Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1.

Opioids are very effective analgesics, but they are also highly addictive. Methadone is used to treat opioid dependence (OD), acting as a selective agonist at the µ-opioid receptor encoded by the gene OPRM1. Determining the optimal methadone maintenance dose is time consuming; currently, no biomarkers are available to guide treatment. In methadone-treated OD subjects drawn from a case and control sample, we conducted a genome-wide association study of usual daily methadone dose. In African-American (AA) OD subjects (n=383), we identified a genome-wide significant association between therapeutic methadone dose (mean=68.0 mg, s.d.=30.1 mg) and rs73568641 (P=2.8 × 10-8), the nearest gene (306 kilobases) being OPRM1. Each minor (C) allele corresponded to an additional ~20 mg day-1 of oral methadone, an effect specific to AAs. In European-Americans (EAs) (n=1027), no genome-wide significant associations with methadone dose (mean=77.8 mg, s.d.=33.9 mg) were observed. In an independent set of opioid-naive AA children being treated for surgical pain, rs73568641-C was associated with a higher required dose of morphine (n=241, P=3.9 × 10-2). Similarly, independent genomic loci previously shown to associate with higher opioid analgesic dose were associated with higher methadone dose in the OD sample (AA and EA: n=1410, genetic score P=1.3 × 10-3). The present results in AAs indicate that genetic variants influencing opioid sensitivity across different clinical settings could contribute to precision pharmacotherapy for pain and addiction.

A comparison of awake versus paralyzed tracheal intubation for infants with pyloric stenosis.

UNLABELLED: This prospective, nonrandomized, observational study of 76 infants with pyloric stenosis was conducted at an academic children's hospital and compared awake versus paralyzed tracheal intubation in terms of successful first attempt rate, intubation time, heart rate (HR) and arterial hemoglobin oxygen saturation (SpO2) changes, and complications. Three groups were determined by intubation method: awake (A) with an oxygen-insufflating laryngoscope, after rapid-sequence induction (R), or after modified rapid-sequence induction (M) including ventilation through cricoid pressure. Successful first attempt intubation rate was 64% for Group A versus 87% for paralyzed Groups R and M (P = 0.028). Median intubation time was 63 s in Group A versus 34 s in Groups R and M (P = 0.004). Transient, mild decreases in mean HR and SpO2 and incidences of significant bradycardia and decreased SpO2 did not vary by group. Complications, including bronchial or esophageal intubation, emesis, and oropharyngeal trauma, were few. Senior anesthesiologists intervened in four tracheal intubations. We advocate anesthetized, paralyzed tracheal intubation because struggling with conscious infants takes longer, often requires multiple attempts, and prevents neither bradycardia nor decreased SpO2. After induction, additional mask ventilation with O2 confers no advantage over immediate tracheal intubation in preserving SpO2. IMPLICATIONS: In our children's hospital, awake tracheal intubation was not superior to anesthetized, paralyzed intubation in maintaining adequate oxygenation and heart rate or in reducing complications, and should be abandoned in favor of the latter technique for routine anesthetic management of otherwise healthy infants with pyloric stenosis.

Endoscopic findings in hypertrophic pyloric stenosis: appearance in classic and evolving disease.

BACKGROUND: Hypertrophic pyloric stenosis (HPS) is the most common abdominal surgical disorder in infants. Although the majority of cases are diagnosed by ultrasound, equivocal cases may require endoscopy. This study was performed to assess the various endoscopic appearances of HPS in infants. METHODS: A prospective study comparing the endoscopic appearance of the antrum and pylorus of 18 children with HPS to 21 children in a normal control group. RESULTS: Antral or pyloric mucosal hypertrophy was visualized endoscopically in all 18 study patients. The degree of mucosal thickening varied depending on the age of presentation and duration of symptoms. Antral fold hypertrophy was first noted at 10 days of age, and in the oldest patient (4 months of age) a pyloric mass was noted. By comparison, 21 control infants had no evidence of antral or pyloric narrowing or mucosal thickening. CONCLUSIONS: Upper endoscopy can be a valuable adjunctive diagnostic tool in select cases of HPS when imaging tests are inconclusive or when infants present with clinical symptoms outside the typical age-time frame for HPS. Because HPS may evolve over time, it is important that the endoscopist recognize the different appearances of HPS.

Gastric fluid volume in infants for pyloromyotomy.

PURPOSE: To quantify gastric fluid volumes in infants with pyloric stenosis presenting for pyloromyotomy and to demonstrate endoscopically the efficacy of blind aspiration for gastric fluid recovery. We hypothesized that previous diagnostic contrast studies, preoperative nasogastric suction, and fasting interval would not affect these volumes. METHODS: Seventy-five infants scheduled for pyloromyotomy were given atropine before induction of anaesthesia. For those who had undergone preoperative nasogastric suction, the nasogastric tube was aspirated and removed. A 14 F multiorificed orogastric catheter was blindly passed to aspirate gastric fluid for measurement. Following tracheal intubation, 15/75 subjects underwent gastroscopy to measure residual gastric fluid. RESULTS: Gastric fluid volume removed by blind aspiration averaged 4.8 +/- 4.3 ml.kg-1 with 83% of patients having > 1.25 ml.kg-1. Although 14 of the 15 patients evaluated by endoscope had < or = 1 ml residual gastric fluid, one had 1.8 ml.kg-1. Recovery of total gastric fluid volume by blind aspiration averaged 96 +/- 7%. The large gastric fluid volumes were independent of a history of barium study, preoperative nasogastric suction, and fasting interval. CONCLUSION: Infants with pyloric stenosis have large gastric fluid volumes which are not substantially reduced by preoperative nasogastric suction. Blind aspiration of gastric contents prior to induction of anaesthesia provides a reliable estimate of total gastric fluid for most of these infants, although the occasional infant may retain a small amount of gastric fluid. The clinical importance of such a residual volume is uncertain.

Gastric fluid measurement by blind aspiration in paediatric patients: a gastroscopic evaluation.

PURPOSE: Numerous investigators have estimated gastric fluid volume using blind aspiration through multi-orificed catheters, but none have confirmed the validity of this technique in infants and children. We sought to validate the accuracy of this technique in a fasted paediatric population by using gastroscopy. Data from several studies were then combined to generate a gastric fluid volume frequency distribution for healthy paediatric patients fasted for surgery. METHODS: This is a prospective study of 17 patients aged six months to 11 yr who underwent elective upper endoscopy at a paediatric teaching hospital. Gastric contents were aspirated blindly with a syringe and a 16 or 18F multi-orificed orogastric tube, and the volume of gastric contents removed in the supine and decubitus positions was measured. Residual gastric fluid was aspirated using an endoscope. Data from 611 infants and children enrolled in previously published studies utilizing the same blind aspiration technique were pooled and a gastric fluid volume frequency distribution was created. RESULTS: Blind aspiration removed 97 +/- 8% of the total gastric fluid volume. In 661 children presenting for elective surgery, the gastric fluid volume was 0.40 +/- 0.45 ml.kg-1. Median volume was 0.27 ml.kg-1, with the 95%ile at 1.25 ml.kg-1 and an upper limit of 4.1 ml.kg-1. CONCLUSION: Blind aspiration of gastric contents accurately estimates gastric fluid volume for paediatric patients fasted for surgery. Population estimates for gastric fluid volume in otherwise healthy fasted paediatric patients are shown.

A simple homemade lighted stylet for neonates and infants: a description and case report of its use in an infant with the Pierre Robin anomalad.

The glossoptosis and micrognathia associated with Pierre Robin anomalad can make tracheal intubation by conventional laryngoscopy quite difficult. Lighted stylets may be helpful in the successful intubation of infants with this anomalad, but those currently available that are small enough to accommodate 3.0 mm ID tracheal tubes have two major drawbacks limiting their utility: an insufficiently rigid stylet component and a nonadjustable, overly bright light. We describe a lighted stylet that can be easily assembled in the operating room which overcomes these problems and allowed us to successfully intubate a six-day-old with severe Pierre Robin anomalad.