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Abstract: In neonates, a noxious stimulus elicits pain-related facial expression changes and distinct brain activity as measured by electroencephalography, but past research has revealed an inconsistent relationship between these responses. Facial activity is the most commonly used index of neonatal pain in clinical settings, with clinical thresholds determining if analgesia should be provided; however, we do not know if these thresholds are associated with differences in how the neonatal brain processes a noxious stimulus. The objective of this study was to examine whether subclinical vs clinically significant levels of pain-related facial activity are related to differences in the pattern of nociceptive brain activity in preterm and term neonates. We recorded whole-head electroencephalography and video in 78 neonates (0-14 days postnatal age) after a clinically required heel lance. Using an optimal constellation of Neonatal Facial Coding System actions (brow bulge, eye squeeze, and nasolabial furrow), we compared the serial network engagement (microstates) between neonates with and without clinically significant pain behaviour. Results revealed a sequence of nociceptive cortical network activation that was independent of pain-related behavior; however, a separate but interleaved sequence of early activity was related to the magnitude of the immediate behavioural response. Importantly, the degree of pain-related behavior is related to how the brain processes a stimulus and not simply the degree of cortical activation. This suggests that neonates who exhibit clinically significant pain behaviours process the stimulus differently and that neonatal pain-related behaviours reflect just a portion of the overall cortical pain response., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Rationale: Implementation of electronic health records may improve the quality, accuracy, timeliness, and availability of documentation. Thus, our institution developed a system that integrated EEG ordering, scheduling, standardized reporting, and billing. Given the importance of user perceptions for successful implementation, we performed a quality improvement study to evaluate electroencephalographer satisfaction with the new EEG report system., Methods: We implemented an EEG report system that was integrated in an electronic health record. In this single-center quality improvement study, we surveyed electroencephalographers regarding overall acceptability, report standardization, workflow efficiency, documentation quality, and fellow education using a 0 to 5 scale (with 5 denoting best)., Results: Eighteen electroencephalographers responded to the survey. The median score for recommending the overall system to a colleague was 5 (range 3-5), which indicated good overall satisfaction and acceptance of the system. The median scores for report standardization (4; 3-5) and workflow efficiency (4.5; 3-5) indicated that respondents perceived the system as useful and easy to use for documentation tasks. The median scores for quality of documentation (4.5; 1-5) and fellow education (4; 1-5) indicated that although most respondents believed the system provided good quality reports and helped with fellow education, a small number of respondents had substantially different views (ratings of 1)., Conclusions: Overall electroencephalographer satisfaction with the new EEG report system was high, as were the scores for perceived usefulness (assessed as standardization, documentation quality, and education) and ease of use (assessed as workflow efficiency). Future study is needed to determine whether implementation yields useful data for clinical research and quality improvement studies or improves EEG report standardization.

There is increasing evidence that long-term outcomes for infants born prematurely are adversely affected by repeated exposure to noxious procedures. These interventions vary widely, for example, in the extent of damage caused and duration. Neonatal intensive care unit (NICU) procedures are therefore likely to each contribute differently to the overall pain burden of individual neonates, ultimately having a different impact on their development. For researchers to quantify the procedural pain burden experienced by infants on NICU, we aimed to estimate the pain severity of common NICU procedures using published pain scores. We extracted pain scores over the first minute (pain reactivity) from the literature, using 59 randomized controlled trials for 15 different procedures. Hierarchical cluster analysis of average pain scores resulted in 5 discrete severity groups; mild (n = 1), mild to moderate (n = 3), moderate (n = 7), severe (n = 3), and very severe (n = 1). The estimate of the severity of individual procedures provided new insight into infant pain reactivity which is not always directly related to the invasiveness and duration of a procedure; thus, both heel lance and skin tape removal are moderately painful procedures. This estimate of procedural pain severity, based on pain reactivity scores, provides a novel platform for retrospective quantification of an individual neonate's pain burden due to NICU procedures. The addition of measures that reflect the recovery from each procedure, such as brain activity and behavioural regulation, would further improve estimates of the pain burden of neonatal intensive care.

Objectives: The education, training, and scope of practice of cardiac ICU advanced practice providers is highly variable. A survey was administered to cardiac ICU advanced practice providers to examine specific variations in orientation format, competency assessment during and at the end of orientation, and scope of clinical practice to determine gaps in resources and need for standardization., Design: This study was a cross-sectional descriptive study utilizing survey responses., Setting: Pediatric cardiac ICUs in the United States., Subjects: The survey was delivered to a convenience sample of advanced practice providers currently practicing in pediatric cardiac ICUs., Interventions: A list of pediatric cardiothoracic surgery programs was generated from the Society of Thoracic Surgery database. A self-administered, electronic survey was delivered via email to advanced practice providers at those institutions. Descriptive data were compared using a chi-square test or Fisher exact test depending on the normalcy of data. Continuous data were compared using a Student t test or Mann-Whitney U test., Measurements and Main Results: Eighty-three of 157 advanced practice providers responded (53% response rate, representing 36 institutions [35% of institutions]). Sixty-five percent of respondents started as new graduates. Ninety-three to one-hundred percent obtain a history and physical, order/interpret laboratory, develop management plans, order/titrate medications, and respiratory support. Ability to perform invasive procedures was highly variable but more likely for those in a dedicated cardiac ICU. Seventy-seven percent were oriented by another advanced practice provider, with a duration of orientation less than 4 months (66%). Fifty percent of advanced practice providers had no guidelines in place to guide learning/competency during orientation. Sixty-seven percent were not evaluated in any way on their knowledge or skills during or at the end of orientation. Orientation was rated as poor/fair by the majority of respondents for electrophysiology (58%) and echocardiography (69%). Seventy-one percent rated orientation as moderately effective or less. Respondents stated they would benefit from more structured didactic education with clear objectives, standardized management guidelines, and more simulation/procedural practice. Eighty-five percent were very/extremely supportive of a standardized cardiac ICU advanced practice provider curriculum., Conclusions: Orientation for cardiac ICU advanced practice providers is highly variable, content depends on the institution/preceptor, and competency is not objectively defined or measured. A cardiac ICU advanced practice provider curriculum is needed to standardize education and promote the highest level of advanced practice provider practice.

Objectives: The Low Risk Ankle Rule (LRAR) can assist pediatric emergency department providers in reducing radiographs without missing significant fractures. Most providers are unaware of this tool. This study sought to educate providers about the LRAR then determine their self-reported use immediately and 2 months after education., Methods: A web-based survey was e-mailed to providers at one large pediatric emergency department. The survey assessed knowledge and use of the rule. Clinical scenarios, in which radiographs were not indicated, helped determine radiograph ordering practices. After a brief LRAR tutorial, respondents were requeried about radiograph ordering practices along with likelihood of future LRAR use. At 2 months, radiograph ordering was again assessed using the same scenarios; interim LRAR use was also determined., Results: Response rates on the initial and follow-up surveys were 61.4% and 96.2%, respectively. A minority (20%) had heard of the LRAR. Providers initially reported ordering radiographs on 84% of ankle injuries and 82.5% ordered radiographs in the scenario. Immediately after education, only 32% ordered a radiograph in the scenario; 85% reported that they would use the tool consistently. At 2 months, there was no significant change in radiograph ordering practices (79.5% vs 84%). In the interim, 30% reported using the rule at least once., Conclusions: Most pediatric emergency department providers were unfamiliar with the LRAR. After a brief tutorial, most providers reported that planning to use the tool and self-reported radiograph ordering was significantly reduced; however, at 2 months, clinical practice was unaffected. Further work to implement the tool into practice is necessary.

Background and Purpose- We aimed to evaluate the effectiveness of an intervention to improve triage, treatment, and transfer for patients with acute stroke admitted to the emergency department (ED). Methods- A pragmatic, blinded, multicenter, parallel group, cluster randomized controlled trial was conducted between July 2013 and September 2016 in 26 Australian EDs with stroke units and tPA (tissue-type plasminogen activator) protocols. Hospitals, stratified by state and tPA volume, were randomized 1:1 to intervention or usual care by an independent statistician. Eligible ED patients had acute stroke <48 hours from symptom onset and were admitted to the stroke unit via ED. Our nurse-initiated T 3 intervention targeted (1) Triage to Australasian Triage Scale category 1 or 2; (2) Treatment: tPA eligibility screening and appropriate administration; clinical protocols for managing fever, hyperglycemia, and swallowing; (3) prompt (<4 hours) stroke unit Transfer. It was implemented using (1) workshops to identify barriers and solutions; (2) face-to-face, online, and written education; (3) national and local clinical opinion leaders; and (4) email, telephone, and site visit follow-up. Outcomes were assessed at the patient level. Primary outcome: 90-day death or dependency (modified Rankin Scale score of ≥2); secondary outcomes: functional dependency (Barthel Index ≥95), health status (Short Form [36] Health Survey), and ED quality of care (Australasian Triage Scale; monitoring and management of tPA, fever, hyperglycemia, swallowing; prompt transfer). Intention-to-treat analysis adjusted for preintervention outcomes and ED clustering. Patients, outcome assessors, and statisticians were masked to group allocation. Results- Twenty-six EDs (13 intervention and 13 control) recruited 2242 patients (645 preintervention and 1597 postintervention). There were no statistically significant differences at follow-up for 90-day modified Rankin Scale (intervention: n=400 [53.5%]; control n=266 [48.7%]; P =0.24) or secondary outcomes. Conclusions- This evidence-based, theory-informed implementation trial, previously effective in stroke units, did not change patient outcomes or clinician behavior in the complex ED environment. Implementation trials are warranted to evaluate alternative approaches for improving ED stroke care. Clinical Trial Registration- URL: http://www.anzctr.org.au. Unique identifier: ACTRN12614000939695.

Background: Attention deficit hyperactivity disorder (ADHD) is associated with impulsive behavior and inattention, making it a potential risk factor for sport-related concussion (SRC). The objectives of this study were to determine whether ADHD is an antecedent risk factor for SRC and whether ADHD complicates recovery from SRC in youth athletes., Methods: Student athletes with a history of SRC were evaluated for the presence of ADHD using diagnostic interview and to determine whether ADHD symptoms began before or after SRC. Concussion-specific measures of concussive symptoms and cognitive function were compared in SRC + ADHD and SRC + No ADHD groups to assess SRC recovery between groups., Results: ADHD was overrepresented in youth with SRC compared with population rates. ADHD was found to be an antecedent risk factor for SRC, with age at ADHD onset earlier than the date of SRC. Student athletes with SRC and ADHD reported more concussive symptoms compared with athletes without ADHD and were more likely to have a history of greater than one concussion., Conclusions: The results of this study support our hypothesis that ADHD is an antecedent risk factor for SRC and may contribute to a more complicated course of recovery from SRC. Future research should focus on determining whether screening, diagnosis, and treating ADHD in youth athletes may prevent SRC. Providers that care for youth athletes with ADHD should be aware of the vulnerabilities of this population toward SRC and its complications.

Noxious stimulation at critical stages of development has long-term consequences on somatosensory processing in later life, but it is not known whether this developmental plasticity is restricted to nociceptive pathways. Here, we investigate the effect of repeated neonatal noxious or innocuous hind paw stimulation on adult spinal dorsal horn cutaneous mechanical sensitivity. Neonatal Sprague-Dawley rats of both sexes received 4 unilateral left hind paw needle pricks (NPs, n = 13) or 4 tactile (cotton swab touch) stimuli, per day (TC, n = 11) for the first 7 days of life. Control pups were left undisturbed (n = 17). When adult (6-8 weeks), lumbar wide-dynamic-range neuron activity in laminae III-V was recorded using in vivo extracellular single-unit electrophysiology. Spike activity evoked by cutaneous dynamic tactile (brush), pinch and punctate (von Frey hair) stimulation, and plantar receptive field areas were recorded, at baseline and 2 and 5 days after left plantar hind paw incision. Baseline brush receptive fields, von Frey hair, and pinch sensitivity were significantly enhanced in adult NP and TC animals compared with undisturbed controls, although effects were greatest in NP rats. After incision, injury sensitivity of adult wide-dynamic-range neurons to both noxious and dynamic tactile hypersensitivity was significantly greater in NP animals compared with TC and undisturbed controls. We conclude that both repeated touch and needle-prick stimulation in the neonatal period can alter adult spinal sensory neuron sensitivity to both innocuous and noxious mechanical stimulation. Thus, spinal sensory circuits underlying touch and pain processing are shaped by a range of early-life somatosensory experiences.

Purpose: We aimed to determine whether conventional standardized EEG features could be consolidated into a more limited number of factors and whether the derived factor scores changed during the acute period after pediatric cardiac arrest., Methods: Children resuscitated after cardiac arrest underwent conventional continuous EEG monitoring. The EEG was scored in 12-hour epochs for up to 72-hours after return of circulation by an electroencephalographer using standardized critical care EEG terminology. We performed a polychoric factor analysis to determine whether numerous observed EEG features could be represented by a smaller number of derived factors. Linear mixed-effects regression models and heat maps evaluated whether the factor scores remained stable across epochs., Results: We performed EEG monitoring in 89 consecutive children, which yielded 453 EEG segments. We identified two factors, which were not correlated. The background features were factor loaded with the features continuity, voltage, and frequency. The intermittent features were factor loaded with the features of seizures, periodic patterns, and interictal discharges. Factor scores were calculated for each EEG segment. Linear, mixed-effect, regression results indicated that the factor scores did not change over time for the background features factor (coefficient, 0.18; 95% confidence interval, 0.04-0.07; P = 0.52) or the intermittent features factor (coefficient, -0.003; 95% confidence interval, -0.02 to 0.01; P = 0.70). However, heat maps showed that some individual subjects did experience factor score changes over time, particularly if they had medium initial factor scores., Conclusions: Subsequent studies assessing whether EEG is informative for neurobehavioral outcomes after pediatric cardiac arrest could combine numerous EEG features into two factors, each reflecting multiple background and intermittent features. Furthermore, the factor scores would be expected to remain stable during the acute period for most subjects.

Objective: Abdominal aortic aneurysms are inflammatory in nature and are associated with some risk factors that also lead to atherosclerotic occlusive disease, most notably smoking. The purpose of our study was to identify differential cytokine expression in patients with abdominal aortic aneurysm and those with atherosclerotic occlusive disease. Based on this analysis, we further explored and compared the mechanism of action of IL (interleukin)-1β versus TNF-α (tumor necrosis factor-α) in abdominal aortic aneurysm formation., Approach and Results: IL-1β was differentially expressed in human plasma with lower levels detected in patients with abdominal aortic aneurysm compared with matched atherosclerotic controls. We further explored its mechanism of action using a murine model and cell culture. Genetic deletion of IL-1β and IL-1R did not inhibit aneurysm formation or decrease MMP (matrix metalloproteinase) expression. The effects of IL-1β deletion on M1 macrophage polarization were compared with another proinflammatory cytokine, TNF-α. Bone marrow-derived macrophages from IL-1β -/- and TNF-α -/- mice were polarized to an M1 phenotype. TNF-α deletion, but not IL-1β deletion, inhibited M1 macrophage polarization. Infusion of M1 polarized TNF-α -/- macrophages inhibited aortic diameter growth; no inhibitory effect was seen in mice infused with M1 polarized IL-1β -/- macrophages., Conclusions: Although IL-1β is a proinflammatory cytokine, its effects on aneurysm formation and macrophage polarization differ from TNF-α. The differential effects of IL-1β and TNF-α inhibition are related to M1/M2 macrophage polarization and this may account for the differences in clinical efficacy of IL-1β and TNF-α antibody therapies in management of inflammatory diseases., (© 2017 American Heart Association, Inc.)

Purpose: We evaluated interrater agreement of EEG interpretation in a cohort of critically ill children resuscitated after cardiac arrest using standardized EEG terminology., Methods: Four pediatric electroencephalographers scored 10-minute EEG segments from 72 consecutive children obtained 24 hours after return of circulation using the American Clinical Neurophysiology Society's (ACNS) Standardized Critical Care EEG terminology. The percent of perfect agreement and the kappa coefficient were calculated for each of the standardized EEG variables and a predetermined composite EEG background category., Results: The overall background category (normal, slow-disorganized, discontinuous, or attenuated-featureless) had almost perfect agreement (kappa 0.89).The ACNS Standardized Critical Care EEG variables had agreement that was (1) almost perfect for the seizures variable (kappa 0.93), (2) substantial for the continuity (kappa 0.79), voltage (kappa 0.70), and sleep transient (kappa 0.65) variables, (3) moderate for the rhythmic or periodic patterns (kappa 0.55) and interictal epileptiform discharge (kappa 0.60) variables, and (4) fair for the predominant frequency (kappa 0.23) and symmetry (kappa 0.31) variables. Condensing variable options led to improved agreement for the continuity and voltage variables., Conclusions: These data support the use of the standardized terminology and the composite overall background category as a basis for standardized EEG interpretation for subsequent studies assessing EEG background for neuroprognostication after pediatric cardiac arrest.

Objective: To describe the long-term outcomes of major trauma patients and factors associated with the rate of recovery., Background: As injury-related mortality decreases, there is increased focus on improving the quality of survival and reducing nonfatal injury burden., Methods: Adult major trauma survivors to discharge, injured between July 2007 and June 2012 in Victoria, Australia, were followed up at 6, 12, and 24 months after injury to measure function (Glasgow Outcome Scale-Extended) and return to work/study. Random-effects regression models were fitted to identify predictors of outcome and differences in the rate of change in each outcome between patient subgroups., Results: Among the 8844 survivors, 8128 (92%) were followed up. Also, 23% had achieved a good functional recovery, and 70% had returned to work/study at 24 months. The adjusted odds of reporting better function at 12 months was 27% (adjusted odds ratio 1.27, 95% confidence interval [CI] 1.19-1.36) higher compared with 6 months, and 9% (adjusted odds ratio 1.09, 95% CI, 1.02-1.17) higher at 24 months compared with 12 months. The adjusted relative risk (RR) of returning to work was 14% higher at 12 months compared with 6 months (adjusted RR 1.14, 95% CI, 1.12-1.16) and 8% (adjusted RR 1.08, 95% CI, 1.06-1.10) higher at 24 months compared with 12 months., Conclusions: Improvement in outcomes over the study period was observed, although ongoing disability was common at 24 months. Recovery trajectories differed by patient characteristics, providing valuable information for informing prognostication and service planning, and improving our understanding of the burden of nonfatal injury.

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.

The rostroventral medial medulla (RVM) is part of a rapidly acting spino-bulbo-spinal loop that is activated by ascending nociceptive inputs and drives descending feedback modulation of spinal nociception. In the adult rat, the RVM can facilitate or inhibit dorsal horn neuron inputs but in young animals descending facilitation dominates. It is not known whether this early life facilitation is part of a feedback loop. We hypothesized that the newborn RVM functions independently of sensory input, before the maturation of feedback control. We show here that noxious hind paw pinch evokes no fos activation in the RVM or the periaqueductal gray at postnatal day (P) 4 or P8, indicating a lack of nociceptive input at these ages. Significant fos activation was evident at P12, P21, and in adults. Furthermore, direct excitation of RVM neurons with microinjection of DL-homocysteic acid did not alter the net activity of dorsal horn neurons at P10, suggesting an absence of glutamatergic drive, whereas the same injections caused significant facilitation at P21. In contrast, silencing RVM neurons at P8 with microinjection of lidocaine inhibited dorsal horn neuron activity, indicating a tonic descending spinal facilitation from the RVM at this age. The results support the hypothesis that early life descending facilitation of spinal nociception is independent of sensory input. Since it is not altered by RVM glutamatergic receptor activation, it is likely generated by spontaneous brainstem activity. Only later in postnatal life can this descending activity be modulated by ascending nociceptive inputs in a functional spinal-bulbo-spinal loop.

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.

Introduction: Pediatric emergencies require effective teamwork. These skills are developed and demonstrated in actual emergencies and in simulated environments, including simulation centers (in center) and the real care environment (in situ). Our aims were to compare teamwork performance across these settings and to identify perceived educational strengths and weaknesses between simulated settings. We hypothesized that teamwork performance in actual emergencies and in situ simulations would be higher than for in-center simulations., Methods: A retrospective, video-based assessment of teamwork was performed in an academic, pediatric level 1 trauma center, using the Team Emergency Assessment Measure (TEAM) tool (range, 0-44) among emergency department providers (physicians, nurses, respiratory therapists, paramedics, patient care assistants, and pharmacists). A survey-based, cross-sectional assessment was conducted to determine provider perceptions regarding simulation training., Results: One hundred thirty-two videos, 44 from each setting, were reviewed. Mean total TEAM scores were similar and high in all settings (31.2 actual, 31.1 in situ, and 32.3 in-center, P = 0.39). Of 236 providers, 154 (65%) responded to the survey. For teamwork training, in situ simulation was considered more realistic (59% vs. 10%) and more effective (45% vs. 15%) than in-center simulation., Discussion: In a video-based study in an academic pediatric institution, ratings of teamwork were relatively high among actual resuscitations and 2 simulation settings, substantiating the influence of simulation-based training on instilling a culture of communication and teamwork. On the basis of survey results, providers favored the in situ setting for teamwork training and suggested an expansion of our existing in situ program.

Inoculation is one of the first and most common experiences of procedural pain in infancy. However, little is known about how needle puncture pain is processed by the central nervous system in children. In this study, we describe for the first time the event-related activity in the infant brain during routine inoculation using electroencephalography. Fifteen healthy term-born infants aged 1 to 2 months (n = 12) or 12 months (n = 5) were studied in an outpatient clinic. Pain behavior was scored using the Modified Behavioral Pain Scale. A distinct inoculation event-related vertex potential, consisting of 2 late negative-positive complexes, was observable in single trials after needle contact with the skin. The amplitude of both negative-positive components was significantly greater in the 12-month group. Both inoculation event-related potential amplitude and behavioral pain scores increased with age but the 2 measures were not correlated with each other. These components are the first recordings of brain activity in response to real-life needle pain in infants up to a year old. They provide new evidence of postnatal nociceptive processing and, combined with more traditional behavioral pain scores, offer a potentially more sensitive measure for testing the efficacy of analgesic protocols in this age group.

Objectives: Levels of stool fatty acid soaps and beneficial bacteria differ between formula-fed and breast-fed infants; addition of specific formula ingredients may reduce these differences. This study evaluated the effects of a term infant formula containing high sn-2 palmitate term infant formula (sn-2) or an identical formula supplemented with oligofructose (OF) at 2 concentrations (sn-2+3 g/L OF, sn-2+5 g/L OF) on stool composition, stool characteristics, and fecal bifidobacteria., Methods: Healthy, term formula-fed infants 7 to 14 days old (n = 300) were randomized in a double-blind manner to receive standard formula (control), sn-2, sn-2+3 g/L OF, or sn-2+5 g/L OF for 8 weeks. Human milk (HM)-fed infants (n = 75) were studied in parallel. Stool samples were collected from all subjects at week 8 for fatty acid soaps and mineral content, and from a subset at baseline and week 8 for bifidobacteria. Stool characteristics were assessed via 3-day diary., Results: The sn-2 group had 46% less stool soap palmitate (P < 0.001) and softer stools than control (20% more mushy soft stools, P = 0.026; 50% fewer formed stools, P = 0.003). Addition of OF resulted in even fewer formed stools versus control (65% fewer for sn-2+3 g/L OF, 79% fewer for sn-2+5 g/L OF), with 5 g/L OF more closely resembling that of HM-fed infants. Both sn-2 (P < 0.05) and sn-2 with OF groups (P < 0.01) had significantly higher fecal bifidobacteria concentrations than control at week 8, not differing from HM-fed infants., Conclusions: High sn-2-palmitate formulas led to reduced stool soaps, softer stools, and increased bifidobacteria, whereas addition of OF further improved stool consistency. Those modifications brought outcomes in formula-fed infants closer to that in HM-fed infants.

Purpose: Pulmonary embolism (PE) is a significant cause of morbidity and mortality. The clinical diagnosis of PE can be quite challenging, necessitating a systematic, evidence-based, and cost-effective approach., Materials and Methods: A sensitive search strategy using keywords associated with PE diagnosis and economic evaluation was conducted. The libraries searched included MEDLINE, EMBASE, Health Technology Assessments, NHS Economic Evaluation Database, and the Cochrane Central Register of Clinical Trials. Studies were required to be a model-based cost-effectiveness analysis (CEA) for PE diagnosis. To be included, studies had to have evaluated both the cost and effectiveness of diagnostic algorithms. In addition, computed tomography (CT) had to have been a component in at least 1 possible algorithm. The characteristics of each CEA were extracted. In addition, the characteristics of CT pulmonary angiography were extracted (sensitivity, specificity, and cost). The most cost-effective strategy and its comparator were presented with the corresponding incremental cost-effectiveness ratio., Results: Thirteen studies met our inclusion criteria. Costs were obtained using a variety of methods. Most studies measured effectiveness using a metric of survival, whereas 3 studies used quality-adjusted life years. Studies varied considerably in terms of the quality of economic evaluation. All but 1 study reported that computed tomographic pulmonary angiography (CTPA)-typically combined with ultrasound or D-dimer-was part of the most cost-effective algorithm., Conclusions: CEA is a useful tool for evaluating potential algorithms for PE diagnosis. Future CEAs would do well to include the use of magnetic resonance angiography and the potential for alternate diagnoses in diagnostic algorithms.

Neurotrophin-3 (NT-3) is a target-derived neurotrophic factor that regulates sensory neuronal survival and growth. Here we report that NT-3 plays a critical permissive role in cutaneous sensory nerve sprouting that contributes to pain and sensitivity following skin wounding in young animals. Sensory terminal sprouting in neonatally wounded dermis and epidermis is accompanied by increased NT-3 transcription, NT-3 protein levels, and NT-3 protein release 3-7 days post skin injury in newborn rats and mice. Functional blockade of NT-3 activity with specific antibodies greatly reduces sensory neurite outgrowth induced by wounded skin, but not by naïve skin, in dorsal root ganglion/skin co-cultures. The requirement for NT-3 for sensory terminal sprouting in vivo is confirmed by the absence of wound-induced hyperinnervation in heterozygous transgenic mice (NT-3(+/-)lacZ). We conclude that upregulation of NT-3 in neonatally wounded skin is a critical factor mediating the sensory nerve sprouting that underlies hypersensitivity and pain following skin injury., (Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

We have previously shown that the balance of electrically evoked descending brainstem control of spinal nociceptive reflexes undergoes a switch from excitation to inhibition in preadolescent rats. Here we show that the same developmental switch occurs when μ-opioid receptor agonists are microinjected into the rostroventral medulla (RVM). Microinjections of the μ-opioid receptor agonist [D-Ala(2), N-MePhe(4), Gly-ol]-enkephalin (DAMGO) into the RVM of lightly anaesthetised adult rats produced a dose-dependent decrease in mechanical nociceptive hindlimb reflex electromyographic activity. However, in preadolescent (postnatal day 21 [P21]) rats, the same doses of DAMGO produced reflex facilitation. RVM microinjection of δ-opioid receptor or GABA(A) receptor agonists, on the other hand, caused reflex depression at both ages. The μ-opioid receptor-mediated descending facilitation is tonically active in naive preadolescent rats, as microinjection of the μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) into the RVM at this age decreases spinal nociceptive reflexes while having no effect in adults. To test whether tonic opioid central activity is required for the preadolescent switch in RVM descending control, naloxone hydrochloride was delivered continuously from subcutaneous osmotic mini-pumps for 7-day periods, at various postnatal stages. Blockade of tonic opioidergic activity from P21 to P28, but not at earlier or later ages, prevented the normal development of descending RVM inhibitory control of spinal nociceptive reflexes. Enhancing opioidergic activity with chronic morphine over P7 to P14 accelerated this development. These results show that descending facilitation of spinal nociception in young animals is mediated by μ-opioid receptor pathways in the RVM. Furthermore, the developmental transition from RVM descending facilitation to inhibition of pain is determined by activity in central opioid networks at a critical period of periadolescence., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Objectives: 'Massive' transfusion is a poorly defined inclusion criteria for studies examining the blood and blood product that are used during trauma resuscitation. We aimed to compare the traditional definition of massive transfusion (≥10 units in 24 h) to a more acute definition of at least 5 units in 4 h., Methods: Multitrauma patients were subgrouped according to the traditional definition and compared with the acute definition. Demographics, presenting vital signs and blood results, management including transfusion practice and outcomes were retrospectively studied. Associations of transfused fresh frozen plasma:packed red blood cells (PRBC) ratios with mortality were studied., Results: There were 927 patients who received PRBCs in the first 24 h, with 314 patients identified using the traditional definition and 303 patients using the acute definition. The patients identified using the traditional definition received 18 (12-29) units of PRBC in 24 h, significantly higher than those identified using the acute definition [15 (9-29) units, P<0.001]. The traditional definition excluded a significant proportion of patients who died in the emergency department. By using the acute definition to select a study sample, there seems to be an increase in mortality with fresh frozen plasma:PRBC ratio of 1 : 1 ratio compared with a 1 : 2 ratio., Conclusion: The traditional 'massive' transfusion definition not only 'dilutes' the potential study samples with a less acute group of patients, but also further excludes patients who die early. This latter group is most likely to be benefitted from any change to resuscitation practice. An acute definition of massive transfusion should be adopted when examining clinical practice during initial trauma resuscitation.

Objective: To determine whether paramedic rapid sequence intubation in patients with severe traumatic brain injury (TBI) improves neurologic outcomes at 6 months compared with intubation in the hospital., Background: Severe TBI is associated with a high rate of mortality and long-term morbidity. Comatose patients with TBI routinely undergo endo-tracheal intubation to protect the airway, prevent hypoxia, and control ventilation. In many places, paramedics perform intubation prior to hospital arrival. However, it is unknown whether this approach improves outcomes., Methods: In a prospective, randomized, controlled trial, we assigned adults with severe TBI in an urban setting to either prehospital rapid sequence intubation by paramedics or transport to a hospital emergency department for intubation by physicians. The primary outcome measure was the median extended Glasgow Outcome Scale (GOSe) score at 6 months. Secondary end-points were favorable versus unfavorable outcome at 6 months, length of intensive care and hospital stay, and survival to hospital discharge., Results: A total of 312 patients with severe TBI were randomly assigned to paramedic rapid sequence intubation or hospital intubation. The success rate for paramedic intubation was 97%. At 6 months, the median GOSe score was 5 (interquartile range, 1-6) in patients intubated by paramedics compared with 3 (interquartile range, 1-6) in the patients intubated at hospital (P = 0.28).The proportion of patients with favorable outcome (GOSe, 5-8) was 80 of 157 patients (51%) in the paramedic intubation group compared with 56 of 142 patients (39%) in the hospital intubation group (risk ratio, 1.28; 95% confidence interval, 1.00-1.64; P = 0.046). There were no differences in intensive care or hospital length of stay, or in survival to hospital discharge., Conclusions: In adults with severe TBI, prehospital rapid sequence intubation by paramedics increases the rate of favorable neurologic outcome at 6 months compared with intubation in the hospital.

Pain in early life can enhance the response to subsequent injury, but effects are influenced by both the nature and timing of neonatal injury. Using plantar hindpaw incision, we investigated how postnatal age influences the response to repeat surgical injury two weeks later. The degree and time course of behavioural changes in mechanical withdrawal threshold were measured, and injury-related hyperalgesia was further quantified by flexion reflex electromyographic responses to suprathreshold mechanical stimuli 24 h following incision. Plantar hindpaw incision produces acute mechanical hyperalgesia in neonatal and adult rats, but incision in neonatal pups has an additional effect on the response to subsequent injury. With initial incision at postnatal day (P) 3 or 6, the degree of hyperalgesia following repeat incision 2 weeks later was greater than in animals having a single incision at the same age. At older ages (initial incision at P10, P21 or P40) responses did not differ in repeat and single incision groups. To test the role of primary afferent activity, levobupivacaine sciatic block was performed prior to P6 plantar incision, and controls received saline or subcutaneous levobupivacaine. Repeat peri-operative, but not a single pre-operative sciatic block, prevented the enhanced response to repeat incision two weeks later. Our results show that the first postnatal week represents a critical period when incision increases hyperalgesia following repeat surgery two weeks later, and effects are initiated by peripheral afferent activity. This has potential therapeutic implications for the type and duration of peri-operative analgesia used for neonatal surgery.

Change in facial expression over a fixed time after a noxious stimulus is the key measure used to calculate pain scores in preterm and newborn infants. We hypothesised that the latency of facial motor responses would be longer in the youngest premature infants and that behavioural scoring methods of pain may need to take this into account. One hundred and seventy-two clinically required heel lances were performed in 95 infants from 25 to 44 weeks postmenstrual age (PMA). Sixty-four percentage of the heel lances evoked a change in facial expression. Change in facial expression was observed in infants across the whole age range from 25 weeks PMA and the latency to the facial expression response ranged from 1 to 17s. Latency to facial expression change was dependent on the infants' PMA at the time of the heel lance. Infants below 32 weeks PMA had a significantly longer latency to change in facial expression than older infants (54% increase in infants below 32 weeks; p < 0.001). Sleep state and presence of brain damage (IVH grades 1-4) did not significantly increase the latency (p > 0.05 for each variable). Intravenous morphine at the time of the heel lance significantly increased the latency to facial expression response (p < 0.001) but the analysis shows that latency is highly dependent on PMA independent of morphine administration. These findings highlight developmental changes underlying infant behaviour that are critically important if pain scores are to be correctly interpreted.

Background: Serial cast correction by using the Cotrel derotation technique is one of several potential treatments for progressive infantile scoliosis. This study reviews our early experience to identify which, if any, patients are likely to benefit from or fail this technique., Methods: We followed all patients treated at our institutions for progressive infantile scoliosis since 2003 prospectively at 1 institution and retrospectively at the other 2. Data, including etiology, Cobb angles, rib vertebral angle difference, Moe-Nash rotation, and space available for the lung, were recorded over time., Results: Fifty-five patients with progressive infantile scoliosis had more than 1 year of follow-up from the initiation of casting. The diagnosis of progressive scoliosis was made based upon either a progressive Cobb angle or a rib vertebral angle difference of more than 20 degrees at presentation. All but 6 patients responded to cast correction. Nine patients have undergone surgery to date, 6 because of worsening and 3 by parent choice. As shown in the table, initiation of cast correction at a younger age, moderate curve size (<60 degrees), and an idiopathic diagnosis carry a better prognosis than an older age of initiation, curve >60 degrees, and a nonidiopathic diagnosis. The space available for the lung improved from 0.89 to 0.93. No patient experienced worsening of rib deformities., Conclusions: Serial cast correction for infantile scoliosis often results in full correction in infants with idiopathic curves less than 60 degrees if started before 20 months of age. Cast correction for older patients with larger curves or nonidiopathic diagnosis still frequently results in curve improvement along with improvement in chest and body shape., Significance: Derotational cast correction seems to play a role in the treatment of progressive infantile scoliosis with cures in young patients and reductions in curve size with a delay in surgery in older and syndromic patients., Level of Evidence: Level 4, therapeutic study.

The sensitization of spinal dorsal horn neurones leads to prolonged enhancement of pain behaviour and can be evoked by intense C-fibre stimulation, tissue inflammation and peripheral nerve injury. Activation of central immune cells plays a key role in establishing pain hypersensitivity but the exact nature of the afferent input that triggers the activation of microglia and other glial cells within the CNS, remains unclear. Here intense but non-damaging, electrical stimulation of intact adult rat C-fibres for 5 min at 10 Hz induced central sensitization characterized by significant decreases in mechanical withdrawal thresholds 3, 24 and 48 h later. This maintained (>3 h) hypersensitivity was not observed following topical skin application of capsaicin. C-fibre evoked sensitization was accompanied by significant microglial activation, shown by increased Iba-1 immunoreactivity throughout the dorsal horn at 24 and 48 h and significant upregulation of markers of microglial activation: IL-6 and Mcp-1 at 3h and Mmp3, CSF-1 and CD163 at 24 and 48 h. C-fibre stimulation caused no nerve damage at ultrastructural and molecular levels. Lower intensity stimulation that did not activate C-fibres or sham stimulation did not increase Iba-1 immunoreactivity or induce behavioural sensitivity. Pre-treatment with minocycline (40 mg/kg, i.p.) prevented the C-fibre evoked sensitization and microglial activation. Identical C-fibre stimulation in 10-day old rat pups failed to activate microglia or change behaviour. These results demonstrate that a brief period of low frequency C-fibre stimulation, in the absence of nerve damage, is sufficient to activate microglia resulting in behavioural hyperalgesia.

Alterations in neural activity due to pain and injury in early development may produce long-term effects on sensory processing and future responses to pain. To investigate persistent alterations in sensory perception, we performed quantitative sensory testing (QST) in extremely preterm (EP) children (n=43) recruited from the UK EPICure cohort (born less than 26 weeks gestation in 1995) and in age and sex matched term-born controls (TC; n=44). EP children had a generalized decreased sensitivity to all thermal modalities, but no difference in mechanical sensitivity at the thenar eminence. EP children who also required neonatal surgery had more marked thermal hypoalgesia, but did not differ from non-surgical EP children in the measures of neonatal brain injury or current cognitive ability. Adjacent to neonatal thoracotomy scars there was a localized decrease in both thermal and mechanical sensitivity that differed from EP children with scars relating to less invasive procedural interventions or from those without scars. No relationship was found between sensory perception thresholds and current pain experience or pain coping styles in EP or TC children. Neonatal care and surgery in EP children are associated with persistent modality-specific changes in sensory processing. Decreases in mechanical and thermal sensitivity adjacent to scars may be related to localized tissue injury, whereas generalized decreases in thermal sensitivity but not in mechanical sensitivity suggest centrally mediated alterations in the modulation of C-fibre nociceptor pathways, which may impact on responses to future pain or surgery.

Background: Pain behavior in response to skin incision is developmentally regulated, but little is known about the underlying neuronal mechanisms. The authors hypothesize that the spatial activation and intensity of dorsal horn neuron responses to skin incision differ in immature and adult spinal cord., Methods: Single wide-dynamic-range dorsal horn cell spike activity was recorded for a minimum of 2 h from anesthetized rat pups aged 7 and 28 days. Cutaneous pinch and brush receptive fields were mapped and von Frey hair thresholds were determined on the plantar hind paw before and 1 h after a skin incision was made., Results: Baseline receptive field areas for brush and pinch were larger and von Frey thresholds lower in the younger animals. One hour after the incision, brush and pinch receptive field area, spontaneous firing, and evoked spike activity had significantly increased in the 7-day-old animals but not in the 28-day-old animals. Von Frey hair thresholds decreased at both ages., Conclusions: Continuous recording from single dorsal horn cells both before and after injury shows that sensitization of receptive fields and of background and afferent-evoked spike activity at 1 h is greater in younger animals. This difference is not reflected in von Frey mechanical thresholds. These results highlight the importance of studying the effects of injury on sensory neuron physiology. Injury in young animals induces a marked and rapid increase in afferent-evoked activity in second-order sensory neurons, which may be important when considering long-term effects and analgesic interventions.

Background: The significant postnatal maturation of gamma-aminobutyric acid signaling in the developing brain is likely to have important implications for infant pain processing. Gamma-aminobutyric acid receptor activation evokes analgesia and sedation in the adult, but the impact of immature gamma-aminobutyric acid signaling on modulators of the gamma-aminobutyric acid type A receptor, such as the benzodiazepines, is not known in infants., Methods: Nociceptive processing was measured using behavioral and electrophysiological recordings of hind limb flexor withdrawal threshold and magnitude to mechanical and thermal stimulation of the hind paw. The effects of midazolam (0.1-10 mg/kg subcutaneously, 0.1 mg/kg intrathecally) or saline treatment were compared in rats aged 3, 10, 21, and 40 days (adult). The sedative action of midazolam was assessed at each age using righting reflex latencies., Results: Midazolam dose-dependently decreased mechanical reflex thresholds and increased mechanical and thermal reflex magnitudes in neonates. In older rat pups and adults, midazolam had the reverse effect, increasing thresholds and decreasing reflex magnitude. These differences were mediated supraspinally; intrathecal administration of midazolam did not affect flexion reflexes at any age. Midazolam had no sedative action in the youngest rats; sedation increased gradually through postnatal development., Conclusions: The results show a striking reversal in the effects of midazolam on nociception and sedation in rats between postnatal days 3 and 10. Midazolam fails to sedate young rats and sensitizes their flexor reflex activity. The sedative and desensitizing effects of midazolam are not observed until later in life after maturation in supraspinal centers. The results indicate a need to better understand the pharmacology of drugs used routinely in neonatal intensive care.

Neuropathic pain behaviour is not observed in neonatal rats and tactile allodynia does not develop in the spared nerve injury (SNI) model until rats are 4 weeks of age at the time of surgery. Since activated spinal microglia are known to play a key role in neuropathic pain, we have investigated whether the microglial response to nerve injury in young rats differs from that in adults. Here we show that dorsal horn microglial activation, visualised with IBA-1 immunostaining, is significantly less in postnatal day (P) 10 rat pups than in adults, 7 days after SNI. This was confirmed by qPCR analysis of IBA-1 mRNA and mRNA of other microglial markers, integrin-alpha M, MHC-II DMalpha and MHC-II DMbeta. Dorsal horn IBA-1+ve microglia could be activated, however, by intraspinal injections of lipopolysaccharide (LPS) or N-methyl-d-aspartate (NMDA) at P10, although the increase in the levels of mRNA for all microglial markers was less than in the adult rat. In addition, P10 rats developed a small but significant mechanical allodynia in response to intrathecal LPS. Intrathecal injection of cultured ATP-activated microglia, known to cause mechanical allodynia in adult rats, had no behavioural effect at P10 and only began to cause allodynia if injections were performed at P16. The results clearly demonstrate immaturity of the microglial response triggered by nerve injury in the first postnatal weeks which may explain the absence of tactile allodynia following peripheral nerve injury in young rats.

Noxious C-fibre stimulation produces increased sensitivity within the injured area (primary hyperalgesia), and a surrounding zone of secondary hyperalgesia. As significant changes in nociceptive processing occur during development, we compared C-fibre induced primary and secondary hyperalgesia in rat pups aged 3, 10 and 21 postnatal (P) days. Hyperalgesia was measured by electromyography flexion reflex recordings following mustard oil or capsaicin at the site of (primary hyperalgesia), or distant to (secondary hyperalgesia) hindpaw mechanical stimuli. Primary hyperalgesia was induced at all postnatal ages, whereas secondary hyperalgesia could not be demonstrated at P3 but was evident at P10 and P21. At P3, extracellular signal-regulated kinase (ERK) protein is present in the dorsal horn, but hindpaw capsaicin produced minimal ERK activation restricted to the fourth lumbar segment. At P21, capsaicin induced intense phosphoERK expression in the superficial dorsal horn throughout several lumbar segments, consistent with the spread of secondary hyperalgesia. Intrathecal administration of the MEK (ERK kinase) inhibitor PD98059 prevented mustard oil and capsaicin-induced secondary hyperalgesia at P21, but had no effect on primary hyperalgesia at P3 or P21. These results provide evidence that primary and secondary hyperalgesia are differentially modulated during development. Furthermore, since ERK activation is required for secondary hyperalgesia, phosphoERK expression can be used to map the spatial distribution of neuronal activation in the spinal cord. Understanding changing responses to injury in the developing nervous system is important for clinical paediatric practice, and will enhance our ability to target the most effective site with a developmentally appropriate analgesic regime.

Some evidences indicate that protein kinase C-beta 1 (PRKCB1) gene may be a predisposition locus of autism. A recent study reported evidence of association between autism and two haplotypes made up of six noncoding single nucleotide polymorphisms in the PRKCB1. To attempt replication of their findings, we examined the same six single nucleotide polymorphisms of PRKCB1 in 171 Irish autism trios. The haploview program was used to calculate D' as a measure of linkage disequilibrium. The transmission disequilibrium test for single nucleotide polymorphism markers and haplotypes was carried out using the TDTPHASE and PDTPHASE from the UNPHASED version 2.404 programs. Transmission disequilibrium test analysis showed no evidence of association for any of the six single nucleotide polymorphisms at the PRKCB1 that we studied, or any of their haplotypes. Our data do not support the finding that the PRKCB1 gene variants contribute risk for the development of autism.

Objectives: Among adults started on antiretroviral treatment (ART) in a rural district hospital (a) to determine the cumulative proportion of deaths that occur within 3 and 6 months of starting ART, and (b) to identify risk factors that may be associated with such mortality., Design and Setting: A cross-sectional analytical study set in Thyolo district, Malawi., Methods: Over a 2-year period (April 2003 to April 2005) mortality within the first 3 and 6 months of starting ART was determined and risk factors were examined., Results: A total of 1507 individuals (517 men and 990 women), whose median age was 35 years were included in the study. There were a total of 190 (12.6%) deaths on ART of which 116 (61%) occurred within the first 3 months (very early mortality) and 150 (79%) during the first 6 months of initiating ART. Significant risk factors associated with such mortality included WHO stage IV disease, a baseline CD4 cell count under 50 cells/mul and increasing grades of malnutrition. A linear trend in mortality was observed with increasing grades of malnutrition (chi for trend = 96.1, P

Neonatal superficial dorsal horn neurons exhibit distinct firing properties in response to nociceptive and tactile inputs, but it is not known whether the intrinsic membrane excitability of these neurons changes during the early postnatal period. We have investigated the evoked firing properties of dorsal horn cells in rat spinal cord slices at different postnatal ages (P3, P10 and P21) and found no significant differences in mean firing frequency, spike frequency adaptation, regularity of action potential discharge or rheobase current levels between age groups. These results demonstrate that the intrinsic excitability of superficial dorsal horn neurons remains stable during early postnatal development and suggest that alterations in the synaptic inputs to these cells explain the changes in response to peripheral stimulation.

Neuropathic pain is known to occur in children but remains poorly understood and treated. The aim here was to establish a model of neuropathic pain in neonatal and young rodents. In the adult the spared nerve injury (SNI) model produced robust mechanical allodynia measured as a fall in cutaneous sensory threshold to 16% of controls, within one postoperative day and lasting at least 28 days. In contrast, animals aged 3, 10 and 21 days at the time of surgery did not display equivalent allodynia at any time up to 28 days later. A small, transient bilateral increased cutaneous sensitivity was observed at day 7 in P10 and P21 animals but this had gone by 14 days. SNI performed at 33 days led to a significant and persistent allodynia with the threshold falling to 55% of control values. A similar lack of neuropathic pain behaviour in younger animals was observed using the chronic constriction injury (CCI) model, which produced a clear allodynia in adult rats but no change in hindpaw sensitivity when performed at 10 days of age. Mechanical allodynia can be evoked in very young animals with inflammatory pain, so this developmental profile is selective for peripheral neuropathic pain and suggests a remarkable ability in young animals to compensate for the sensory consequences of nerve injury. The results are consistent with human neonatal responses to nerve injury; further study of underlying mechanisms are likely to yield important information about the pathogenesis and treatment of neuropathic pain.

Background: There is no consensus on the most appropriate method of cervical spine assessment in unconscious trauma patients. Passive flexion-extension imaging is one option for further investigating unconscious patients whose plain cervical radiographs are normal. This study examines the usefulness of this passive imaging in investigating for occult cervical injury., Methods: All unconscious patients admitted to The Alfred Trauma Intensive Care Unit over 1 year (January 1-December 31, 1998), who could not be clinically assessed within 48 hours in regard to their cervical spine, were identified. Results of passive flexion-extension radiography were compared with final injury status and clinical outcome as determined by retrospective review of the imaging reports, radiographic films, and case notes., Results: One hundred twenty-three patients with normal three-view plain radiographs proceeded to passive functional investigation. These were false-negative in four of the seven patients with cervical spine injuries at presentation. No patients suffered any adverse neurologic events from their delayed diagnoses or from the flexion-extension procedure., Conclusion: Passive flexion-extension imaging has inadequate sensitivity for detecting occult cervical spine injuries. Although no patients suffered adverse neurologic complications, the potential for devastating consequences from missed cervical injury has resulted in the removal of passive flexion-extension imaging from the screening protocol.

Background: Epidural alpha2-adrenergic agonists produce analgesic effects in children and adults, but efficacy and safety have not been established in neonates and infants. The aim of this study was to determine the effect of epidural dexmedetomidine on sensory processing, reversal of inflammatory hyperalgesia, and sedation during early development in rats., Methods: In rat pups aged 3, 10, and 21 postnatal days, mechanical withdrawal thresholds of the hind limbs were measured at baseline and after unilateral inflammation due to carrageenan. The effect of epidural dexmedetomidine on withdrawal thresholds was measured for 90 min after injection, and dose-response curves were constructed for each age group. The duration of the righting reflex was measured to assess sedation. The effects of epidural and systemic administration of dexmedetomidine were compared., Results: At all ages, carrageenan-induced hyperalgesia was reversed by doses of epidural dexmedetomidine that did not affect the threshold of the contralateral paw or prolong the righting reflex. Higher doses of epidural dexmedetomidine affected baseline nociception in the contralateral paw and produced sedation but had no effect when given systemically. Reversal of hyperalgesia and sedation were produced by lower doses of epidural dexmedetomidine in the youngest pups., Conclusions: Spinally mediated selective reversal of inflammatory hyperalgesia by epidural dexmedetomidine can be achieved at all ages; relatively lower doses are effective in early life, but the therapeutic window is narrow. These data have implications for the use and dosing of epidural alpha2 agonists in neonates and infants.

Objective: To examine brain activation associated with receptive language in patients with left temporal lobe epilepsy (TLE) before and after an anterior temporal lobectomy using magnetoencephalography (MEG), and to evaluate which patients were most likely to show a change in the lateralization and localization of the mechanisms supporting receptive language and if such changes were associated with neuropsychological function., Methods: Twelve patients with left TLE underwent preoperative Wada testing, and pre- and postoperative neuropsychological testing and MEG language mapping. The anatomic location of receptive language-related activity sources observed with MEG was determined by coregistering MEG data with structural MRI scans. Language laterality indices were calculated based on the number of reproducible activity sources in each hemisphere. The proximity of language-specific activity sources to Wernicke's area was also examined., Results: Although the small sample size precluded formal statistical analyses, patients with atypical (bilateral) hemispheric dominance preoperatively were more likely than patients with typical (left-hemisphere) dominance to show evidence of increased right hemisphere participation in language functions after surgery. Patients with left hemispheric dominance preoperatively were more likely to show intrahemispheric changes involving a slight inferior shift of the putative location of Wernicke's area. Patients with bilateral representation tended to perform worse on neuropsychological test measures obtained both pre- and postoperatively., Conclusion: Interhemispheric functional reorganization of language-specific areas may occur in patients undergoing left anterior temporal lobectomy. Intrahemispheric reorganization may take place even when the resection does not directly impinge upon Wernicke's area.

Opioid requirements in neonatal patients are reported to be lower than older infants and this may be a reflection of the developmental regulation of opioid receptors. In this study we have investigated the postnatal regulation of Mu opioid receptor (MOR) function in both rat lumbar dorsal root ganglion (DRG) cultures and behavioural mechanical and thermal reflex tests in rat pups. Immunostaining with MOR and selective neurofilament (NF200) antibodies was combined with calcium imaging of MOR function in cultured neonatal and adult rat dorsal root ganglion cells. Calcium imaging showed that a significantly greater number of neonatal DRG neurons expressed functional MOR compared to adult (56.5+/-3.4 versus 39.9+/-1.5%, n=8, mean+/-SEM, P<0.001). This expression is confined to the large, neurofilament positive sensory neurons, while expression in small, nociceptive, neurofilament negative neurons remains unchanged. Sensory threshold testing in rat pups showed that the analgesic potency of systemic morphine to mechanical stimulation is significantly greater in the neonate and declines with postnatal age. Morphine analgesic potency in thermal nociceptive tests did not change with postnatal age. These experiments show that the MOR expressed on large DRG neurons in neonates are functional and are subject to postnatal developmental regulation. This changing functional receptor profile is consistent with greater morphine potency in mechanical, but not thermal, sensory tests in young animals. These results have important clinical implications for the use of morphine in neonates and provide a possible explanation for the differences in morphine requirements observed in the youngest patients.