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.

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.

Informed consent in pediatric anesthesiology.

BACKGROUND: Informed consent for pediatric anesthesia is unique because it is (1) obtained from surrogates (ie, parents) rather than from the patient and (2) sought after parents have authorized the surgical intervention. There are limited data on how pediatric anesthesia informed and consent discussions are conducted. The purpose of this study was to characterize the content of preanesthesia informed consent discussions and assess their impact on parent recall and understanding. METHODS: We conducted a cross-sectional observational study at a tertiary pediatric hospital. We audio-recorded and transcribed preanesthesia consent discussions between pediatric anesthesia providers and parents of children undergoing elective surgery. Parents were recruited on the day of surgery and completed a survey postdiscussion to assess their recall and perceived understanding. We used directed content analysis to identify 7 informed consent elements: (i) description of the plan; mention of (ii) alternatives, (iii) risks, and (iv) benefits; (v) discussion of uncertainties; (vi) assessment of comprehension; and (vii) solicitation of a decision. We used multivariable logistic regression to explore the association between discussions that included 3 informed consent elements (description of plan, mention of risks, and mention of benefits) and parent recall and understanding of these elements. RESULTS: We analyzed 97 discussions involving 41 different anesthesia providers. The element most frequently included in preanesthesia discussions was a description of the plan (100%); the least frequently included was decision solicitation (18%). Seventy-one percent of discussions included ≥5 informed consent elements and 70% included a description of the plan, mention of risks, and mention of benefits. Parental recall of these 3 informed consent elements was associated with their inclusion in the preanesthesia discussion (75% vs 34%), and more parents understood all 3 elements if they had reported (vs not reported) recall of all 3 elements (97% vs 53%). CONCLUSION: Most pediatric preanesthesia discussions include ≥5 informed consent elements and describe the plan, mention risks, and mention benefits. Inclusion of these latter 3 consent elements was associated with parental recall of these elements but not understanding.

Early developmental exposure to volatile anesthetics causes behavioral defects in Caenorhabditis elegans.

BACKGROUND: Mounting evidence from animal studies shows that anesthetic exposure in early life leads to apoptosis in the developing nervous system. This loss of neurons has functional consequences in adulthood. Clinical retrospective reviews have suggested that multiple anesthetic exposures in early childhood are associated with learning disabilities later in life as well. Despite much concern about this phenomenon, little is known about the mechanism by which anesthetics initiate neuronal cell death. Caenorhabditis elegans, a powerful genetic animal model, with precisely characterized neural development and cell death pathways, affords an excellent opportunity to study anesthetic-induced neurotoxicity. We hypothesized that exposing the nematode to volatile anesthetics early in life would induce neuron cell death, producing a behavioral defect that would be manifested in adulthood. METHODS: After synchronization and hatching, larval worms were exposed to volatile anesthetics at their 95% effective concentration for 4 hours. On day 4 of life, exposed and control worms were tested for their ability to sense and move to an attractant (i.e., to chemotax). We determined the rate of successful chemotaxis using a standardized chemotaxis index. RESULTS: Wild-type nematodes demonstrated striking deficits in chemotaxis indices after exposure to isoflurane (ISO) or sevoflurane (SEVO) in the first larval stage (chemotaxis index: untreated, 85 ± 2; ISO, 52 ± 2; SEVO, 47 ± 2; P < 0.05 for both exposures). The mitochondrial mutant gas-1 had a heightened effect from the anesthetic exposure (chemotaxis index: untreated, 71 ± 2; ISO, 29 ± 12; SEVO, 24 ± 13; P < 0.05 for both exposures). In contrast, animals unable to undergo apoptosis because of a mutation in the pathway that mediates programmed cell death (ced-3) retained their ability to sense and move toward an attractant (chemotaxis index: untreated, 76 ± 10; ISO, 73 ± 9; SEVO, 76 ± 10). Furthermore, we discovered that the window of greatest susceptibility to anesthetic neurotoxicity in nematodes occurs in the first larval stage after hatching (L1). This coincides with a period of neurogenesis in this model. All values are means ± SD. CONCLUSION: These data indicate that anesthetics affect neurobehavior in nematodes, extending the range of phyla in which early exposure to volatile anesthetics has been shown to cause functional neurological deficits. This implies that anesthetic-induced neurotoxicity occurs via an ancient underlying mechanism. C elegans is a tractable model organism with which to survey an entire genome for molecules that mediate the toxic effects of volatile anesthetics on the developing nervous system.

Acupuncture therapy for infants: a preliminary report on reasons for consultation, feasibility, and tolerability.

OBJECTIVES/AIMS: The aim of this retrospective review was to determine the feasibility, safety, and potential therapeutic effects of acupuncture in an inpatient infant population and to obtain data that would support the design of a randomized, controlled trial of acupuncture in infants. BACKGROUND: Hospitalized infants are often exposed to sedative and analgesic medications to facilitate intensive and invasive medical care. With increasing concern about the potential neurotoxic effects of common analgesic and sedative medications, minimizing an infant's exposure to such agents is desirable. Acupuncture can be therapeutic in adults and children, but data in infants are lacking. METHODS/MATERIALS: We performed a retrospective chart review of infants who received acupuncture during hospitalizations between 2008 and 2010. Demographic data, diagnoses, reason for acupuncture consult, ventilator settings, sedative/analgesic medication regimens, details of acupuncture therapy, and adverse effects were among data collected. RESULTS: Ten infants were identified in this review, seven of whom had agitation issues, two of whom had feeding difficulties, and one had both symptoms. Six of the eight infants with agitation had a decrease in the use of sedative and analgesic medications over the acupuncture therapy period, and four of five initially requiring mechanical ventilation were successfully weaned. One of the three infants with oral aversion transitioned rapidly to oral intake. Acupuncture therapy was well tolerated, and there were no complications observed. CONCLUSIONS: In this small group of hospitalized infants, acupuncture was found to be safe, well tolerated, and therapeutic. More studies are warranted to define the role of acupuncture in this population.

The genetics of isoflurane-induced developmental neurotoxicity.

INTRODUCTION: Neurotoxicity induced by early developmental exposure to volatile anesthetics is a characteristic of organisms across a wide range of species, extending from the nematode C. elegans to mammals. Prevention of anesthetic-induced neurotoxicity (AIN) will rely upon an understanding of its underlying mechanisms. However, no forward genetic screens have been undertaken to identify the critical pathways affected in AIN. By characterizing such pathways, we may identify mechanisms to eliminate isoflurane induced AIN in mammals. METHODS: Chemotaxis in adult C. elegans after larval exposure to isoflurane was used to measure AIN. We initially compared changes in chemotaxis indices between classical mutants known to affect nervous system development adding mutants in response to data. Activation of specific genes was visualized using fluorescent markers. Animals were then treated with rapamycin or preconditioned with isoflurane to test effects on AIN. RESULTS: Forty-four mutations, as well as pharmacologic manipulations, identified two pathways, highly conserved from invertebrates to humans, that regulate AIN in C. elegans. Activation of one stress-protective pathway (DAF-2 dependent) eliminates AIN, while activation of a second stress-responsive pathway (endoplasmic reticulum (ER) associated stress) causes AIN. Pharmacologic inhibition of the mechanistic Target of Rapamycin (mTOR) blocks ER-stress and AIN. Preconditioning with isoflurane prior to larval exposure also inhibited AIN. DISCUSSION: Our data are best explained by a model in which isoflurane acutely inhibits mitochondrial function causing activation of responses that ultimately lead to ER-stress. The neurotoxic effect of isoflurane can be completely prevented by manipulations at multiple points in the pathways that control this response. Endogenous signaling pathways can be recruited to protect organisms from the neurotoxic effects of isoflurane.

Immunofluorescent spectral analysis reveals the intrathecal cannabinoid agonist, AM1241, produces spinal anti-inflammatory cytokine responses in neuropathic rats exhibiting relief from allodynia.

During pathological pain, the actions of the endocannabinoid system, including the cannabinoid 2 receptor (CB(2)R), leads to effective anti-allodynia and modifies a variety of spinal microglial and astrocyte responses. Here, following spinal administration of the CB(2)R compound, AM1241, we examined immunoreactive alterations in markers for activated p38 mitogen-activated protein kinase, interleukin-1ß (IL-1ß), the anti-inflammatory cytokine, interleukin-10 (IL-10) as well as degradative endocannabinoid enzymes, and markers for altered glial responses in neuropathic rats. In these studies, the dorsal horn of the spinal cord and dorsal root ganglia were examined. AM1241 produced profound anti-allodynia with corresponding immunoreactive levels of p38 mitogen-activated kinase, IL-1ß, IL-10, the endocannabinoid enzyme monoacylglycerol lipase, and astrocyte activation markers that were similar to nonneuropathic controls. In contrast, spinal AM1241 did not suppress the increased microglial responses observed in neuropathic rats. The differences in fluorescent markers were determined within discrete anatomical regions by applying spectral analysis methods, which virtually eliminated nonspecific signal during the quantification of specific immunofluorescent intensity. These data reveal expression profiles that support the actions of intrathecal AM1241 control pathological pain through anti-inflammatory mechanisms by modulating critical glial factors, and additionally decrease expression levels of endocannabinoid degradative enzymes.

Intrathecal cannabilactone CB(2)R agonist, AM1710, controls pathological pain and restores basal cytokine levels.

Spinal glial and proinflammatory cytokine actions are strongly implicated in pathological pain. Spinal administration of the anti-inflammatory cytokine interleukin (IL)-10 abolishes pathological pain and suppresses proinflammatory IL-1ß and tumor necrosis factor alpha (TNF-α). Drugs that bind the cannabinoid type-2 receptor (CB(2)R) expressed on spinal glia reduce mechanical hypersensitivity. To better understand the CB(2)R-related anti-inflammatory profile of key anatomical nociceptive regions, we assessed mechanical hypersensitivity and protein profiles following intrathecal application of the cannabilactone CB(2)R agonist, AM1710, in 2 animal models; unilateral sciatic nerve chronic constriction injury (CCI), and spinal application of human immunodeficiency virus-1 glycoprotein 120 (gp120), a model of peri-spinal immune activation. In CCI animals, lumbar dorsal spinal cord and corresponding dorsal root ganglia (DRG) were evaluated by immunohistochemistry for expression of IL-10, IL-1ß, phosphorylated p38-mitogen-activated-kinase (p-p38MAPK), a pathway associated with proinflammatory cytokine production, glial cell markers, and degradative endocannabinoid enzymes, including monoacylglycerol lipase (MAGL). AM1710 reversed bilateral mechanical hypersensitivity. CCI revealed decreased IL-10 expression in dorsal spinal cord and DRG, while AM1710 resulted in increased IL-10, comparable to controls. Adjacent DRG and spinal sections revealed increased IL-1ß, p-p38MAPK, glial markers, and/or MAGL expression, while AM1710 suppressed all but spinal p-p38MAPK and microglial activation. In spinal gp120 animals, AM1710 prevented bilateral mechanical hypersensitivity. For comparison to immunohistochemistry, IL-1ß and TNF-α protein quantification from lumbar spinal and DRG homogenates was determined, and revealed increased DRG IL-1ß protein levels from gp120, that was robustly prevented by AM1710 pretreatment. Cannabilactone CB(2)R agonists are emerging as anti-inflammatory agents with pain therapeutic implications.