Airway management in the paediatric difficult intubation registry: a propensity score matched analysis of outcomes over time.

Background: The Paediatric Difficult Intubation Collaborative identified multiple attempts and persistence with direct laryngoscopy as risk factors for complications in children with difficult tracheal intubations and subsequently engaged in initiatives to reduce repeated attempts and persistence with direct laryngoscopy in children. We hypothesised these efforts would lead to fewer attempts, fewer direct laryngoscopy attempts and decrease complications. Methods: Paediatric patients less than 18 years of age with difficult direct laryngoscopy were enrolled in the Paediatric Difficult Intubation Registry. We define patients with difficult direct laryngoscopy as those in whom (1) an attending or consultant obtained a Cormack Lehane Grade 3 or 4 view on direct laryngoscopy, (2) limited mouth opening makes direct laryngoscopy impossible, (3) direct laryngoscopy failed in the preceding 6 months, and (4) direct laryngoscopy was deferred due to perceived risk of harm or poor chance of success. We used a 5:1 propensity score match to compare an early cohort from the initial Paediatric Difficult Intubation Registry analysis (August 6, 2012-January 31, 2015, 785 patients, 13 centres) and a current cohort from the Registry (March 4, 2017-March 31, 2023, 3925 patients, 43 centres). The primary outcome was first attempt success rate between cohorts. Success was defined as confirmed endotracheal intubation and assessed by the treating clinician. Secondary outcomes were eventual success rate, number of attempts at intubation, number of attempts with direct laryngoscopy, the incidence of persistence with direct laryngoscopy, use of supplemental oxygen, all complications, and severe complications. Findings: First-attempt success rate was higher in the current cohort (42% vs 32%, OR 1.5 95% CI 1.3-1.8, p < 0.001). In the current cohort, there were fewer attempts (2.2 current vs 2.7 early, regression coefficient -0.5 95% CI -0.6 to -0.4, p < 0.001), fewer attempts with direct laryngoscopy (0.6 current vs 1.0 early, regression coefficient -0.4 95% CI -0.4 to 0.3, p < 0.001), and reduced persistence with direct laryngoscopy beyond two attempts (7.3% current vs 14.1% early, OR 0.5 95% CI 0.4-0.6, p < 0.001). Overall complication rates were similar between cohorts (19% current vs 20% early). Severe complications decreased to 1.8% in the current cohort from 3.2% in the early cohort (OR 0.55 95% CI 0.35-0.87, p = 0.011). Cardiac arrests decreased to 0.8% in the current cohort from 1.8% in the early cohort. We identified persistence with direct laryngoscopy as a potentially modifiable factor associated with severe complications. Interpretation: In the current cohort, children with difficult tracheal intubations underwent fewer intubation attempts, fewer attempts with direct laryngoscopy, and had a nearly 50% reduction in severe complications. As persistence with direct laryngoscopy continues to be associated with severe complications, efforts to limit direct laryngoscopy and promote rapid transition to advanced techniques may enhance patient safety. Funding: None.

Difficult intubation in syndromic versus nonsyndromic forms of micrognathia in children.

BACKGROUND: We investigated how syndromic versus nonsyndromic forms of micrognathia impacted difficult intubation outcomes in children. Primary outcome was the first-attempt success rate of tracheal intubation, secondary outcomes were number of intubation attempts and complications. We hypothesized that syndromic micrognathia would be associated with lower first-attempt success rate. METHODS: In micrognathic patients enrolled in the Pediatric Difficult Intubation Registry (08/2012-03/2019) we retrospectively compared demographic and clinical characteristics between children with nonsyndromic and syndromic micrognathia using standardized mean differences (SMD) and assessed the association of the presence of syndrome with the primary and secondary outcomes using propensity score matching analysis with and without matching for airway assessment findings. RESULTS: Nonsyndromic patients (628) were less likely to have additional airway abnormalities. Syndromic patients (216) were less likely to have unanticipated difficult intubation (2% vs. 20%, SMD 0.59). First-attempt success rates of intubation were: 38% in the syndromic versus 34% in the nonsyndromic group (odds ratio [OR] 1.18; 95% confidence intervals [95% CI] 0.74, 1.89; p = .478), and 37% versus 37% (OR 0.99; 95% CI 0.66, 1.48; p = .959). Median number of intubation attempts were 2 (interquartile range [IQR]: 1, 3; range: 1, 8) versus 2 (IQR: 1, 3; range 1, 12) (median regression coefficient = 0; 95% CI: -0.7, 0.7; p = .999) and 2 (IQR: 1, 3; range: 1, 12) versus 2 (IQR: 1, 3; range 1, 8) (median regression coefficient = 0; 95% CI: -0.5, 0.5; p = .999). Complication rates were 14% versus 22% (OR 0.6; 95% CI 0.34, 1.04; p = .07) and 16% versus 21% (OR 0.71; 95% CI 0.43, 1.17; p = .185). CONCLUSIONS: Presence of syndrome was not associated with lower first-attempt success rate on intubation, number of intubation attempts, or complication rate among micrognathic patients difficult to intubate, despite more associated craniofacial abnormalities. Nonsyndromic patients were more likely to have unanticipated difficult intubations, first attempt with direct laryngoscopy.

Downregulation of PACAP and the PAC1 Receptor in the Basal Ganglia, Substantia Nigra and Centrally Projecting Edinger-Westphal Nucleus in the Rotenone model of Parkinson's Disease.

Numerous in vitro and in vivo models of Parkinson's disease (PD) demonstrate that pituitary adenylate cyclase-activating polypeptide (PACAP) conveys its strong neuroprotective actions mainly via its specific PAC1 receptor (PAC1R) in models of PD. We recently described the decrease in PAC1R protein content in the basal ganglia of macaques in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD that was partially reversed by levodopa therapy. In this work, we tested whether these observations occur also in the rotenone model of PD in the rat. The rotarod test revealed motor skill deterioration upon rotenone administration, which was reversed by benserazide/levodopa (B/L) treatment. The sucrose preference test suggested increased depression level while the open field test showed increased anxiety in rats rendered parkinsonian, regardless of the received B/L therapy. Reduced dopaminergic cell count in the substantia nigra pars compacta (SNpc) diminished the dopaminergic fiber density in the caudate-putamen (CPu) and decreased the peptidergic cell count in the centrally projecting Edinger-Westphal nucleus (EWcp), supporting the efficacy of rotenone treatment. RNAscope in situ hybridization revealed decreased PACAP mRNA (Adcyap1) and PAC1R mRNA (Adcyap1r1) expression in the CPu, globus pallidus, dopaminergic SNpc and peptidergic EWcp of rotenone-treated rats, but no remarkable downregulation occurred in the insular cortex. In the entopeduncular nucleus, only the Adcyap1r1 mRNA was downregulated in parkinsonian animals. B/L therapy attenuated the downregulation of Adcyap1 in the CPu only. Our current results further support the evolutionarily conserved role of the PACAP/PAC1R system in neuroprotection and its recruitment in the development/progression of neurodegenerative states such as PD.

Outcomes for 41 260 pediatric surgical patients with opioid-free anesthesia: One center's experience.

BACKGROUND: Opioid use is common and associated with side effects and risks. Consequently, analgesic strategies to reduce opioid utilization have been developed. Regional anesthesia and multimodal strategies are central tenets of enhanced recovery pathways and facilitate reduced perioperative opioid use. Opioid-free anesthesia (OFA) protocols eliminate all intraoperative opioids, reserving opioids for postoperative rescue treatment. Systematic reviews show variable results for OFA. METHODS: In a series of Quality Improvement (QI) projects, multidisciplinary teams developed interventions to test and spread OFA first in our ambulatory surgery center (ASC) and then in our hospital. Outcome measures were tracked using statistical process control charts to increase the adoption of OFA. RESULTS: Between January 1, 2016, and September 30, 2022, 19 872 of 28 574 ASC patients received OFA, increasing from 30% to 98%. Post Anesthesia Care Unit (PACU) maximum pain score, opioid-rescue rate, and postoperative nausea and vomiting (PONV) treatment all decreased concomitantly. The use of OFA now represents our ambulatory standard practice. Over the same timeframe, the spread of this practice to our hospital led to 21 388 of 64 859 patients undergoing select procedures with OFA, increasing from 15% to 60%. Opioid rescue rate and PONV treatment in PACU decreased while hospital maximum pain scores and length of stay were stable. Two procedural examples with OFA benefits were identified. The use of OFA allowed relaxation of adenotonsillectomy admission criteria, resulting in 52 hospital patient days saved. Transition to OFA for laparoscopic appendectomy occurred concomitantly with a decrease in the mean hospital length of stay from 2.9 to 1.4 days, representing a savings of >500 hospital patient days/year. CONCLUSIONS: These QI projects demonstrated that most pediatric ambulatory and select inpatient surgeries are amenable to OFA techniques which may reduce PONV without worsening pain.

IL-1 Mediates Chronic Stress-Induced Hyperalgesia Accompanied by Microglia and Astroglia Morphological Changes in Pain-Related Brain Regions in Mice.

Chronic stress causes several pain conditions including fibromyalgia. Its pathophysiological mechanisms are unknown, and the therapy is unresolved. Since the involvement of interleukin-1 (IL-1) has been described in stress and inflammatory pain but no data are available regarding stress-induced pain, we studied its role in a chronic restraint stress (CRS) mouse model. Female and male C57Bl/6J wild-type (WT) and IL-1αß-deficient (knock-out: IL-1 KO) mice were exposed to 6 h of immobilization/day for 4 weeks. Mechanonociception, cold tolerance, behavioral alterations, relative thymus/adrenal gland weights, microglia ionized calcium-binding adaptor molecule 1 (IBA1) and astrocyte glial fibrillary acidic protein (GFAP) integrated density, number and morphological transformation in pain-related brain regions were determined. CRS induced 15-20% mechanical hyperalgesia after 2 weeks in WT mice in both sexes, which was significantly reduced in female but not in male IL-1 KOs. Increased IBA1+ integrated density in the central nucleus of amygdala, primary somatosensory cortex hind limb representation part, hippocampus cornu ammonis area 3 (CA3) and periaqueductal gray matter (PAG) was present, accompanied by a cell number increase in IBA1+ microglia in stressed female WTs but not in IL-1 KOs. CRS induced morphological changes of GFAP+ astrocytes in WT but not in KO mice. Stress evoked cold hypersensitivity in the stressed animals. Anxiety and depression-like behaviors, thymus and adrenal gland weight changes were detectable in all groups after 2 but not 4 weeks of CRS due to adaptation. Thus, IL-1 mediates chronic stress-induced hyperalgesia in female mice, without other major behavioral alterations, suggesting the analgesic potentials of IL-1 in blocking drugs in stress-related pain syndromes.

First-attempt success rate of video laryngoscopy in small infants (VISI): a multicentre, randomised controlled trial.

BACKGROUND: Orotracheal intubation of infants using direct laryngoscopy can be challenging. We aimed to investigate whether video laryngoscopy with a standard blade done by anaesthesia clinicians improves the first-attempt success rate of orotracheal intubation and reduces the risk of complications when compared with direct laryngoscopy. We hypothesised that the first-attempt success rate would be higher with video laryngoscopy than with direct laryngoscopy. METHODS: In this multicentre, parallel group, randomised controlled trial, we recruited infants without difficult airways abnormalities requiring orotracheal intubation in operating theatres at four quaternary children's hospitals in the USA and one in Australia. We randomly assigned patients (1:1) to video laryngoscopy or direct laryngoscopy using random permuted blocks of size 2, 4, and 6, and stratified by site and clinician role. Guardians were masked to group assignment. The primary outcome was the proportion of infants with a successful first attempt at orotracheal intubation. Analysis (modified intention-to-treat [mITT] and per-protocol) used a generalised estimating equation model to account for clustering of patients treated by the same clinician and institution, and adjusted for gestational age, American Society of Anesthesiologists physical status, weight, clinician role, and institution. The trial is registered at ClinicalTrials.gov, NCT03396432. FINDINGS: Between June 4, 2018, and Aug 19, 2019, 564 infants were randomly assigned: 282 (50%) to video laryngoscopy and 282 (50%) to direct laryngoscopy. The mean age of infants was 5·5 months (SD 3·3). 274 infants in the video laryngoscopy group and 278 infants in the direct laryngoscopy group were included in the mITT analysis. In the video laryngoscopy group, 254 (93%) infants were successfully intubated on the first attempt compared with 244 (88%) in the direct laryngoscopy group (adjusted absolute risk difference 5·5% [95% CI 0·7 to 10·3]; p=0·024). Severe complications occurred in four (2%) infants in the video laryngoscopy group compared with 15 (5%) in the direct laryngoscopy group (-3·7% [-6·5 to -0·9]; p=0·0087). Fewer oesophageal intubations occurred in the video laryngoscopy group (n=1 [<1%]) compared with in the direct laryngoscopy group (n=7 [3%]; -2·3 [-4·3 to -0·3]; p=0·028). INTERPRETATION: Among anaesthetised infants, using video laryngoscopy with a standard blade improves the first-attempt success rate and reduces complications. FUNDING: Anaesthesia Patient Safety Foundation, Society for Airway Management, and Karl Storz Endoscopy.

Longer upper airway lengths in Robin Sequence: A case-control study using computed tomography.

BACKGROUND: Direct laryngoscopy and intubation are often difficult in children with Robin Sequence. Previous research characterizing anatomic airway differences has focused on parameters influencing airway patency; there is a paucity of data pertaining to intubation trajectories and depth. Such information could impact airway management approaches and decrease the incidence of endotracheal tube malpositioning. AIM: The study goal was to examine whether longitudinal airway parameters pertaining to intubation are different in children with Robin Sequence compared with age-matched controls. METHOD: This case-control study compared patients with RS <4 years of age who had computed tomography scans of the head and neck to age- and sex-matched controls. Measurements were made of the nasopharynx, oropharynx, hypopharynx, tongue, hyoid, and the front teeth to vocal cord, nares to vocal cord, and nasion-basion distances. Statistical analysis was performed using multiple ANCOVA models with the categorical predictor of Robin Sequence vs control and potential covariates including subject height/length, weight, and age. RESULTS: Thirty-three patients with Robin Sequence and 33 control subjects were included. After controlling for subject height/length, mean front teeth to vocal cord distance was 1.2 cm longer (95% CI: 0.9 to 1.6 cm, P < .001) and mean nares to vocal cord distance was 0.8 cm longer (95% CI: 0.4 to 1.2 cm, P < .001) in patients with Robin Sequence than in controls. The tongue was positioned on average 0.5 cm higher (95% CI: 0.3 to 0.8, P < .001) and 0.9 cm more posterior (95% CI: 0.6 to 1.0 cm, P < .001) in cases than in controls. Moreover, in patients with Robin Sequence, the hyoid was positioned on average 0.5 cm more inferiorly (95% CI: 0.2 to 0.8 cm, P < .001) and 0.2 cm more posteriorly (95% CI: 0.1 to 0.4 cm, P < .01) than controls. CONCLUSION: In patients with Robin Sequence under 4 years of age, the mean front teeth to vocal cord distance was found to be 1.2 cm longer while the mean nares to vocal cord distance was found to be 0.8 cm longer controlling for subject length. Clinicians should account for these differences when selecting and placing endotracheal tubes, particularly those with a preformed bend.

Pediatric Airway Management in COVID-19 Patients: Consensus Guidelines From the Society for Pediatric Anesthesia's Pediatric Difficult Intubation Collaborative and the Canadian Pediatric Anesthesia Society.

The severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) pandemic has challenged medical systems and clinicians globally to unforeseen levels. Rapid spread of COVID-19 has forced clinicians to care for patients with a highly contagious disease without evidence-based guidelines. Using a virtual modified nominal group technique, the Pediatric Difficult Intubation Collaborative (PeDI-C), which currently includes 35 hospitals from 6 countries, generated consensus guidelines on airway management in pediatric anesthesia based on expert opinion and early data about the disease. PeDI-C identified overarching goals during care, including minimizing aerosolized respiratory secretions, minimizing the number of clinicians in contact with a patient, and recognizing that undiagnosed asymptomatic patients may shed the virus and infect health care workers. Recommendations include administering anxiolytic medications, intravenous anesthetic inductions, tracheal intubation using video laryngoscopes and cuffed tracheal tubes, use of in-line suction catheters, and modifying workflow to recover patients from anesthesia in the operating room. Importantly, PeDI-C recommends that anesthesiologists consider using appropriate personal protective equipment when performing aerosol-generating medical procedures in asymptomatic children, in addition to known or suspected children with COVID-19. Airway procedures should be done in negative pressure rooms when available. Adequate time should be allowed for operating room cleaning and air filtration between surgical cases. Research using rigorous study designs is urgently needed to inform safe practices during the COVID-19 pandemic. Until further information is available, PeDI-C advises that clinicians consider these guidelines to enhance the safety of health care workers during airway management when performing aerosol-generating medical procedures. These guidelines have been endorsed by the Society for Pediatric Anesthesia and the Canadian Pediatric Anesthesia Society.

In Silico, In Vitro and In Vivo Pharmacodynamic Characterization of Novel Analgesic Drug Candidate Somatostatin SST4 Receptor Agonists.

Background: Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via its receptor subtype 4 (SST4) without influencing endocrine functions. Therefore, SST4 is considered to be a novel target for drug development in pain, especially chronic neuropathy which is a great unmet medical need. Purpose and Experimental Approach: Here, we examined the in silico binding, SST4-linked G protein activation and ß-arrestin activation on stable SST4 expressing cells and the effects of our novel pyrrolo-pyrimidine molecules (20, 100, 500, 1,000, 2,000 µg·kg-1) on partial sciatic nerve ligation-induced traumatic mononeuropathic pain model in mice. Key Results: The novel compounds bind to the high affinity binding site of SST4 the receptor and activate the G protein. However, unlike the reference SST4 agonists NNC 26-9100 and J-2156, they do not induce ß-arrestin activation responsible for receptor desensitization and internalization upon chronic use. They exert 65-80% maximal anti-hyperalgesic effects in the neuropathy model 1 h after a single oral administration of 100-500 µg·kg-1 doses. Conclusion and Implications: The novel orally active compounds show potent and effective SST4 receptor agonism in vitro and in vivo. All four novel ligands proved to be full agonists based on G protein activation, but failed to recruit ß-arrestin. Based on their potent antinociceptive effect in the neuropathic pain model following a single oral administration, they are promising candidates for drug development.

Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons.

The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain. Arthritis was induced by i.p. K/BxN serum (passive transfer of inflammatory cytokines, autoantibodies), intra-articular mast cell tryptase or Complete Freund's Adjuvant (CFA, active immunization) in wild type, HK-1- and NK1-deficient mice. Mechanical- and heat hyperalgesia determined by dynamic plantar esthesiometry and increasing temperature hot plate, respectively, swelling measured by plethysmometry or micrometry were significantly reduced in HK-1-deleted, but not NK1-deficient mice in all models. K/BxN serum-induced histopathological changes (day 14) were also decreased, but early myeloperoxidase activity detected by luminescent in vivo imaging increased in HK-1-deleted mice similarly to the CFA model. However, vasodilation and plasma protein extravasation determined by laser Speckle and fluorescent imaging, respectively, were not altered by HK-1 deficiency in any models. HK-1 induced Ca2+-influx in primary sensory neurons, which was also seen in NK1-deficient cells and after pertussis toxin-pretreatment, but not in extracellular Ca2+-free medium. These are the first results showing that HK-1 mediates arthritic pain and cellular, but not vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via Ca2+ channel-linked receptor. Identifying its target opens new directions to understand joint pain leading to novel therapeutic opportunities.

Pediatric airway management education and training.

Education in medicine, informed by research findings, is moving away from the traditional apprenticeship model and increasingly embraces new, active learning methodologies. In this article, we will review these methodologies along with adult learning theories; we explore the available evidence on acquisition and maintenance of pediatric airway management skills, including technical and nontechnical skills. We recall the elements of a competency-based curriculum and how they can be applied in pediatric airway skill training and suggest mapping strategies based on research evidence. We propose future directions in education and educational research in the field.

Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain.

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 µM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1-C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives.

Important regulatory function of transient receptor potential ankyrin 1 receptors in age-related learning and memory alterations of mice.

Expression of the transient receptor potential ankyrin 1 (TRPA1) receptor has been demonstrated not only in the dorsal root and trigeminal ganglia but also in different brain regions (e.g., hippocampus, hypothalamus, and cortex). However, data concerning their role in neurodegenerative and age-related diseases of the CNS is still indistinct. The aim of our study was to investigate the potential role of TRPA1 in a mouse model of senile dementia. For the investigation of changes during aging, we used male young (3-4-month-old) and old (18-month-old) wild-type (TRPA1+/+;WT) and TRPA1 receptor gene-deleted (TRPA1-/-) mice. Novel object recognition (NOR) test as well as Y maze (YM), radial arm maze (RAM), and Morris water maze (MWM) tests were used to assess the decline of memory and learning skills. In the behavioral studies, significant memory loss was detected in aged TRPA1+/+ mice with the NOR and RAM, but there was no difference measured by YM and MWM tests regarding the age and gene. TRPA1-/- showed significantly reduced memory loss, which could be seen as higher discrimination index in the NOR and less exploration time in the RAM. Furthermore, young TRPA1-/- animals showed significantly less reference memory error in the RAM and notably higher mobility in NOR, RAM, and YM compared with the age-matched WTs. Our present work has provided the first evidence that TRPA1 receptors mediate deteriorating effects in the old age memory decline. Understanding the underlying mechanisms could open new perspectives in the pharmacotherapy of dementia.

Hemokinin-1 is an important mediator of pain in mouse models of neuropathic and inflammatory mechanisms.

The Tac4 gene-derived hemokinin-1 (HK-1) is present in pain-related regions and activates the tachykinin NK1 receptor, but with binding site and signaling pathways different from Substance P (SP). NK1 receptor is involved in nociception, but our earlier data showed that it has no role in chronic neuropathic hyperalgesia, similarly to SP. Furthermore, NK1 antagonists failed in clinical trials as analgesics due to still unknown reasons. Therefore, we investigated the role of HK-1 in pain conditions of distinct mechanisms using genetically modified mice. Chronic neuropathic mechanical and cold hyperalgesia after partial sciatic nerve ligation (PSL) were determined by dynamic plantar aesthesiometry and withdrawal latency from icy water, motor coordination on the accelerating Rotarod. Peripheral nerve growth factor (NGF) production was measured by ELISA, neuronal and glia cell activation by immunohistochemistry in pain-related regions. Acute somatic and visceral chemonocifensive behaviors were assessed after intraplantar formalin or intraperitoneal acetic-acid injection, respectively. Resiniferatoxin-induced inflammatory mechanical and thermal hyperalgesia by aesthesiometry and increasing temperature hot plate. Chronic neuropathic mechanical and cold hypersensitivity were significantly decreased in HK-1 deficient mice. NGF level in the paw homogenates of intact mice were significantly lower in case of HK-1 deletion. However, it significantly increased under neuropathic condition in contrast to wildtype mice, where the higher basal concentration did not show any changes. Microglia, but not astrocyte activation was observed 14 days after PSL in the ipsilateral spinal dorsal horn of wildtype, but not HK-1-deficient mice. However, under neuropathic conditions, the number of GFAP-positive astrocytes was significantly smaller in case of HK-1 deletion. Acute visceral, but not somatic nocifensive behavior, as well as neurogenic inflammatory mechanical and thermal hypersensitivity were significantly reduced by HK-1 deficiency similarly to NK1, but not to SP deletion. We provide evidence for pro-nociceptive role of HK-1, via NK1 receptor activation in acute inflammation models, but differently from SP-mediated actions. Identification of its targets and signaling can open new directions in pain research.

Enrollment challenges in multicenter, international studies: The example of the GAS trial.

INTRODUCTION: Randomized trials are important for generating high-quality evidence, but are perceived as difficult to perform in the pediatric population. Thus far there has been poor characterization of the barriers to conducting trials involving children, and the variation in these barriers between countries remains undescribed. The General Anesthesia compared to Spinal anesthesia (GAS) trial, conducted in seven countries between 2007 and 2013, provides an opportunity to explore these issues. METHODS: We undertook a descriptive analysis to evaluate the reasons for variation in enrollment between countries in the GAS trial, looking specifically at the number of potential subjects screened, and the subsequent application of four exclusion criteria that were applied in a hierarchical order. RESULTS: A total of 4023 patients were screened by 28 centers in seven countries. Australia and the USA screened the most subjects, accounting for 84% of all potential trial participants. The percentage of subjects eliminated from the screened pool by each exclusion criterion varied between countries. Exclusion due to a predefined condition (H1) eliminated only 5% of potential subjects in Italy and the UK, but 37% in Canada. Exclusions due to a contraindication or a physician's refusal most impacted enrollment in Australia and the USA. The patient being "too large for spinal anesthesia" was the most commonly cited by anesthetists who refused to enroll a patient (64% of anesthetist refusals). The majority of surgeon refusals came from the USA, where surgeons preferred the patient to receive a general anesthetic. The percentage of approached parents refusing to consent ranged from a low of 3% in Italy to a high of 70% in the USA and Netherlands. The most frequently cited reason for parent refusal in all countries was a preference for general anesthesia (median: 43%, range: 32%-67%). However, a sizeable proportion of parents in all countries had a contrasting preference for spinal anesthesia (median: 25%, range: 13%-31%), and 23% of U.S. parents expressed concern about randomization. CONCLUSION: The GAS trial highlights enrollment challenges that can occur when conducting multicenter, international, pediatric studies. Investigators planning future trials should be aware of potential differences in screening processes across countries, and that exclusions by anesthetists and surgeons may vary in reason, in frequency, and by country. Furthermore, investigators should be aware that the U.S. centers encountered particularly high surgeon and parental refusal rates and that U.S. parents were uniquely concerned about randomization. Planning trials that address these difficulties should increase the likelihood of successfully recruiting subjects in pediatric trials.

Videolaryngoscopy versus Fiber-optic Intubation through a Supraglottic Airway in Children with a Difficult Airway: An Analysis from the Multicenter Pediatric Difficult Intubation Registry.

BACKGROUND: The success rates and related complications of various techniques for intubation in children with difficult airways remain unknown. The primary aim of this study is to compare the success rates of fiber-optic intubation via supraglottic airway to videolaryngoscopy in children with difficult airways. Our secondary aim is to compare the complication rates of these techniques. METHODS: Observational data were collected from 14 sites after management of difficult pediatric airways. Patient age, intubation technique, success per attempt, use of continuous ventilation, and complications were recorded for each case. First-attempt success and complications were compared in subjects managed with fiber-optic intubation via supraglottic airway and videolaryngoscopy. RESULTS: Fiber-optic intubation via supraglottic airway and videolaryngoscopy had similar first-attempt success rates (67 of 114, 59% vs. 404 of 786, 51%; odds ratio 1.35; 95% CI, 0.91 to 2.00; P = 0.16). In subjects less than 1 yr old, fiber-optic intubation via supraglottic airway was more successful on the first attempt than videolaryngoscopy (19 of 35, 54% vs. 79 of 220, 36%; odds ratio, 2.12; 95% CI, 1.04 to 4.31; P = 0.042). Complication rates were similar in the two groups (20 vs. 13%; P = 0.096). The incidence of hypoxemia was lower when continuous ventilation through the supraglottic airway was used throughout the fiber-optic intubation attempt. CONCLUSIONS: In this nonrandomized study, first-attempt success rates were similar for fiber-optic intubation via supraglottic airway and videolaryngoscopy. Fiber-optic intubation via supraglottic airway is associated with higher first-attempt success than videolaryngoscopy in infants with difficult airways. Continuous ventilation through the supraglottic airway during fiber-optic intubation attempts may lower the incidence of hypoxemia.

Airway management complications in children with difficult tracheal intubation from the Pediatric Difficult Intubation (PeDI) registry: a prospective cohort analysis.

BACKGROUND: Despite the established vulnerability of children during airway management, remarkably little is known about complications in children with difficult tracheal intubation. To address this concern, we developed a multicentre registry (Pediatric Difficult Intubation [PeDI]) to characterise risk factors for difficult tracheal intubation, establish the success rates of various tracheal intubation techniques, catalogue the complications of children with difficult tracheal intubation, and establish the effect of more than two tracheal intubation attempts on complications. METHODS: The PeDI registry consists of prospectively collected tracheal intubation data from 13 children's hospitals in the USA. We established standard data collection methods before implementing the secure web-based registry. After establishing standard definitions, we collected and analysed patient, clinician, and practice data and tracheal intubation outcomes. We categorised complications as severe or non-severe. FINDINGS: Between August, 2012, and January, 2015, 1018 difficult paediatric tracheal intubation encounters were done. The most frequently attempted first tracheal intubation techniques were direct laryngoscopy (n=461, 46%), fibre-optic bronchoscopy (n=284 [28%]), and indirect video laryngoscopy (n=183 [18%]) with first attempt success rates of 16 (3%) of 461 with direct laryngoscopy, 153 (54%) of 284 with fibre-optic bronchoscopy, and 101 (55%) of 183 with indirect video laryngoscopy. Tracheal intubation failed in 19 (2%) of cases. 204 (20%) children had at least one complication; 30 (3%) of these were severe and 192 (19%) were non-severe. The most common severe complication was cardiac arrest, which occurred in 15 (2%) patients. The occurrence of complications was associated with more than two tracheal intubation attempts, a weight of less than 10 kg, short thyromental distance, and three direct laryngoscopy attempts before an indirect technique. Temporary hypoxaemia was the most frequent non-severe complication. INTERPRETATION: More than two direct laryngoscopy attempts in children with difficult tracheal intubation are associated with a high failure rate and an increased incidence of severe complications. These results suggest that limiting the number of direct laryngoscopy attempts and quickly transitioning to an indirect technique when direct laryngoscopy fails would enhance patient safety. FUNDING: None.

Are preformed endotracheal tubes appropriately designed for pediatric patients?

BACKGROUND: The aim of the study was to examine different brands of preformed oral and nasal endotracheal tubes (ETT) and to assess whether the bend placement gave acceptable guidance for ETT depth positioning in children. METHODS: The distance from the vertex of the bend to the tip (bend-to-tip distance) of seven brands of preformed oral and nasal ETTs were measured. Front teeth-to-carina (FTC) and nares-to-carina (NC) distance data from orally (0-19 years) and nasally (0-8 years) intubated children were used to assess the risk of endobronchial intubation if a preformed ETT had been placed with its bend at the front teeth or nares. RESULTS: While the bend-to-tip distance of a cuffed oral preformed ETT only differed by 0-1 cm from a same size ETT from another brand, uncuffed oral ETTs differed by 0-4 cm. The bend-to-tip distance of cuffed and uncuffed ETTs of the same brand and size differed by 0-3 cm. Had preformed cuffed oral ETTs been placed with their bends at the front teeth in children of the FTC reference group, endobronchial intubation would have occurred in 0-27% of the patients, depending on the size and brand of the used ETT. In contrast to oral ETTs, the bend-to-tip distance of cuffed nasal ETTs differed more (0-5.5 cm) between brands, and uncuffed nasal ETTs less (0-3 cm). Also, the bend-to-tip distance of a cuffed nasal ETT was consistently greater (2-9 cm) than that of a same brand and size nasal uncuffed ETT. Had a preformed cuffed nasal ETT been placed with its bend at the nares in the NC reference group, 50-100% of the patients would have been endobronchially intubated. CONCLUSION: The bend-to-tip distance of preformed ETTs varies between brands, especially for nasal tubes. Some preformed tubes are not well suited for routine use in children. There is a high risk for accidental endobronchial intubation if a cuffed preformed ETT is positioned with its bend at the front teeth or nares in a young child. ETT tube tip position needs to be carefully controlled when a preformed ETT is used in a child.

Nares-to-carina distance in children: does a 'modified Morgan formula' give useful guidance during nasal intubation?

BACKGROUND: Knowledge of the normal nares-to-carina (NC) distance might prevent accidental bronchial intubation and be helpful when designing preformed endotracheal tubes (ETT). OBJECTIVE: The aim was to measure NC distance and to examine whether a height/length-based 'modified Morgan formula' would give useful guidance for nasotracheal ETT depth positioning. METHODS: Two groups were studied. A younger group consisted of nasally intubated postoperative patients. In these, NC distance was obtained as the sum of ETT length and the distance from the ETT tip to the carina, as measured from an anteroposterior chest X-ray. An older group consisted of children who had undergone computerized tomography (CT) examination including head, neck, and chest. In these, NC was measured directly from the CT image. The modified Morgan formula was derived from the NC vs height/length relationship. RESULTS: Nares-to-carina distance was best predicted by a linear equation based on patient height. The equation in the younger group (1 day-8 years, n = 57) was: NC (cm) = 0.14 × height + 5.8, R(2) = 0.90, and in the older group (2.1-20 years, n = 45): NC (cm) = 0.15 × height + 3.4, R(2) = 0.93. The equation for the groups combined (n = 102) was: NC (cm) = 0.14 × height + 6.2, R(2) = 0.97. Based on the latter equation, a modified Morgan formula was identified as: ETT position at nares in cm = 0.12 × height + 5. If the ETT had been placed as calculated by this formula, the ETT tip would have been at 85 + 5% (mean ± sd) of NC distance, and the ETT tip-to-carina distance would have been 3.1 ± 1.1 cm (range 0-6.6). Bronchial intubation would not have occurred in any child, but a comparison to tracheal length measurements indicates that ETT tip position could be too proximal in some children. CONCLUSION: The study confirms previous reports: NC distance can be well predicted from height/length. A modified Morgan formula might decrease the risk for accidental endobronchial intubation in infants and children, but ETT position need to be confirmed by auscultation or other verification.