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It is increasingly reported that a history of concussion may be associated with chronic deleterious consequences. While the pathophysiology that contributes to these consequences is not well understood, neuroinflammation is postulated to be critical. Activation of multi-protein complexes termed inflammasomes, a key component of this inflammatory response, has been reported in more severe TBIs; however, it has not been investigated in milder TBIs, such as concussion. This study investigated serum levels of interleukin (IL)-1β and IL-18 (key proteins activated downstream of these inflammasomes) at acute, sub-acute, and chronic time-points post-concussion. We recruited 105 Australian footballers (65 male, 40 female) during the pre-season, then prospectively followed these players for the occurrence of concussion during the season. At baseline, 58 footballers reported a previous concussion history, and 47 reported no previous concussion history. Additionally, 25 players sustained a mid-season concussion and were sampled at 2, 6, and 13 days post-concussion. Serum levels of IL-1β and IL-18 were quantified using highly sensitive Simoa HD-X Analyzer assays. At baseline, IL-1β levels were higher in male, but not female, footballers with a previous concussion history compared with footballers with no concussion history. There was also a positive correlation between years of collision sport participation and IL-18 levels in males. No evidence was found in males or females to indicate that IL-1β or IL-18 levels differed at 2, 6, or 13 days post-concussion. These findings provide novel insights into potential sex-specific physiological consequences of concussion, and suggest that neuroinflammation may be persistent chronically following concussion in male athletes.

Background Biomarkers that can objectively guide the diagnosis of sports-related concussion, and consequent return-to-play decisions, are urgently needed. In this study, we aimed to determine the temporal profile and diagnostic ability of serum levels of neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), glial fibrillary acidic protein (GFAP), and tau in concussed male and female Australian footballers. Methods Blood was collected from 28 Australian rules footballers (20 males, 8 females) at 2-, 6-, and 13-days after a diagnosed concussion for comparison to their levels at baseline (i.e. pre-season), and with 27 control players (19 males, 8 females) without a diagnosis of concussion. Serum concentrations of protein markers associated with damage to neurons (UCHL1), axons (NfL, tau), and astrocytes (GFAP) were quantified using a Simoa HD-X Analyzer. Biomarker levels for concussed players were compared over time and between sex using generalised linear mixed effect models, and diagnostic performance was assessed using area under the receiver operating characteristic curve (AUROC) analysis. Results Serum NfL was increased from baseline in male footballers at 6- and 13-days post-concussion. GFAP and tau were increased in male footballers with concussion at 2- and 13-days respectively. NfL concentrations discriminated between concussed and non-concussed male footballers at all time-points (AUROC: 2d = 0.73, 6d = 0.85, 13d = 0.79), with tau also demonstrating utility at 13d (AUROC = 0.72). No biomarker differences were observed in female footballers after concussion. Conclusions Serum NfL may be a useful biomarker for the acute and sub-acute diagnosis of concussion in males, and could inform neurobiological recovery and return-to-play decisions. Future adequately powered studies are still needed to investigate biomarker changes in concussed females.

Contains fulltext : 230742.pdf (Publisher’s version ) (Open Access) Although adverse early experiences prime individuals to be at increased risk for chronic pain, little research has examined the trauma-pain relationship in early life or the underlying mechanisms that drive pathology over time. Given that early experiences can potentiate the nociceptive response, this study aimed to examine the effects of a high-fat high-sugar (HFHS) diet and early life stress (maternal separation; [MS]) on pain outcomes in male and female adolescent rats. Half of the rats also underwent a plantar-incision surgery to investigate how the pain system responded to a mildly painful stimuli in adolescence. Compared to controls, animals on the HFHS diet, experienced MS, or had exposure to both, exhibited increased anxiety-like behavior and altered thermal and mechanical nociception at baseline and following the surgery. Advanced MRI demonstrated that the HFHS diet and MS altered maturation of the brain, leading to changes in brain volume and diffusivity within the anterior cingulate, amygdala, corpus callosum, nucleus accumbens, and thalamus, while also modifying integrity of the corticospinal tracts. The effects of MS and HFHS diet were often cumulative, producing exacerbated pain sensitivity and increased neurobiological change. As early experiences are modifiable, understanding their role in pain may provide targets for early intervention/prevention. 15 p.

There is a widely recognized need for blood biomarkers to assist clinical decisions surrounding mild traumatic brain injury (mTBI). Serum neurofilament light (NfL), an indicator of neuroaxonal damage, is one such candidate, with early mTBI clinical investigations demonstrating significant promise. To facilitate the translation of pre-clinical mTBI findings, clinically relevant outcomes should be integrated into animal studies wherever possible. Despite this, the temporal profile and potential utility of NfL as a blood biomarker in pre-clinical mTBI is poorly understood. Here, we quantified serum NfL at 2-h, 1-, 3-, 7- and 14-days following mTBI in rats and compared these to pre-injury levels. We also investigated cumulative effects of repeat-mTBI by delivering 0, 1 or 5 mTBIs separated by 24 h. Sensorimotor performance was evaluated with the beam task at 1- and 4-h after mTBI, and serum was collected 1-day after the final procedure. We found that serum NfL levels were substantially elevated at all acute and sub-acute time-points after a single-mTBI, peaked at 1-day, and remained elevated 14-days post-injury. An mTBI dose-dependent effect on serum NfL levels was also observed, with substantially higher NfL levels found at 1-day post repeat-mTBI when compared to single-mTBI and sham-injured rats. Furthermore, NfL levels were found to be greatest in rats with the highest degree of sensorimotor impairment. In conclusion, these findings have described the temporal profile of serum NfL elevations following a single-mTBI in rats, and indicate a profile with some similarities and differences to that seen in the clinical condition. Moreover, we found that serum NfL levels were potentiated by repeat-mTBI, and that this biomarker may have utility as an indicator of injury severity. As such, future pre-clinical TBI studies may benefit from incorporating measures of serum NfL as an objective injury outcome.

A history of mild traumatic brain injury (mTBI) is linked to a number of chronic neurological conditions, however there is still much unknown about the underlying mechanisms. To provide new insights, this study used a clinically relevant model of repeated mTBI in rats to characterize the acute and chronic neuropathological and neurobehavioral consequences of these injuries. Rats were given four sham-injuries or four mTBIs and allocated to 7-day or 3.5-months post-injury recovery groups. Behavioral analysis assessed sensorimotor function, locomotion, anxiety, and spatial memory. Neuropathological analysis included serum quantification of neurofilament light (NfL), mass spectrometry of the hippocampal proteome, and ex vivo magnetic resonance imaging (MRI). Repeated mTBI rats had evidence of acute cognitive deficits and prolonged sensorimotor impairments. Serum NfL was elevated at 7 days post injury, with levels correlating with sensorimotor deficits; however, no NfL differences were observed at 3.5 months. Several hippocampal proteins were altered by repeated mTBI, including those associated with energy metabolism, neuroinflammation, and impaired neurogenic capacity. Diffusion MRI analysis at 3.5 months found widespread reductions in white matter integrity. Taken together, these findings provide novel insights into the nature and progression of repeated mTBI neuropathology that may underlie lingering or chronic neurobehavioral deficits.

OBJECTIVES Evaluate differences in tracheal intubation-associated events and process variances (i.e., multiple intubation attempts and oxygen desaturation) between pediatric cardiac ICUs and noncardiac PICUs in children with underlying cardiac disease. DESIGN Retrospective cohort study using a multicenter tracheal intubation quality improvement database (National Emergency Airway Registry for Children). SETTING Thirty-six PICUs (five cardiac ICUs, 31 noncardiac ICUs) from July 2012 to March 2016. PATIENTS Children with medical or surgical cardiac disease who underwent intubation in an ICU. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Our primary outcome was the rate of any adverse tracheal intubation-associated event. Secondary outcomes were severe tracheal intubation-associated events, multiple tracheal intubation attempt rates, and oxygen desaturation. There were 1,502 tracheal intubations in children with underlying cardiac disease (751 in cardiac ICUs, 751 in noncardiac ICUs) reported. Cardiac ICUs and noncardiac ICUs had similar proportions of patients with surgical cardiac disease. Patients undergoing intubation in cardiac ICUs were younger (median age, 1 mo [interquartile range, 0-6 mo]) compared with noncardiac ICUs (median 3 mo [interquartile range, 1-11 mo]; p < 0.001). Tracheal intubation-associated event rates were not different between cardiac ICUs and noncardiac ICUs (16% vs 19%; adjusted odds ratio, 0.74; 95% CI, 0.54-1.02; p = 0.069). However, in a sensitivity analysis comparing cardiac ICUs with mixed ICUs (i.e., ICUs caring for children with either general pediatric or cardiac diseases), cardiac ICUs had decreased odds of adverse events (adjusted odds ratio, 0.71; 95% CI, 0.52-0.97; p = 0.033). Rates of severe tracheal intubation-associated events and multiple attempts were similar. Desaturations occurred more often during intubation in cardiac ICUs (adjusted odds ratio, 1.61; 95% CI, 1.04-1.15; p = 0.002). CONCLUSIONS In children with underlying cardiac disease, rates of adverse tracheal intubation-associated events were not lower in cardiac ICUs as compared to noncardiac ICUs, even after adjusting for differences in patient characteristics and care models.

Oxygen desaturation during tracheal intubation is known to be associated with adverse ICU outcomes in critically ill children. We aimed to determine the occurrence and severity of desaturation during tracheal intubations and the association with adverse hemodynamic tracheal intubation-associated events.Retrospective cohort study as a part of the National Emergency Airway Registry for Children Network's quality improvement project from January 2012 to December 2014.International PICUs.Critically ill children younger than 18 years undergoing primary tracheal intubations in the ICUs.tracheal intubation processes of care and outcomes were prospectively collected using standardized operational definitions. We defined moderate desaturation as oxygen saturation less than 80% and severe desaturation as oxygen saturation less than 70% during tracheal intubation procedures in children with initial oxygen saturation greater than 90% after preoxygenation. Adverse hemodynamic tracheal intubation-associated event was defined as cardiac arrests, hypo or hypertension requiring intervention, and dysrhythmia.A total of 5,498 primary tracheal intubations from 31 ICUs were reported. Moderate desaturation was observed in 19.3% associated with adverse hemodynamic tracheal intubation-associated events (9.8% among children with moderate desaturation vs 4.4% without desaturation; p0.001). Severe desaturation was observed in 12.9% of tracheal intubations, also significantly associated with hemodynamic tracheal intubation-associated events. After adjusting for patient, provider, and practice factors, the occurrence of moderate desaturation was independently associated with hemodynamic tracheal intubation-associated events: adjusted odds ratio 1.83 (95% CI, 1.34-2.51; p0.001). The occurrence of severe desaturation was also independently associated with hemodynamic tracheal intubation-associated events: adjusted odds ratio 2.16 (95% CI, 1.54-3.04; p0.001). Number of tracheal intubation attempts was also significantly associated with the frequency of moderate and severe desaturations (p0.001).In this large tracheal intubation quality improvement database, we found moderate and severe desaturation are reported among 19% and 13% of all tracheal intubation encounters. Moderate and severe desaturations were independently associated with the occurrence of adverse hemodynamic events. Future quality improvement interventions may focus to reduce desaturation events.

IntroductionChildren with CHD and acquired heart disease have unique, high-risk physiology. They may have a higher risk of adverse tracheal-intubation-associated events, as compared with children with non-cardiac disease.Materials and methodsWe sought to evaluate the occurrence of adverse tracheal-intubation-associated events in children with cardiac disease compared to children with non-cardiac disease. A retrospective analysis of tracheal intubations from 38 international paediatric ICUs was performed using the National Emergency Airway Registry for Children (NEAR4KIDS) quality improvement registry. The primary outcome was the occurrence of any tracheal-intubation-associated event. Secondary outcomes included the occurrence of severe tracheal-intubation-associated events, multiple intubation attempts, and oxygen desaturation.ResultsA total of 8851 intubations were reported between July, 2012 and March, 2016. Cardiac patients were younger, more likely to have haemodynamic instability, and less likely to have respiratory failure as an indication. The overall frequency of tracheal-intubation-associated events was not different (cardiac: 17% versus non-cardiac: 16%, p=0.13), nor was the rate of severe tracheal-intubation-associated events (cardiac: 7% versus non-cardiac: 6%, p=0.11). Tracheal-intubation-associated cardiac arrest occurred more often in cardiac patients (2.80 versus 1.28%; pConclusionsThe overall incidence of adverse tracheal-intubation-associated events in cardiac patients was not different from that in non-cardiac patients. However, the presence of a cardiac diagnosis was associated with a higher occurrence of both tracheal-intubation-associated cardiac arrest and oxygen desaturation.

Tracheal intubation in PICUs is a common procedure often associated with adverse events. The aim of this study is to evaluate the association between immediate events such as tracheal intubation associated events or desaturation and ICU outcomes: length of stay, duration of mechanical ventilation, and mortality.Prospective cohort study with 35 PICUs using a multicenter tracheal intubation quality improvement database (National Emergency Airway Registry for Children: NEAR4KIDS) from January 2013 to June 2015. Desaturation defined as Spo2 less than 80%.PICUs participating in NEAR4KIDS.All patients less than18 years of age undergoing primary tracheal intubations with ICU outcome data were analyzed.Five thousand five hundred four tracheal intubation encounters with median 108 (interquartile range, 58-229) tracheal intubations per site. At least one tracheal intubation associated event was reported in 892 (16%), with 364 (6.6%) severe tracheal intubation associated events. Infants had a higher frequency of tracheal intubation associated event or desaturation than older patients (48% infants vs 34% for 1-7 yr and 18% for 8-17 yr). In univariate analysis, the occurrence of tracheal intubation associated event or desaturation was associated with a longer mechanical ventilation (5 vs 3 d; p0.001) and longer PICU stay (14 vs 11 d; p0.001) but not with PICU mortality. The occurrence of severe tracheal intubation associated events was associated with longer mechanical ventilation (5 vs 4 d; p0.003), longer PICU stay (15 vs 12 d; p0.035), and PICU mortality (19.9% vs 9.6%; p0.0001). In multivariable analyses, the occurrence of tracheal intubation associated event or desaturation was significantly associated with longer mechanical ventilation (+12%; 95% CI, 4-21%; p = 0.004), and severe tracheal intubation associated events were independently associated with increased PICU mortality (OR = 1.80; 95% CI, 1.24-2.60; p = 0.002), after adjusted for patient confounders.Adverse tracheal intubation associated events and desaturations are common and associated with longer mechanical ventilation in critically ill children. Severe tracheal intubation associated events are associated with higher ICU mortality. Potential interventions to decrease tracheal intubation associated events and oxygen desaturation, such as tracheal intubation checklist, use of apneic oxygenation, and video laryngoscopy, may need to be considered to improve ICU outcomes.

Extracorporeal membrane oxygenation (ECMO) use in poisoned patients is increasing, but is rare post cardiac arrest. We report a case of ECMO use with complete recovery in a patient who arrested twice after a cardiotoxicant overdose. A 17-year-old male presented after an unknown overdose. He rapidly became hypotensive and bradycardic and received aggressive supportive care without improvement. He was transferred to our institution and suffered a cardiac arrest shortly after arrival. Six minutes of advanced cardiac life support resulted in return of spontaneous circulation. High-dose insulin, lipid emulsion, and ECMO were initiated. While awaiting ECMO deployment, he again became pulseless. Compressions resumed, and after 30 min, ROSC was achieved, and he was cannulated for veno-arterial ECMO. Within 48 h, he was decannulated, and then weaned off epinephrine 2 days later. Upon extubation, he was neurologically intact. Amlodipine and metoprolol were later confirmed in serum. Adolescent poisoned patients represent an ideal population for ECMO due to lack of comorbidities. As experience with ECMO in overdose increases, additional research is needed to determine appropriate indications and timing for its use. ECMO is an option for patients poisoned with a cardiotoxicant drug, even following witnessed cardiac arrest.

BACKGROUND: An increasing number of centers are using active rehabilitation and ambulation for critically ill patients on extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation. This investigation assessed the economic impact at a single center of ambulatory versus non-ambulatory ECMO strategies as a bridge to lung transplantation. METHODS: We conducted a single-center retrospective cohort analysis of all subjects supported with ECMO as a bridge to lung transplantation ( N = 9) from 2007 to 2012. Subjects who were rehabilitated while supported with ECMO before lung transplantation were compared with those who were not rehabilitated during ECMO. Hospital cost data for the month before transplantation through 12 months after the initial post-transplant hospital discharge were compared. RESULTS: The median cost (interquartile range [IQR]) in the 30 d before transplant for the ambulatory cohort was $88,137 (IQR $38,589-$122,111) compared with $52,124 (IQR $23,824-$69,929) for the non-ambulatory cohort ( P = .08). The median post-transplant ICU cost for the ambulatory cohort was $38,468 (IQR $23,611-$64,126) compared with $143,407 (IQR $112,199-$168,993) for the non-ambulatory cohort ( P = .01). The median total hospital cost for subjects supported with ambulatory ECMO was $213,086 (IQR $166,767-$264,536) compared with $273,291 (IQR $237,299–$374,175) for non-ambulatory ECMO subjects ( P = .05). The median total cost for the ambulatory cohort was $268,194 (IQR $219,972–$517,320) compared with $300,307 (IQR $274,262–$394,913) for the non-ambulatory cohort ( P = .14). CONCLUSIONS: Subjects supported with ambulatory ECMO had a 22% ($60,204) reduction in total hospital cost, 73% ($104,939) reduction in post-transplant ICU cost, and 11% ($32,133) reduction in total cost compared with non-ambulatory ECMO subjects. This analysis demonstrates the potential economic benefit of rehabilitation and ambulation during ECMO compared with a traditional strategy.