Impact of enantiomer-specific changes in pharmacokinetics between infants and adults on the target concentration of racemic ketorolac: A pooled analysis.

AIMS: Ketorolac is a nonsteroidal anti-inflammatory racemic drug with analgesic effects only attributed to its S-enantiomer. The aim of this study is to quantify enantiomer-specific maturational pharmacokinetics (PK) of ketorolac and investigate if the contribution of both enantiomers to the total ketorolac concentration remains equal between infants and adults or if a change in target racemic concentration should be considered when applied to infants. METHODS: Data were pooled from 5 different studies in adults, children and infants, with 1020 plasma concentrations following single intravenous ketorolac administration. An allometry-based enantiomer-specific population PK model was developed with NONMEM 7.3. Simulations were performed in typical adults and infants to investigate differences in S- and R-ketorolac exposure. RESULTS: S- and R-ketorolac PK were best described with a 3- and a 2-compartment model, respectively. The allometry-based PK parameters accounted for changes between populations. No maturation function of ketorolac clearance could be identified. All model parameters were estimated with adequate precision (relative standard error <50%). Single dose simulations showed that a previously established analgesic concentration at half maximal effect in adults of 0.37 mg/L, had a mean S-ketorolac concentration of 0.057 mg/L, but a mean S-ketorolac concentration of 0.046 mg/L in infants. To match the effective adult S-ketorolac-concentration (0.057 mg/L) in typical infants, the EC50-racemic should be increased to 0.41 mg/L. CONCLUSION: Enantiomer-specific changes in ketorolac PK yield different concentrations and S- and R-ketorolac ratios between infants and adults at identical racemic concentrations. These PK findings should be considered when studies on maturational pharmacodynamics are considered.

Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial.

BACKGROUND: In laboratory animals, exposure to most general anaesthetics leads to neurotoxicity manifested by neuronal cell death and abnormal behaviour and cognition. Some large human cohort studies have shown an association between general anaesthesia at a young age and subsequent neurodevelopmental deficits, but these studies are prone to bias. Others have found no evidence for an association. We aimed to establish whether general anaesthesia in early infancy affects neurodevelopmental outcomes. METHODS: In this international, assessor-masked, equivalence, randomised, controlled trial conducted at 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand, we recruited infants of less than 60 weeks' postmenstrual age who were born at more than 26 weeks' gestation and were undergoing inguinal herniorrhaphy, without previous exposure to general anaesthesia or risk factors for neurological injury. Patients were randomly assigned (1:1) by use of a web-based randomisation service to receive either awake-regional anaesthetic or sevoflurane-based general anaesthetic. Anaesthetists were aware of group allocation, but individuals administering the neurodevelopmental assessments were not. Parents were informed of their infants group allocation upon request, but were told to mask this information from assessors. The primary outcome measure was full-scale intelligence quotient (FSIQ) on the Wechsler Preschool and Primary Scale of Intelligence, third edition (WPPSI-III), at 5 years of age. The primary analysis was done on a per-protocol basis, adjusted for gestational age at birth and country, with multiple imputation used to account for missing data. An intention-to-treat analysis was also done. A difference in means of 5 points was predefined as the clinical equivalence margin. This completed trial is registered with ANZCTR, number ACTRN12606000441516, and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 4023 infants were screened and 722 were randomly allocated: 363 (50%) to the awake-regional anaesthesia group and 359 (50%) to the general anaesthesia group. There were 74 protocol violations in the awake-regional anaesthesia group and two in the general anaesthesia group. Primary outcome data for the per-protocol analysis were obtained from 205 children in the awake-regional anaesthesia group and 242 in the general anaesthesia group. The median duration of general anaesthesia was 54 min (IQR 41-70). The mean FSIQ score was 99·08 (SD 18·35) in the awake-regional anaesthesia group and 98·97 (19·66) in the general anaesthesia group, with a difference in means (awake-regional anaesthesia minus general anaesthesia) of 0·23 (95% CI -2·59 to 3·06), providing strong evidence of equivalence. The results of the intention-to-treat analysis were similar to those of the per-protocol analysis. INTERPRETATION: Slightly less than 1 h of general anaesthesia in early infancy does not alter neurodevelopmental outcome at age 5 years compared with awake-regional anaesthesia in a predominantly male study population. FUNDING: US National Institutes of Health, US Food and Drug Administration, Thrasher Research Fund, Australian National Health and Medical Research Council, Health Technologies Assessment-National Institute for Health Research (UK), Australian and New Zealand College of Anaesthetists, Murdoch Children's Research Institute, Canadian Institutes of Health Research, Canadian Anesthesiologists Society, Pfizer Canada, Italian Ministry of Health, Fonds NutsOhra, UK Clinical Research Network, Perth Children's Hospital Foundation, the Stan Perron Charitable Trust, and the Callahan Estate.

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.

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial.

BACKGROUND: Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. METHODS: In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600. FINDINGS: Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0.169, 95% CI -2.30 to 2.64). The median duration of anaesthesia in the general anaesthesia group was 54 min. INTERPRETATION: For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia. FUNDING: Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN).

Hemodynamic instability during prone spine surgery in a patient with merosin-deficient congenital muscular dystrophy.

Trans-esophageal echocardiography (TEE) and/or central venous pressure (CVP) monitoring are important in the anesthetic management of spine fusion of pediatric patients with severe muscular weakness. This case highlights an unusual situation of apparent acute right ventricular mechanical obstruction after prone positioning and its prompt recognition with CVP monitoring. The anesthetic management of a patient with congenital muscular dystrophy, an uncommon neuromuscular disorder, is presented. Good communication and planning between the anesthesiology and surgical teams allowed completion of the procedure using a lateral approach.

Clinical significance of large rearrangements in BRCA1 and BRCA2.

BACKGROUND: Current estimates of the contribution of large rearrangement (LR) mutations in the BRCA1 (breast cancer 1, early onset) and BRCA2 (breast cancer 2, early onset) genes responsible for hereditary breast and ovarian cancer are based on limited studies of relatively homogeneous patient populations. The prevalence of BRCA1/2 LRs was investigated in 48,456 patients with diverse clinical histories and ancestries, referred for clinical molecular testing for suspicion of hereditary breast and ovarian cancer. METHODS: Sanger sequencing analysis was performed for BRCA1/2 and LR testing for deletions and duplications using a quantitative multiplex polymerase chain reaction assay. Prevalence data were analyzed for patients from different risk and ethnic groups between July 2007 and April 2011. Patients were designated as "high-risk" if their clinical history predicted a high prior probability, wherein LR testing was performed automatically in conjunction with sequencing. "Elective" patients did not meet the high-risk criteria, but underwent LR testing as ordered by the referring health care provider. RESULTS: Overall BRCA1/2 mutation prevalence among high-risk patients was 23.8% versus 8.2% for the elective group. The mutation profile for high-risk patients was 90.1% sequencing mutations versus 9.9% LRs, and for elective patients, 94.1% sequencing versus 5.9% LRs. This difference may reflect the bias in high-risk patients to carry mutations in BRCA1, which has a higher penetrance and frequency of LRs compared with BRCA2. There were significant differences in the prevalence and types of LRs in patients of different ancestries. LR mutations were significantly more common in Latin American/Caribbean patients. CONCLUSIONS: Comprehensive LR testing in conjunction with full gene sequencing is an appropriate strategy for clinical BRCA1/2 analysis.

The PREMM(1,2,6) model predicts risk of MLH1, MSH2, and MSH6 germline mutations based on cancer history.

BACKGROUND & AIMS: We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6 based on personal and family history of cancer. METHODS: Data were analyzed from 4539 probands tested for mutations in MLH1, MSH2, and MSH6. A multivariable polytomous logistic regression model (PREMM(1,2,6)) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases. RESULTS: Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1, 250 in MSH2, and 71 in MSH6). The PREMM(1,2,6) model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.5-2.4), a CRC (4.3; 3.3-5.6), multiple CRCs (13.7; 8.5-22), endometrial cancer (6.1; 4.6-8.2), and extracolonic cancers (3.3; 2.4-4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82-0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83-0.92) for MSH2, and 0.81 (95% CI, 0.69-0.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.86-0.90) and the population-based cases (95% CI, 0.83-0.92). CONCLUSIONS: We developed the PREMM(1,2,6) model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1, MSH2, and MSH6. This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.

CT-guided percutaneous lung biopsy under general anesthesia: a pediatric case series and literature review.

We describe 14 consecutive children who received computed tomography-guided percutaneous lung biopsy (CT-PLB) under general anesthesia over an 18-month period at our institution. Pulmonary hemorrhage (occurring in 36%) and pneumothorax (29%) were the two most common complications; the overall complication rate was 64%. When complications did occur, immediate airway management was facilitated by the presence of an endotracheal tube (ETT). We conclude as follows: (i) CT-PLB in our series is associated with a high risk of both overall and severe complications; (ii) risk of complications is increased by both patient and procedure-related factors; (iii) airway management with ETT may be preferable should a complication arise; (iv) severe complications may necessitate ICU admission, which should be available before proceeding.

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.

Is ethnicity associated with morphine's side effects in children? Morphine pharmacokinetics, analgesic response, and side effects in children having tonsillectomy.

OBJECTIVES/AIMS: To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid-related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non-Latino Caucasian (NL) children. BACKGROUND: Morphine has high interindividual variability in its analgesic response and side effects profile. Earlier studies suggest that morphine response may vary by race and ethnicity. METHODS: Prospective cohort study in L and NL children, 3-17 years of age comparing pain scores, occurrence of side effects, plasma morphine, morphine-6- and morphine-3-glucuronide concentrations measured after a single morphine IV bolus administration. Noncompartmental pharmacokinetic analysis and genotyping for 28 polymorphisms in eight genes (UGT1A8, UGT2B7, ABCB1, COMT, STAT6, MC1R, OPRM1, and ARRB2) were performed. RESULTS: We enrolled 68 children (33 L, 35 NL). There were no differences in pain scores or need for rescue analgesia. Statistically significant differences in the occurrence of side effects were documented: While 58% of L children experienced at least one side effect only 20% of NL did (P = 0.001). Pruritus was four times (P = 0.006) and emesis seven times (P = 0.025) more frequent in L compared with NL. PK parameters were similar between groups. None of the assessed polymorphisms mediated the association between ethnicity and side effects. CONCLUSIONS: We found statistically significant differences in the occurrence of side effects after morphine administration between L and NL children. Neither differences in morphine or metabolite concentrations, nor the genetic polymorphisms examined explain these findings. Studies are needed to further investigate reasons for the increase in morphine side effects by Latino ethnicity.

Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas.

CONTEXT: Patients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes. OBJECTIVES: To determine the prevalence of pathogenic APC and MUTYH mutations in patients with multiple colorectal adenomas who had undergone genetic testing and to compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study conducted among 8676 individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the 2 most common MUTYH mutations (Y179C and G396D) between 2004 and 2011. Individuals with either mutation underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by polyp burden; the clinical characteristics associated with a pathogenic mutation were evaluated using logistic regression analyses. MAIN OUTCOME MEASURE: Prevalence of pathogenic mutations in APC and MUTYH genes. RESULTS: Colorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis (≥100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% [95% CI, 71%-87%]) and 2 of 119 (2% [95% CI, 0.2%-6%]), respectively, among individuals with 1000 or more adenomas, 756 of 1338 (56% [95% CI, 54%-59%]) and 94 of 1338 (7% [95% CI, 6%-8%]) among those with 100 to 999 adenomas, 326 of 3253 (10% [95% CI, 9%-11%]) and 233 of 3253 (7% [95% CI, 6%-8%]) among those with 20 to 99 adenomas, and 50 of 970 (5% [95% CI, 4%-7%]) and 37 of 970 (4% [95% CI, 3%-5%]) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses. CONCLUSIONS: Among patients with multiple colorectal adenomas, pathogenic APC and MUTYH mutation prevalence varied considerably by adenoma count, including within those with a classic polyposis phenotype. APC mutations predominated in patients with classic polyposis, whereas prevalence of APC and MUTYH mutations was similar in attenuated polyposis. These findings require external validation.

Successful implementation of a pediatric sedation protocol for mechanically ventilated patients.

OBJECTIVE: To evaluate the effect of a nursing-driven sedation protocol for mechanically ventilated pediatric patients on duration of use of analgesic and sedative medications. We hypothesized that a protocol would decrease length of sedation use and decrease days of mechanical ventilation and length of stay. DESIGN: Retrospective cohort study with historical controls. SETTING: Thirty-one-bed tertiary care, medical-surgical-cardiac pediatric intensive care unit in a metropolitan university-affiliated children's hospital. PATIENTS: Children requiring mechanical ventilation longer than 48 hrs not meeting exclusion criteria. INTERVENTIONS: Before protocol implementation, sedation was managed per individual physician orders. During the intervention period, analgesia and sedation were managed by nurses following an algorithm-based sedation protocol based on a comfort score. MEASUREMENTS AND MAIN RESULTS: The observation group included consecutive patients admitted during the 12-month period before protocol education and implementation (n = 153). The intervention group included patients admitted during the 12 months following protocol implementation (n = 166). The median duration of total sedation days (intravenous plus enteral) was 7 days for the observation period and 5 days for the intervention period (p = .026). Specifically, the median duration of morphine infusion was 6 days for the observation period and 5 days for the intervention period (p = .015), whereas the median duration of lorazepam infusion was 2 days for the observation period and 0 days for the intervention period. After adjusting for severity of illness with the pediatric risk of mortality III (PRISM III) score, the Cox proportional hazards regression analysis demonstrated that at any point in time, patients in the intervention group were 23% more likely to be off all sedation (heart rate 0.77, p = .020). Additionally, the intervention group tended to be associated with fewer days of mechanical ventilation (heart rate 0.81, p = .060) and decreased pediatric intensive care unit length of stay (heart rate 0.81, p = .058), although these associations did not quite reach statistical significance. CONCLUSION: A pediatric sedation protocol can significantly decrease days of benzodiazepine and opiate administration, which may improve pediatric intensive care unit resource utilization.

Hypertension despite dehydration during severe pediatric diabetic ketoacidosis.

OBJECTIVE: Diabetic ketoacidosis (DKA) may result in both dehydration and cerebral edema but these processes may have opposing effects on blood pressure. We examined the relationship between dehydration and blood pressure in pediatric DKA. DESIGN: A retrospective review was performed at Seattle Children's Hospital, Seattle, WA. Participants were hospitalized children less than 18 yr. Intervention(s) or main exposure was to patients with DKA (venous pH < 7.3, glucose > 300 mg/dL, HCO(3) < 15 mEq/L, and urinary ketosis). Dehydration was calculated as percent body weight lost at admission compared to discharge. Hypertension (systolic and/or diastolic blood pressure (DBP) percentile > 95%) was defined based on National Heart, Lung, and Blood Institute (NHLBI, 2004) nomograms and hypotension was defined as systolic blood pressure (SBP) <70 + 2 [age]. RESULTS: Thirty-three patients (median 10.9 yr; range 10 months to 17 yr) were included. Fifty-eight percent of patients (19/33) had hypertension on admission before treatment and 82% had hypertension during the first 6 h of admission. None had admission hypotension. Hypertension 48 h after treatment and weeks after discharge was common (28 and 19%, respectively). Based on weight gained by discharge, 27% of patients had mild, 61% had moderate, and 12% presented with severe dehydration. CONCLUSION: Despite dehydration, most children admitted with severe DKA had hypertension.

Ketorolac tromethamine: stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2-6 months.

OBJECTIVE: We determined the postoperative pharmacokinetics (PK), safety, and analgesic effects of ketorolac in 14 infants (aged <6 months) receiving a single intravenous (IV) administration of racemic ketorolac or placebo. BACKGROUND: Information on the PK of ketorolac in infants is limited. Unblinded studies suggest ketorolac may be useful in infants. METHODS: This double-blinded, placebo-controlled study enrolled 14 infants (aged <6 months) postoperatively. At 6-18 h after surgery, infants were randomized to receive placebo, 0.5 mg·kg(-1), or 1 mg·kg(-1) ketorolac IV. All infants received morphine sulfate as needed for pain control. Blood was collected up to 12-h postdosing. Analysis used noncompartmental and compartmental population modeling methods. RESULTS: In addition to noncompartmental and empirical Bayes PK modeling, data were integrated with a previously studied data set comprising 25 infants and toddlers (aged 6-18 months). A two-compartmental model described the comprehensive data set. The population estimates of the R (+) isomer were (%CV): central volume of distribution 1130 (10%) ml, peripheral volume of distribution 626 (25%) ml, and clearance from the central compartment 7.40 (8%) ml·min(-1). Those of the S (-) isomer were 1930 (15%) ml, 319 (58%) ml, and 39.5 (13%) ml·min(-1). Typical elimination half-lives were 191 and 33 min, respectively. There was a trend for increased clearance and central volume with increasing age and weight. The base model suggested that clearance of the S (-) isomer was weakly related to age; however, when body size adjustment was added to the model, no covariates were significant. Safety assessment showed no changes in renal or hepatic function tests, surgical drain output, or continuous oximetry between groups. Cumulative morphine administration showed large inter-patient variability and was not different between groups. CONCLUSION: Stereo-isomer-specific clearance of ketorolac in infants (aged 2-6 months) shows rapid elimination of the analgesic S (-) isomer as reported in infants aged 6-18 months. No adverse effects were seen after a single IV ketorolac dose.

Acute unilateral enlargement of the parotid gland immediately post craniotomy in a pediatric patient: a case report.

A temporary acute unilateral enlargement of the parotid gland or "anesthesia mumps" has been described in both surgical and anesthesia literature. It has been described in elderly, dehydrated, poorly nourished, and post-operative patients. We present a 5-year-old patient who underwent a left temporal craniotomy for seizure focus resection and quadriceps muscle biopsy. Immediately post procedure, he was noted to have an acute unilateral enlargement of the right parotid gland. We report acute unilateral parotitis as a possible, but uncommon, complication of positioning in the pediatric population and to discuss possible pathophysiology and prevention, as well as a review of the available literature.

Two-agent analgesia versus acetaminophen in children having bilateral myringotomies and tubes surgery.

OBJECTIVES: The objective of this study was to determine whether the incidence of emergence agitation (EA) can be reduced by adding an additional, faster onset, non-IV analgesic, intranasal fentanyl or intramuscular (im) ketorolac to rectal acetaminophen. AIM: To compare the incidence of EA after analgesia with two agents vs acetaminophen alone in pediatric patients after bilateral myringotomy procedures (BM&T). BACKGROUND: Anesthesia for BM&T is usually performed with volatile anesthetics as a single agent without securing intravenous access. The anesthetic agent most commonly used is sevoflurane; however, EA has been reported in up to 67% of patients. Emergence agitation is distressing for parents, can impair the ability of nursing staff to adequately monitor the child, and can result in a child injuring him/herself if it is severe. METHODS/MATERIALS: A standardized anesthetic was used with oral midazolam premedication and sevoflurane for induction, and maintenance of anesthesia. All patients received 40 mg·kg(-1) rectal acetaminophen, group 1 received acetaminophen alone, group 2 received acetaminophen and 1 mcg·kg(-1) of intranasal fentanyl, and group 3 received acetaminophen and 1 mg·kg(-1) of intramuscular ketorolac. Incidence of EA was compared using chi-square test between the acetaminophen group alone vs the two-agent analgesia groups combined. RESULTS: There were no differences in demographic and clinical characteristics between the two groups. There were no statistically significant differences between the three groups for the incidence of EA at any time point during recovery from anesthesia nor were there any significant differences in pain scores or side effects. No significant side effects because of the administration of a second analgesic agent were reported. CONCLUSIONS: We conclude that two-agent analgesia is not superior to acetaminophen alone for decreasing the incidence of EA after inhalation anesthesia with sevoflurane for BM&T surgery. Our overall incidence of EA was low compared to previous studies, which could potentially have decreased our ability to detect differences between groups.

Feasibility of Acupuncture to Induce Sleep for Brainstem Auditory Evoked Response Testing.

Purpose Brainstem auditory evoked response (BAER) testing is often performed under general anesthesia for children unable to complete behavioral audiologic evaluation. Alternatively, acupuncture treatment may be considered appropriate for BAER. Reports of acupuncture treatment in pediatric patients are scarce but are needed to demonstrate effectiveness. This study had 2 main objectives: (a) to examine the feasibility and effectiveness of acupuncture to achieve sleep to perform diagnostic BAER testing in medically complex (Cohort I) and nonmedically complex (Cohort II) children and (b) to assess acceptability to parents and audiologists of acupuncture as an alternative to anesthesia for BAER testing. Method A prospective feasibility study at Seattle Children's Hospital Outpatient Audiology Clinic from August 2015 through December 2018 was performed. A total of 31 pediatric patients were included. The median age for Cohort I was 29 months (interquartile range: 19-37 months), and the median age for Cohort II was 25.5 months (interquartile range: 16-32 months). Variables included number of BAER thresholds obtained, sleep indicators, and acceptability. The cost of BAER with acupuncture and the cost of BAER under anesthesia were compared. Results Acupuncture treatment effectively contributed to an adequate sleep state to obtain BAER results for most patients in both cohorts. Across cohorts, most patients (81%) fell asleep after acupuncture treatment. Complete test results were obtained in 48% of patients. Audiologists and parents reported high satisfaction rates with this procedure (87%). There were no adverse safety effects. Acupuncture treatment was less costly than anesthesia for BAER testing. Conclusions Acupuncture to induce sleep for BAER testing is effective, safe, and cost-efficient in small samples of medically and nonmedically complex pediatric patients. This procedure allowed earlier detection of hearing status and avoided potential adverse effects of anesthesia. Audiologists and parents reported that acupuncture treatment was an acceptable alternative to anesthesia for the BAER procedure.

Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance.

Classification of rare missense variants as neutral or disease causing is a challenge and has important implications for genetic counseling. A multifactorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 has previously been developed, which uses data on co-occurrence of the unclassified variant with pathogenic mutations in the same gene, cosegregation of the unclassified variant with affected status, and Grantham analysis of the fit between the missense substitution and the evolutionary range of variation observed at its position in the protein. We have further developed this model to take into account relevant features of BRCA1- and BRCA2-associated tumors, such as the characteristic histopathology and immunochemical profiles associated with pathogenic mutations in BRCA1, and the fact that approximately 80% of tumors from BRCA1 and BRCA2 carriers undergo inactivation of the wild-type allele by loss of heterozygosity. We examined 10 BRCA1 and 15 BRCA2 unclassified variants identified in Australian, multiple-case breast cancer families. By a combination of genetic, in silico, and histopathologic analyses, we were able to classify one BRCA1 variant as pathogenic and six BRCA1 and seven BRCA2 variants as neutral. Five of these neutral variants were also found in at least 1 of 180 healthy controls, suggesting that screening a large number of appropriate controls might be a useful adjunct to other methods for evaluation of unclassified variants.

Surgical practice and outcome in 711 neonates and infants undergoing hernia repair in a large multicenter RCT: Secondary results from the GAS Study.

BACKGROUND: The GAS study is an international RCT to evaluate neurodevelopmental outcome comparing general plus regional anesthesia versus regional anesthesia alone in 722 neonates and infants who had inguinal hernia repair up to 60 weeks of postmenstrual age. This paper comprises a secondary descriptive analysis of hernias, aspects of surgery and outcomes. METHODS: The incidence of unilateral and bilateral hernias, side preponderance, predictive factors for bilateral hernias and surgical approaches were collated. Follow-up outcome data were examined at 2 years. RESULTS: Of 711 eligible patients, there were 679 with hernia data showing that 321 hernias were right-sided, 190 left and 168 bilateral. Male to female ratio was 5:1. Of those with unilateral hernias, 25.8% underwent contralateral exploration and in these cases a patent processus vaginalis was found in 68.9%. Bilateral hernias were more common in younger and female patients. At 2 years there was a recurrence rate of 0.99% and in 2.7% of patients a hernia was evident on the contralateral side (metachrony), and this was unrelated to the anesthesia technique. CONCLUSIONS: Bilateral hernias are associated with lower gestational age at birth and female gender. There was a low incidence of complications and the anesthesia technique did not affect surgical outcome. LEVEL OF EVIDENCE: Level 1 evidence from prospective treatment study.

Clinical trial designs and models for analgesic medications for acute pain in neonates, infants, toddlers, children, and adolescents: ACTTION recommendations.

Clinical trials to test the safety and efficacy of analgesics across all pediatric age cohorts are needed to avoid inappropriate extrapolation of adult data to children. However, the selection of acute pain models and trial design attributes to maximize assay sensitivity, by pediatric age cohort, remains problematic. Acute pain models used for drug treatment trials in adults are not directly applicable to the pediatric age cohorts-neonates, infants, toddlers, children, and adolescents. Developmental maturation of metabolic enzymes in infants and children must be taken into consideration when designing trials to test analgesic treatments for acute pain. Assessment tools based on the levels of cognitive maturation and behavioral repertoire must be selected as outcome measures. Models and designs of clinical trials of analgesic medications used in the treatment of acute pain in neonates, infants, toddlers, children, and adolescents were reviewed and discussed at an Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) Pediatric Pain Research Consortium consensus meeting. Based on extensive reviews and continuing discussions, the authors recommend a number of acute pain clinical trial models and design attributes that have the potential to improve the study of analgesic medications in pediatric populations. Recommendations are also provided regarding additional research needed to support the use of other acute pain models across pediatric age cohorts.