Artemin growth factor increases nicotinic cholinergic receptor subunit expression and activity in nociceptive sensory neurons.

BACKGROUND: Artemin (Artn), a member of the glial cell line-derived growth factor (GDNF) family, supports the development and function of a subpopulation of peptidergic, TRPV1-positive sensory neurons. Artn (enovin, neublastin) is elevated in inflamed tissue and its injection in skin causes transient thermal hyperalgesia. A genome wide expression analysis of trigeminal ganglia of mice that overexpress Artn in the skin (ART-OE mice) showed elevation in nicotinic acetylcholine receptor (nAChR) subunits, suggesting these ion channels contribute to Artn-induced sensitivity. Here we have used gene expression, immunolabeling, patch clamp electrophysiology and behavioral testing assays to investigate the link between Artn, nicotinic subunit expression and thermal hypersensitivity. RESULTS: Reverse transcriptase-PCR validation showed increased levels of mRNAs encoding the nAChR subunits α3 (13.3-fold), ß3 (4-fold) and ß4 (7.7-fold) in trigeminal ganglia and α3 (4-fold) and ß4 (2.8-fold) in dorsal root ganglia (DRG) of ART-OE mice. Sensory ganglia of ART-OE mice had increased immunoreactivity for nAChRα3 and exhibited increased overlap in labeling with GFRα3-positive neurons. Patch clamp analysis of back-labeled cutaneous afferents showed that while the majority of nicotine-evoked currents in DRG neurons had biophysical and pharmacological properties of α7-subunit containing nAChRs, the Artn-induced increase in α3 and ß4 subunits resulted in functional channels. Behavioral analysis of ART-OE and wildtype mice showed that Artn-induced thermal hyperalgesia can be blocked by mecamylamine or hexamethonium. Complete Freund's adjuvant (CFA) inflammation of paw skin, which causes an increase in Artn in the skin, also increased the level of nAChR mRNAs in DRG. Finally, the increase in nAChRs transcription was not dependent on the Artn-induced increase in TRPV1 or TRPA1 in ART-OE mice since nAChRs were elevated in ganglia of TRPV1/TRPA1 double knockout mice. CONCLUSIONS: These findings suggest that Artn regulates the expression and composition of nAChRs in GFRα3 nociceptors and that these changes contribute to the thermal hypersensitivity that develops in response to Artn injection and perhaps to inflammation.

The effect of cisatracurium and rocuronium on lung function in anesthetized children.

BACKGROUND: Neuromuscular blocking drugs have been implicated in intraoperative bronchoconstrictive episodes. We examined the effects of clinically relevant doses of cisatracurium and rocuronium on the lung mechanics of pediatric subjects. We hypothesized that cisatracurium and rocuronium would have bronchoconstrictive effects. METHODS: We studied ASA physical status I and II pediatric subjects having elective dental or urological procedures, requiring general anesthesia with endotracheal intubations with either cisatracurium or rocuronium. Pulmonary function tests were performed before and after neuromuscular blocking drug dosing and again after albuterol administration. Using forced deflation and passive deflation techniques, forced vital capacity (FVC) and maximum expiratory flow rate at 10% (MEF10) of FVC were obtained. Fractional changes from the baseline were used to compare subjects. Changes in MEF10 of >30% were considered clinically significant. A Shapiro-Wilk test, paired t test, and Wilcoxon rank sum test were used to analyze the data. RESULTS: Twenty-five subjects (median age = 5.25 years; range = 9 months-9.9 years) were studied; 12 subjects received cisatracurium and 13 subjects received rocuronium. Data are shown as mean proportional change ± SD or, in the case of not normally distributed, median proportional change (first, third quartile) with P values. In the cisatracurium group, there were no differences between baseline and postneuromuscular blocker administration in the fractional change from the baselines of FVC (1.00 ± 0.04, P = 0.5), but there was a significant decrease in MEF10 (0.80 ± 0.18, P = 0.002). In the rocuronium group, there were small yet significant decreases of FVC (0.99 [first quartile 0.97, third quartile 1], P = 0.02) and significant decreases in MEF10 (0.78 ± 0.26, P = 0.008). After administration of albuterol in the cisatracurium group, FVC increased slightly but significantly from baseline values (1.02 ± 0.02, P = 0.005). MEF10 increased significantly beyond baseline values (1.24 ± 0.43, P =0.04). In the rocuronium group, there were also significant differences between baseline and postalbuterol administration from the baseline value of FVC (1.02 ± 0.02, P = 0.004) and MEF10 (1.23 ± 0.29, P = 0.01). CONCLUSIONS: At clinically relevant doses, both cisatracurium and rocuronium caused changes in lung function, indicating constriction of smaller airways. In general, these changes were mild and not clinically detectable. However, in the rocuronium group, 3 of 13 patients showed more noticeable decreases in MEF10 (≤50%), demonstrating the potential for significant broncho-bronchiolar constriction in susceptible patients.

Thoracic malformation with early-onset scoliosis: effect of serial VEPTR expansion thoracoplasty on lung growth and function in children.

The effect on pulmonary function of serial VEPTR expansion thoracoplasty was studied longitudinally in anesthetized children with spondylothoracic dysplasia using a special mobile unit. The median age of 24 children at the start of surgery was 4.6 years (1.8-10.8) and most exhibited a moderate-to-severe restrictive lung defect. After a median of 3.2 years (1.0-6.5), their forced vital capacity (FVC) was found to have increased by an average of 11.1%/year. The rate of increase was greater in children who were younger than 6 years at the start of the study than in older children (14.5% versus 6.5%, p<0.01). The average specific respiratory system compliance (C(rs)) was mildly-to-moderately decreased at the start, and over the study it decreased on average to 56% of the initial value in spite of clinically successful expansion thoracoplasty and lung growth, indicating increasing stiffness of the thorax with growth.

Paravertebral Nerve Block for Donor Site Pain in Stage I Microtia Reconstruction: A Pilot Study.

Acute Interventional Perioperative Pain Service consultants have routinely placed paravertebral nerve block (PVB) catheters for the continuous release of ropivacaine following stage I microtia reconstruction with costal cartilage graft at our institution since 2010. A retrospective chart review from July 2006 was performed to compare the length of hospital stay, median pain score (0-10 scale), and opioid use of patients receiving PVB with those of historical controls. Statistical analysis included t, Mann-Whitney U, and Fisher's exact tests. A total of 15 stage I microtia surgeries were included, 10 with PVB and 5 without. Patients with and without PVB had high peak pain scores (8.4 vs 7.8), remained in the hospital for 3.5 and 3.8 days, and consumed 0.69 and 0.36 mg/kg morphine equivalents, respectively. These findings highlight the feasibility of PVB, but larger studies are needed to optimize pain relief in this population.

Pulmonary and Radiographic Outcomes of VEPTR (Vertical Expandable Prosthetic Titanium Rib) Treatment in Early-Onset Scoliosis.

BACKGROUND: VEPTR (vertical expandable prosthetic titanium rib) expansion thoracoplasty is used to manage thoracic insufficiency syndrome in early-onset scoliosis. Literature regarding the effects of this technique on pulmonary function is scarce. The aim of this study was to report the intermediate-term results of VEPTR expansion thoracoplasty. METHODS: Twenty-one children with thoracic insufficiency syndrome underwent VEPTR expansion thoracoplasty from 2002 to 2012 and had complete chart data, preoperative and follow-up radiographs, and pulmonary function tests performed at the index implantation, first expansion, and last expansion. Pulmonary function tests with forced and passive deflation techniques developed for children under general anesthesia were performed prior to the index implantation and each expansion surgery under the same anesthetic conditions. Pulmonary and radiographic parameters were analyzed longitudinally. RESULTS: Mean follow-up was six years, and mean age at implantation was 4.8 years. The mean number of expansion procedures per patient was eleven, and the mean number of pulmonary function tests was ten. The mean interval between surgical procedures was 6.4 months. Mean forced vital capacity (FVC) increased from 0.65 to 0.96 L (p < 0.0001). However, the percentage of the predicted FVC decreased from 77% to 58%. Respiratory system compliance normalized on the basis of body weight, Crs/kg, decreased by 39%, from 1.4 to 0.86 mL/cm H2O/kg. The mean Cobb angle before treatment was 80°, and the mean maximum thoracic kyphosis angle was 57° (range, 7° to 107°). The initial coronal correction was maintained at the time of final follow-up (67°); however, there was a trend toward a decrease in the maximum thoracic kyphosis angle (to 66°, p = 0.08). Clinically apparent proximal thoracic kyphosis occurred in four patients, and spinal imbalance occurred in seven. The mean gain in T1-T12 height during the treatment period was 18 mm (2.9 mm/year). CONCLUSIONS: FVC improved over time; however, this increase in lung volume did not keep up with the growth of the child, as the percentage of the predicted FVC decreased, and the chest wall stiffness increased. Coronal correction was maintained, but the increase in proximal thoracic kyphosis is concerning. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Effects on lung function of multiple expansion thoracoplasty in children with thoracic insufficiency syndrome: a longitudinal study.

STUDY DESIGN: Longitudinal study of intraoperative pulmonary function in young children with thoracic hypoplasia and scoliosis undergoing multiple expansion thoracoplasty using the vertical expandable prosthetic titanium ribs (VEPTRs). OBJECTIVE: To test the long-term efficacy of VEPTR multiple expansion thoracoplasty. SUMMARY OF BACKGROUND DATA: To our knowledge, no direct measurements of pulmonary function have been reported with VEPTR expansion thoracoplasty. METHODS: There were 10 children with thoracic insufficiency syndrome, secondary to thoracic hypoplasia with progressive scoliosis, studied. A mobile pulmonary function laboratory unit was used to study forced vital capacity (FVC), maximum expiratory flow volume curves, and respiratory system compliance (Crs) with the patient under general anesthesia immediately before and after expansion thoracoplasty. Studies were repeated every 6 months at each subsequent operation for expansion thoracoplasty for the duration up to 33 months. RESULTS: At the baseline studies, FVC showed a moderate-to-severe decrease (69% of predicted values), indicating the presence of significant restrictive lung defect. Only 1 of 10 children had severe airway obstruction. The baseline Crs was markedly decreased in part because of the presence of significant atelectasis. Crs increased with an average of 42% after repeated hyperinflation (deep sighs). There was no change in lung volume or function immediately before versus after completion of expansion thoracoplasty. FVC increased significantly over time, with an average rate of 26.8% per year, the rate of increase similar to that of healthy children of comparative ages. In terms of percent-predicted values, FVC did not change significantly between the baseline and last test, indicating that in most children studied, lung growth kept up with body growth. CONCLUSION: Although it is difficult to assess the extent of the efficacy without a proper or historical control group for comparison, the present study indicates that in children with severe thoracic insufficiency syndrome, the insertion of VEPTRs with multiple expansion thoracoplasties is beneficial over time, by allowing the lungs to expand with body growth without further deterioration in lung function.

Sedation and analgesia in pediatric patients for procedures outside the operating room.

Sedation and analgesia in pediatric patients for procedures outside the operating room are becoming more frequent as health care is being driven to be more cost effective and "efficient." Although anesthesiologists may not be directly involved in sedation or analgesia outside of the operating room, there is a high likelihood that they will be asked by their institutions to be integrally involved in creating and supervising sedation policy given that the American Society of Anesthesiologists and the Joint Commission on Accreditation of Healthcare Organizations consider sedation and analgesia as part of a continuum ranging from minimal sedation to moderate sedation and analgesia, deep sedation and analgesia, and, finally, general anesthesia. Further, anesthesiologists will be asked to define, teach, and credential nonanesthesiology practitioners who perform deep sedation because these practitioners are now required to be qualified to "rescue from general anesthesia."

Neuroselective sensory electrodiagnostic evaluation of 4% liposomal topical lidocaine.

UNLABELLED: We used a neuroselective transcutaneous electrical stimulus to determine the onset time of cutaneous anesthesia with 4% liposomal lidocaine under occluded and nonoccluded conditions. The pain tolerance threshold (PTT) was used to atraumatically evaluate nociception. Twenty adult volunteers had liposomal lidocaine applied to the volar surface of each forearm for durations ranging from 0 through 30 min (at 5-min intervals) under occluded and nonoccluded conditions. The PTT was determined using three different frequencies (2000 Hz, 250 Hz, 5 Hz) stimulating A beta, A delta, and C fibers, respectively. The time to reach the maximum PTT achieved defined the anesthetic onset time for each frequency. A differential onset of cutaneous anesthesia among the three frequencies was clearly demonstrated, however there was no significant difference in onset time between occluded and nonoccluded conditions. Blockade of C fiber transmission occurred significantly earlier than that of A delta (P = 0.029), which occurred earlier than that of A beta (P = 0.001) as determined using the Wilcoxon's signed rank test. We conclude that a mean onset time of approximately 4 +/- 2 min for blockade of C fiber transmission and 6 +/- 4 min for A delta fiber transmission suggests that painful stimuli such as venipuncture may be attenuated as early as 7 min. IMPLICATIONS: An average onset time of approximately 7 min for topical 4% liposomal lidocaine was determined using neuroselective neurostimulation. This suggests that procedural pain such as venipuncture may be attenuated in this time frame. This technique requires correlation with conventional sensory measurements.