly with developmental stage and age. The involvement of parents/carers is essential as they frequently act as surrogate responders for preverbal and developmentally delayed children, parental response may influence child outcome, and parental and/or child ranking of outcomes may differ from those of health professionals. Here, we describe the formation of the international Pediatric Perioperative Outcomes Group, which aims to identify and create validated, broadly applicable, patient-centered outcome measures for infants, children, and young people. Methodologies parallel that of the StEP and COMPAC projects, and systematic literature searches have been performed within agreed age-dependent subpopulations to identify reported outcomes and measurement tools. This represents the first steps for developing core outcome sets for pediatric perioperative care.
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Anestesia , Pediatría , Proyectos de Investigación , Procedimientos Quirúrgicos Operativos , Revisiones Sistemáticas como Asunto , Adolescente , Niño , Preescolar , Humanos , Lactante , Anestesia/métodos , Consenso , Pediatría/métodos , Periodo Perioperatorio , Procedimientos Quirúrgicos Operativos/métodos , Revisiones Sistemáticas como Asunto/métodos , Resultado del TratamientoRESUMEN
The Pediatric Perioperative Outcomes Group (PPOG) is an international collaborative of clinical investigators and clinicians within the subspecialty of pediatric anesthesiology and perioperative care which aims to use COMET (Core Outcomes Measures in Effectiveness Trials) methodology to develop core outcome setsfor infants, children and young people that are tailored to the priorities of the pediatric surgical population.Focusing on four age-dependent patient subpopulations determined a priori for core outcome set development: i) neonates and former preterm infants (up to 60 weeks postmenstrual age); ii) infants (>60 weeks postmenstrual age - <1 year); iii) toddlers and school age children (>1-<13 years); and iv) adolescents (>13-<18 years), we conducted a systematic review of outcomes reported in perioperative studies that include participants within age-dependent pediatric subpopulations. Our review of pediatric perioperative controlled trials published from 2008 to 2018 identified 724 articles reporting 3192 outcome measures. The proportion of published trials and the most frequently reported outcomes varied across pre-determined age groups. Outcomes related to patient comfort, particularly pain and analgesic requirement, were the most frequent domain for infants, children and adolescents. Clinical indicators, particularly cardiorespiratory or medication-related adverse events, were the most common outcomes for neonates and infants < 60 weeks and were the second most frequent domain at all other ages. Neonates and infants <60 weeks of age were significantly under-represented in perioperative trials. Patient-centered outcomes, heath care utilization, and bleeding/transfusion related outcomes were less often reported. In most studies, outcomes were measured in the immediate perioperative period, with the duration often restricted to the post-anesthesia care unit or the first 24 postoperative hours. The outcomes identified with this systematic review will be combined with patient centered outcomes identified through a subsequent stakeholder engagement study to arrive at a core outcome set for each age-specific group.
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OBJECTIVES: To evaluate the clinical features of erythromelalgia in childhood associated with gain-of-function SCN9A mutations that increase activity of the Nav1.7 voltage-gated sodium channel, we conducted a systematic review of pediatric presentations of erythromelalgia related to SCN9A mutations, and compared pediatric clinical presentations of symptomatic erythromelalgia, with or without SCN9A mutations. STUDY DESIGN: PubMed, Embase, and PsycINFO Databases were searched for reports of inherited erythromelalgia in childhood. Clinical features, management, and genotype were extracted. Case notes of pediatric patients with erythromelalgia from the Great Ormond Street Hospital Pain Service were reviewed for clinical features, patient-reported outcomes, and treatments. Children aged over 10 years were recruited for quantitative sensory testing. RESULTS: Twenty-eight publications described erythromelalgia associated with 15 different SCN9A gene variants in 25 children. Pain was severe and often refractory to multiple treatments, including nonspecific sodium channel blockers. Skin damage or other complications of cold immersion for symptomatic relief were common (60%). SCN9A mutations resulting in greater hyperpolarizing shifts in Nav1.7 sodium channels correlated with symptom onset at younger ages (P = .016). Variability in reporting, and potential publication bias toward severe cases, limit any estimations of overall prevalence. In our case series, symptoms were similar but comorbidities were more common in children with SCN9A mutations. Quantitative sensory testing revealed marked dynamic warm allodynia. CONCLUSIONS: Inherited erythromelalgia in children is associated with difficult-to-manage pain and significant morbidity. Standardized reporting of outcome and management in larger series will strengthen identification of genotype-phenotype relationships. More effective long-term therapies are a significant unmet clinical need.
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Eritromelalgia/complicaciones , Eritromelalgia/genética , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Dolor/etiología , Adolescente , Niño , Femenino , Humanos , Masculino , Estudios Retrospectivos , Evaluación de SíntomasRESUMEN
BACKGROUND: The effect of neonatal anesthesia and pain on the developing brain is of considerable clinical importance, but few studies have evaluated noxious surgical input to the infant brain under anesthesia. Herein, the authors tested the effect of increasing isoflurane concentration on spontaneous and evoked nociceptive activity in the somatosensory cortex of rats at different postnatal ages. METHODS: Intracortical extracellular field potentials evoked by hind paw C-fiber electrical stimulation were recorded in the rat somatosensory cortex at postnatal day (P) 7, P14, P21, and P30 during isoflurane anesthesia (n = 7 per group). The amplitudes of evoked potentials and the energies of evoked oscillations (1 to 100 Hz over 3 s) were measured after equilibration at 1.5% isoflurane and during step increases in inspired isoflurane. Responses during and after plantar hind paw incision were compared at P7 and P30 (n = 6 per group). RESULTS: At P7, cortical activity was silent at 1.5% isoflurane but noxious-evoked potentials decreased only gradually in amplitude and energy with step increases in isoflurane. The resistance of noxious-evoked potentials to isoflurane at P7 was significantly enhanced after surgical hind paw incision (69 ± 16% vs. 6 ± 1% in nonincised animals at maximum inspired isoflurane). This resistance was age dependent; at P14 to P30, noxious-evoked responses decreased sharply with increasing isoflurane (step 3 [4%] P7: 50 ± 9%, P30: 4 ± 1% of baseline). Hind paw incision at P30 sensitized noxious-evoked potentials, but this was suppressed by higher isoflurane concentrations. CONCLUSIONS: Despite suppression of spontaneous activity, cortical-evoked potentials are more resistant to isoflurane in young rats and are further sensitized by surgical injury.
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Anestésicos por Inhalación/farmacología , Potenciales Evocados Somatosensoriales/efectos de los fármacos , Isoflurano/farmacología , Corteza Somatosensorial/efectos de los fármacos , Animales , Animales Recién Nacidos , Estimulación Eléctrica , Electroencefalografía , Masculino , Fibras Nerviosas Amielínicas , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Neonatal pain and injury can alter long-term sensory thresholds. Descending rostroventral medulla (RVM) pathways can inhibit or facilitate spinal nociceptive processing in adulthood. As these pathways undergo significant postnatal maturation, the authors evaluated long-term effects of neonatal surgical injury on RVM descending modulation. METHODS: Plantar hind paw or forepaw incisions were performed in anesthetized postnatal day (P)3 Sprague-Dawley rats. Controls received anesthesia only. Hind limb mechanical and thermal withdrawal thresholds were measured to 6 weeks of age (adult). Additional groups received pre- and post-incision sciatic nerve levobupivacaine or saline. Hind paw nociceptive reflex sensitivity was quantified in anesthetized adult rats using biceps femoris electromyography, and the effect of RVM electrical stimulation (5-200 µA) measured as percentage change from baseline. RESULTS: In adult rats with previous neonatal incision (n = 9), all intensities of RVM stimulation decreased hind limb reflex sensitivity, in contrast to the typical bimodal pattern of facilitation and inhibition with increasing RVM stimulus intensity in controls (n = 5) (uninjured vs. neonatally incised, P < 0.001). Neonatal incision of the contralateral hind paw or forepaw also resulted in RVM inhibition of hind paw nociceptive reflexes at all stimulation intensities. Behavioral mechanical threshold (mean ± SEM, 28.1 ± 8 vs. 21.3 ± 1.2 g, P < 0.001) and thermal latency (7.1 ± 0.4 vs. 5.3 ± 0.3 s, P < 0.05) were increased in both hind paws after unilateral neonatal incision. Neonatal perioperative sciatic nerve blockade prevented injury-induced alterations in RVM descending control. CONCLUSIONS: Neonatal surgical injury alters the postnatal development of RVM descending control, resulting in a predominance of descending inhibition and generalized reduction in baseline reflex sensitivity. Prevention by local anesthetic blockade highlights the importance of neonatal perioperative analgesia.
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Bulbo Raquídeo/lesiones , Bulbo Raquídeo/cirugía , Anestésicos Locales/farmacología , Animales , Animales Recién Nacidos , Conducta Animal/fisiología , Estimulación Eléctrica , Femenino , Pie/inervación , Hiperalgesia/psicología , Masculino , Bulbo Raquídeo/crecimiento & desarrollo , Bloqueo Nervioso , Neuronas Aferentes/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo/fisiología , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones , Umbral SensorialRESUMEN
BACKGROUND: Neonatal surgical injury triggers developmentally regulated long-term changes that include enhanced hyperalgesia and spinal microglial reactivity after reinjury. To further evaluate priming of response by neonatal hindpaw incision, the authors investigated the functional role of spinal microglial p38 mitogen-activated protein kinase after reincision in adult rodents. METHODS: Plantar hindpaw incision was performed in anesthetized adult rats, with or without previous incision on postnatal day 3. Numbers and distribution of phosphorylated-p38 (1, 3, 24 h) and phosphorylated extracellular signal-regulated kinase (15 min, 24 h) immunoreactive cells in the lumbar dorsal horn were compared after adult or neonatal plus adult incision. Withdrawal thresholds evaluated reversal of incision-induced hyperalgesia by p38 inhibition with intrathecal SB203850. RESULTS: Neonatal injury significantly increased phosphorylated-p38 expression 3 h after adult incision (55 ± 4 vs. 35 ± 4 cells per section, mean ± SEM, n = 6 to 7, P < 0.01). Increased expression was restricted to microglia, maintained across lumbar segments, and also apparent at 1 and 24 h. Preincision intrathecal SB203850 prevented the enhanced mechanical hyperalgesia in adults with previous neonatal injury and was effective at a lower dose (0.2 vs. 1 mg/kg, n = 8, P < 0.05) and for a longer duration (10 vs. 3 days). Lumbar neuronal phosphorylated extracellular signal-regulated kinase expression reflected the distribution of hindpaw primary afferents, but was not significantly altered by previous incision. CONCLUSIONS: Neonatal incision primes spinal neuroglial signaling, and reincision in adult rats unmasks centrally mediated increases in functional microglial reactivity and persistent hyperalgesia. After early life injury, p38 inhibitors may have specific benefit as part of multimodal analgesic regimes to reduce the risk of persistent postsurgical pain.
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Traumatismos de los Pies/patología , Hiperalgesia/patología , Microglía/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacos , Animales , Animales Recién Nacidos , Pie/cirugía , Inyecciones Espinales , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Sprague-Dawley , Médula Espinal/patología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
PURPOSE OF REVIEW: This article summarizes recent data related to the safety and efficacy of postoperative analgesia in children that influence clinical practice recommendations. RECENT FINDINGS: Postoperative pain continues to be experienced by hospitalized children and following discharge after short stay or ambulatory surgery. Updated recommendations for post-tonsillectomy analgesia exclude codeine and suggest regular administration of paracetamol and NSAID, but evidence for the most appropriate dose and type of opioid for rescue analgesia is limited. The incidence of opioid-related respiratory depression/oversedation in hospitalized children ranges from 0.11 to 0.41%, with recent large series identifying high-risk groups and contributory factors that can be targeted to minimize the risk of serious or permanent harm. Data demonstrating feasibility and safety of regional analgesic techniques is increasing, but additional and procedure-specific evidence would improve technique selection and inform discussions of efficacy and safety with patients and families/carers. Persistent postsurgical pain is increasingly recognized following major surgery in adolescents. Evaluation of potential predictive factors in clinical studies and investigation of underlying mechanisms in laboratory studies can identify targets for both pharmacological and nonpharmacological interventions. SUMMARY: Recommendations for postoperative pain in children continue to evolve, with data incorporated from randomized controlled trials, case series and large audits. Management of pain following surgery in children needs to not only encompass efficacy and safety in the immediate perioperative period, but also consider pain following discharge after ambulatory surgery and the potential risk of persistent postsurgical pain following major surgery.
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Analgésicos Opioides/uso terapéutico , Analgésicos/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Analgésicos/efectos adversos , Analgésicos Opioides/efectos adversos , Niño , Dolor Crónico/tratamiento farmacológico , Humanos , Manejo del DolorRESUMEN
Effective management of procedural and postoperative pain in neonates is required to minimize acute physiological and behavioral distress and may also improve acute and long-term outcomes. Painful stimuli activate nociceptive pathways, from the periphery to the cortex, in neonates and behavioral responses form the basis for validated pain assessment tools. However, there is an increasing awareness of the need to not only reduce acute behavioral responses to pain in neonates, but also to protect the developing nervous system from persistent sensitization of pain pathways and potential damaging effects of altered neural activity on central nervous system development. Analgesic requirements are influenced by age-related changes in both pharmacokinetic and pharmacodynamic response, and increasing data are available to guide safe and effective dosing with opioids and paracetamol. Regional analgesic techniques provide effective perioperative analgesia, but higher complication rates in neonates emphasize the importance of monitoring and choice of the most appropriate drug and dose. There have been significant improvements in the understanding and management of neonatal pain, but additional research evidence will further reduce the need to extrapolate data from older age groups. Translation into improved clinical care will continue to depend on an integrated approach to implementation that encompasses assessment and titration against individual response, education and training, and audit and feedback.
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Manejo del Dolor/métodos , Dolor/epidemiología , Acetaminofén/efectos adversos , Acetaminofén/farmacocinética , Acetaminofén/uso terapéutico , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/farmacocinética , Analgésicos Opioides/uso terapéutico , Anestesia de Conducción/efectos adversos , Anestesia de Conducción/métodos , Humanos , Recién Nacido , Dolor/fisiopatología , Dimensión del DolorRESUMEN
Neuropathic screening tools improve recognition of neuropathic pain in adults. Although utilized in pediatric populations, the sensitivity, specificity and methodology of screening tool delivery have not been compared in children. We evaluated the Self-Report Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) in adolescents (10-18 years) referred to a tertiary pediatric pain clinic. History and examination by specialist clinicians and multidisciplinary assessment informed classification of the primary pain type. In a prospective cohort, scores were obtained at interview (S-LANSS interview; n = 161, 70% female), and following substitution of self-reported signs with examination findings in the primary pain region (Leeds Assessment of Neuropathic Symptoms and Signs, LANSS examination). Secondly, we retrospectively retrieved questionnaires self-completed by adolescents at their initial clinic appointment (S-LANSS self-completed; n = 456, 73% female). Thirdly, we explored relationships between patient-reported outcomes and S-LANSS scores. S-LANSS interview scores varied with pain classification, and S-LANSS self-completed scores were similarly highest with neuropathic pain (median [interquartile range]: 18 [11, 21]) and complex regional pain syndrome (21 [14, 24]), variable with musculoskeletal pain (13 [7, 19]) and lowest with visceral pain (6.5 [2, 11.5]) and headache (8.5 [4, 14]). As in adults, the cutpoint score of 12/24 was optimal. Sensitivity was highest with inclusion of examination findings and lowest with self-completion (LANSS examination vs S-LANSS interview vs S-LANSS self-completed: 86.3% vs 80.8% vs 74.7%), but specificity was relatively low (37.8% vs 36.7% vs 48%). High S-LANSS scores in non-neuropathic groups were associated with female sex and high pain catastrophizing. The S-LANSS is a sensitive screening tool for pain with neuropathic features in adolescents, but needs to be interpreted in the context of clinical evaluation (clinicaltrials.gov NCT03312881). PERSPECTIVE: This article reports high sensitivity of the S-LANSS screening tool for identifying pain with neuropathic features in adolescents with moderate-severe chronic pain. However, as sensitivity is lower than in adult populations, further interdisciplinary evaluation is necessary to inform diagnosis and management.
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Dolor Crónico , Neuralgia , Adulto , Humanos , Femenino , Adolescente , Niño , Masculino , Autoinforme , Dolor Crónico/diagnóstico , Estudios Prospectivos , Estudios Retrospectivos , Dimensión del Dolor/métodos , Neuralgia/diagnóstico , Encuestas y CuestionariosRESUMEN
BACKGROUND: Age and sex differences may exist in the frequency (incidence, prevalence) or symptoms of neuropathic pain (NP) and complex regional pain syndrome (CRPS) due to biopsychosocial factors (eg, neurodevelopment, physiological and hormonal changes, psychosocial differences) that evolve through childhood and adolescence. Age and sex differences may have implications for evaluating screening and diagnostic tools and treatment interventions. OBJECTIVE: To map the existing literature on pediatric NP and CRPS with respect to age and sex distributions, and age and sex differences in symptomology and frequency. METHODS: A scoping literature review was conducted. Databases were searched from inception to January 2023. Data were collected on study design, setting, demographics, and age and sex differences in frequency and symptoms. RESULTS: Eighty-seven studies were included. Distribution of participants with CRPS (n=37 studies) was predominantly early adolescence (10 to 14 y) and female sex, while NP (n=42 studies) was most commonly reported throughout adolescence (10 to 19 y) in both sexes. Forty-one studies examined age and sex differences in frequency; 6 studies reported higher frequency in adolescence. Very few studies (n=11) examined differences in symptomology. DISCUSSION: Large epidemiological studies are required to further understand age and sex differences in frequency of pediatric NP and CRPS. Age and sex differences must be considered when evaluating screening and diagnostic tools and treatment interventions to ensure relevance and validity to both sexes and across ages. Validated tools will improve understanding of age-dependent and sex-dependent differences in symptoms, pathophysiology, and psychosocial impact of pediatric NP and CRPS.
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Síndromes de Dolor Regional Complejo , Neuralgia , Adolescente , Niño , Femenino , Humanos , Masculino , Adulto Joven , Factores de Edad , Síndromes de Dolor Regional Complejo/epidemiología , Síndromes de Dolor Regional Complejo/diagnóstico , Neuralgia/epidemiología , Neuralgia/diagnóstico , Factores SexualesRESUMEN
BACKGROUND: Neuraxial anesthesia is utilized in children of all ages. Local anesthetics produce dose-dependent toxicity in certain adult models, but the developing spinal cord may also be susceptible to drug-induced apoptosis. In postnatal rodents, we examined the effects of intrathecal levobupivacaine on neuropathology and long-term sensorimotor outcomes. METHODS: Postnatal day 3 (P3) or P7 rat pups received intrathecal levobupivacaine 2.5 mg/kg (0.5%) or saline. Mechanical withdrawal thresholds and motor block were assessed. Spinal cord tissue analysis included apoptosis counts (activated caspase-3, Fluoro-Jade C) at 24 h, glial reactivity at 7 days, and histopathology in cord and cauda equina at 24 h and 7 days. Long-term spinal function in young adults (P35) was assessed by hind limb withdrawal thresholds, electromyography responses to suprathreshold stimuli, and gait analysis. RESULTS: Intrathecal levobupivacaine produced spinal anesthesia at P3 and P7. No increase in apoptosis or histopathological change was seen in the cord or cauda equina. In the P3 saline group, activated caspase-3 (mean±SEM per lumbar cord section 6.1±0.3) and Fluoro-Jade C (12.1±1.2) counts were higher than at P7, but were not altered by levobupivacaine (P=0.62 and P=0.11, two-tailed Mann-Whitney test). At P35, mechanical withdrawal thresholds, thermal withdrawal latency, and electromyographic reflex responses did not differ across P3 or P7 levobupivacaine or saline groups (one way ANOVA with Bonferroni comparisons). Intrathecal bupivacaine at P3 did not alter gait. CONCLUSION: Single dose intrathecal levobupivacaine 0.5% did not increase apoptosis or produce spinal toxicity in neonatal rat pups. This study provides preclinical safety data relevant to neonatal use of neuraxial local anesthesia.
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Anestésicos Locales/toxicidad , Enfermedades de la Médula Espinal/inducido químicamente , Anestesia Caudal , Anestésicos Locales/administración & dosificación , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Bupivacaína/administración & dosificación , Bupivacaína/análogos & derivados , Bupivacaína/toxicidad , Proteínas de Unión al Calcio/metabolismo , Caspasa 3/metabolismo , Cauda Equina/patología , Electromiografía , Femenino , Marcha/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Inyecciones Espinales , Levobupivacaína , Proteínas de Microfilamentos/metabolismo , Dimensión del Dolor/efectos de los fármacos , Embarazo , Ratas , Ratas Sprague-Dawley , Médula Espinal/patología , Raíces Nerviosas Espinales/patologíaRESUMEN
Adult brain connectivity is shaped by the balance of sensory inputs in early life. In the case of pain pathways, it is less clear whether nociceptive inputs in infancy can have a lasting influence upon central pain processing and adult pain sensitivity. Here, we show that adult pain responses in the rat are 'primed' by tissue injury in the neonatal period. Rats that experience hind-paw incision injury at 3 days of age, display an increased magnitude and duration of hyperalgesia following incision in adulthood when compared with those with no early life pain experience. This priming of spinal reflex sensitivity was measured by both reductions in behavioural withdrawal thresholds and increased flexor muscle electromyographic responses to graded suprathreshold hind-paw stimuli in the 4 weeks following adult incision. Prior neonatal injury also 'primed' the spinal microglial response to adult injury, resulting in an increased intensity, spatial distribution and duration of ionized calcium-binding adaptor molecule-1-positive microglial reactivity in the dorsal horn. Intrathecal minocycline at the time of adult injury selectively prevented both the hyperalgesia and early microglial reactivity associated with prior neonatal injury. The enhanced neuroimmune response seen in neonatally primed animals could also be demonstrated in the absence of peripheral tissue injury by direct electrical stimulation of tibial nerve fibres, confirming that centrally mediated mechanisms contribute to these long-term effects. These data suggest that early life injury may predispose individuals to enhanced sensitivity to painful events.
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Microglía/fisiología , Neuroinmunomodulación , Neuronas/fisiología , Dolor/fisiopatología , Reflejo/fisiología , Animales , Animales Recién Nacidos , Proteínas de Unión al Calcio/metabolismo , Femenino , Masculino , Proteínas de Microfilamentos/metabolismo , Músculo Esquelético/fisiopatología , Dimensión del Dolor , Umbral del Dolor/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND AND OBJECTIVES: Perioperative pain in children can be effectively managed with systemic opioids, but addition of paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce opioid requirements and potentially improve analgesia and/or reduce adverse effects. METHODS: A systematic literature search was conducted to identify trials evaluating postoperative opioid requirements in children and comparing NSAID and/or paracetamol with placebo. Studies were stratified according to design: continuous availability of intravenous opioid (PCA/NCA) vs intermittent 'as needed' bolus; and single vs multiple dose paracetamol/NSAIDs. Primary outcome data were extracted, and the percentage decrease in mean opioid consumption was calculated for statistically significant reductions compared with placebo. Secondary outcomes included differences in pain intensity, adverse effects (sedation, respiratory depression, postoperative nausea and vomiting, pruritus, urinary retention, bleeding), and patient/parent satisfaction. RESULTS: Thirty-one randomized controlled studies, with 48 active treatment arms compared with placebo, were included. Significant opioid sparing was reported in 38 of 48 active treatment arms, across 21 of the 31 studies. Benefit was most consistently reported when multiple doses of study drug were administered, and 24 h PCA or NCA opioid requirements were assessed. The proportion of positive studies was less with paracetamol, but was influenced by dose and route of administration. Despite availability of opioid for titration, a reduction in pain intensity by NSAIDs and/or paracetamol was reported in 16 of 29 studies. Evidence for clinically significant reductions in opioid-related adverse effects was less robust. CONCLUSION: This systematic review supports addition of NSAIDs and/or paracetamol to systemic opioid for perioperative pain management in children.