Suboptimal Imaging on Obstetric Ultrasound Should Prompt Early Referral for Fetal Echocardiography.

Recent studies suggest that suboptimal cardiac imaging on routine obstetric anatomy ultrasound (OB-scan) is not associated with a higher risk for congenital heart disease (CHD) and, therefore, should not be an indication for fetal echocardiography (F-echo). We aim to determine the incidence of CHD in patients referred for suboptimal imaging in a large catchment area, including regions that are geographically distant from a tertiary care center. We conducted a retrospective chart review of patients referred to Seattle Children's Hospital (SCH) and SCH Regional Cardiology sites (SCH-RC) from 2011 to 2021 for F-echo with the indication of suboptimal cardiac imaging by OB-scan. Of 454 patients referred for suboptimal imaging, 21 (5%) of patients were diagnosed with CHD confirmed on postnatal echo. 10 patients (2%) required intervention by age one. Mean GA at F-echo was significantly later for suboptimal imaging compared to all other referral indications (27.5 ± 3.9 vs 25.2 ± 5.2 weeks, p < 0.01). Mean GA at F-echo was also significantly later at SCH-RC compared to SCH (29.2 ± 4.6 vs 24.2 ± 2.9 weeks; p < 0.01). In our experience, CHD in patients referred for suboptimal imaging is higher (5%) than previously described, suggesting that routine referral for is warranted. Furthermore, while suboptimal imaging was associated with a delayed F-echo compared to other indications, this delay was most striking for those seen at regional sites. This demonstrates a potential disparity for these patients and highlights opportunities for targeted education in cardiac assessment for primary providers in these regions.

Sitting height and subischial leg length centile curves for boys and girls from Southeast England.

PRIMARY OBJECTIVES: The only reference centile curves currently available for body proportions of children in the UK were constructed more than 20 years ago by Tanner and Whitehouse. The current study was designed to produce up-to-date sitting height and subischial leg length centile curves for boys and girls in Southeast England. RESEARCH DESIGN AND METHODS: A convenience sample of 1424 boys and 1208 girls aged under 25 years from Southeast England was measured by a single observer in 1995-1996. Using Cole's LMS method, centile curves were constructed for sitting height and subischial leg length, and the medians by age and sex were then scaled to sum to the corresponding median height of the British 1990 reference. RESULTS: The new centile curves for boys and girls are presented. They differ significantly from those of Tanner and Whitehouse in leg length (boys p < 0.001; girls p < 0.01), but not in sitting height. CONCLUSIONS: The Tanner and Whitehouse reference curves for body segment length are not suitable for contemporary British children, whose legs are longer than they were a generation ago. It is proposed that the curves presented here be adopted provisionally as the new British reference.

Growth reference charts for use in the United Kingdom.

Since the introduction of new growth charts in the mid 1990s, there has been confusion about which charts should be used, with many districts using more than one version. Because of this uncertainty, an expert working party, the Growth Reference Review Group, was convened by the Royal College of Paediatrics and Child Health to provide guidance on the validity and comparability of the different charts currently in use. This paper describes the technical background to the construction and evaluation of growth charts and outlines the group's findings on the validity of each growth reference in relation to contemporary British children. The group concluded that for most clinical purposes the UK90 reference is superior and for many measures is the only usable reference that can be recommended, while the original Tanner-Whitehouse and the Gairdner-Pearson charts are no longer reliable for use at any age. After the age of 2 the revised Buckler-Tanner references are still suitable for assessing height. There are presently no reliable head circumference reference charts for use beyond infancy. The group propose that apart from refinements of chart design and layout, the new UK90 reference should now be "frozen", with any future revisions only undertaken after careful planning and widespread consultation.

Simultaneous assay of morphine, morphine-3-glucuronide and morphine-6-glucuronide in human plasma using normal-phase liquid chromatography-tandem mass spectrometry with a silica column and an aqueous organic mobile phase.

Morphine (MOR) is an opioid analgesic used for the treatment of moderate to severe pain. MOR is extensively metabolized to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). A rapid and sensitive method that was able to reliably detect at least 0.5 ng/ml of MOR and 1.0 ng/ml of M6G was required to define their pharmacokinetic profiles. An LC-MS-MS method was developed in our laboratory to quantify all three analytes with the required sensitivity and a rapid turnaround time. A solid-phase extraction (SPE) was used to isolate MOR, M3G, M6G, and their corresponding deuterated internal standards from heparinized plasma. The extract was injected on a LC tandem mass spectrometer with a turbo ion-spray interface. Baseline chromatographic separation among MOR, M3G, and M6G peaks was achieved on a silica column with an aqueous organic mobile phase consisting of formic acid, water, and acetonitrile. The total chromatographic run time was 3 min per injection, with retention times of 1.5, 1.9 and 2.4 min for MOR, M6G, and M3G, respectively. Chromatographic separation of M3G and M6G from MOR was paramount in establishing the LC-MS-MS method selectivity because of fragmentation of M3G and M6G to MOR at the LC-MS interface. The standard curve range in plasma was 0.5-50 ng/ml for MOR, 1.0-100 ng/ml for M6G, and 10-1000 ng/ml for M3G. The inter-day precision and accuracy of the quality control (QC) samples were <7% relative standard deviation (RSD) and <6% relative error (R.E.) for MOR, <9% RSD and <5% R.E. for M6G, and <3% RSD and <6% R.E. for M3G. Analyte stability during sample processing and storage were established. Method ruggedness was demonstrated by the reproducible performance from multiple analysts using several LC-MS-MS systems to analyze over one thousand samples from clinical trials.

Steady-state relative bioavailability of three oral ganciclovir dosage regimens delivering 6,000 mg/day in patients with human immunodeficiency virus.

This study was designed to determine the steady-state relative bioavailability of ganciclovir after three dosage regimens designed to deliver 6,000 mg/day. The study design was an open-label, randomized, three-treatment crossover design in which 22 human immunodeficiency virus (HIV) and cytomegalovirus (CMV) seropositive patients received in random order multiple oral doses of ganciclovir 1,000 mg six times a day, 1,500 mg four times a day, and 2,000 mg three times a day. Blood samples were obtained on day 3 of each oral regimen over a 24-hour time interval. Mean steady-state average serum concentrations of ganciclovir were greater than 1.0 microgram/mL, which exceeds the median in vitro inhibitory concentration (IC50) of most CMV isolates (0.5-1.0 microgram/mL). All three regimens resulted in values for area under the concentration-time curve from 0 to 24 hours (AUC0-24) that were comparable to those seen after maintenance ganciclovir intravenous infusions of 5 mg/kg/day. The 1,000 mg six times daily regimen resulted in an AUC0-24 that was significantly higher than that of the 1,500 mg four times daily or the 2,000 mg three times daily regimens, although the differences were less than 12.5%.

Effect of high-dose oral ganciclovir on didanosine disposition in human immunodeficiency virus (HIV)-positive patients.

This study was designed to investigate the interaction between high-dose oral ganciclovir (6,000 mg/day) and didanosine at steady state in patients who were seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection. The study was conducted as an open-label, randomized, three-period crossover study. Patients received (in random order) multiple oral doses of didanosine 200 mg every 12 hours alone, ganciclovir 2,000 mg every 8 hours alone, and ganciclovir 2,000 mg every 8 hours in combination with didanosine 200 mg every 12 hours. Blood and urine samples for determinations of drug concentrations were obtained on day 3 of each dose regimen. When ganciclovir was administered either before or 2 hours after didanosine, the mean increases in maximum concentration (Cmax), area under the concentration-time curve (AUC0-12), and percent excreted in urine of didanosine were 58.6% and 87.3%, 87.3% and 124%, and 100% and 153%, respectively. There were no statistically significant effects of didanosine on the steady-state pharmacokinetics of ganciclovir in the presence of didanosine, irrespective of sequence of administration. There were no significant changes in renal clearance of didanosine, suggesting that the mechanism for the interaction does not involve competition for active renal tubular secretion. The mechanism responsible for increased didanosine concentrations and percent excreted in urine during concurrent ganciclovir therapy may be a result of increased bioavailability of didanosine. However, the mechanism appears to be saturated at oral ganciclovir doses of 3 g/day.

Absolute bioavailability and dose proportionality of oral ganciclovir after ascending multiple doses in human immunodeficiency virus (HIV)-positive patients.

This study was designed to determine the bioavailability and dose linearity and proportionality of ganciclovir after multiple oral administrations of 3,000 mg to 6,000 mg per day. In an open-label, randomized, four-treatment crossover design, 24 patients seropositive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) received in random order multiple oral doses of ganciclovir 1,000 mg every 3 hours (six times a day), 1,000 mg four times a day, and 1,000 mg three times a day and a single 5-mg/kg intravenous infusion (over 1 hour) of ganciclovir. Blood samples for pharmacokinetic determinations were obtained on day 3 of each oral regimen and on the day of the intravenous infusion over a 24-hour time interval. Mean steady-state average serum concentrations of ganciclovir were 0.54, 0.79, and 0.99 microgram/mL, respectively, with the 3, 4, and 6 g/day oral regimens. The steady-state area under the concentration-time curve (AUC0-24) for the 6,000 mg/day oral regimen approached that of the single-dose intravenous regimen. There was a proportional increase in AUC0-24 between the 3 and 4 g/day dosage regimens, but not between the 4 and 6 g/day regimens. This suggests nonlinear absorption of ganciclovir at higher dosages, although the departure from proportionality was less than 11%.

Effects of dual-chamber pacing for pediatric patients with hypertrophic obstructive cardiomyopathy.

OBJECTIVES: The effects of both temporary and permanent dual-chamber pacing (DCP) were evaluated in symptomatic pediatric patients with hypertrophic obstructive cardiomyopathy (HOCM) unresponsive to medications. BACKGROUND: Permanent DCP pacing can reduce left ventricular outflow tract (LVOT) gradient and relieve symptoms in adult patients with HOCM. METHODS: Ten patients (mean [+/-SD] age 11.1 +/- 6 years, range 1 to 17.5) with HOCM and a Doppler LVOT gradient > or = 40 mm Hg were studied. The seven patients showing hemodynamic improvement during temporary pacing at cardiac catheterization underwent surgical implantation of a permanent DCP system. The effects of permanent pacing were evaluated using a questionnaire, Doppler evaluation, treadmill testing and repeat cardiac catheterization. RESULTS: At initial cardiac catheterization, three patients failed to respond to temporary pacing (inadequate pace capture in two; congenital mitral valve abnormality in one). The remaining seven patients (70%, 95% confidence interval 38.0% to 91.7%, mean age 13 +/- years, range 4 to 17.5) showed a significant reduction (p < 0.05) in LVOT gradient, left ventricular systolic pressure and pulmonary capillary wedge pressure. After pacemaker implantation, these seven patients reported a significant reduction in dyspnea on exertion and exercise intolerance. Serial Doppler evaluation showed a significant reduction in LVOT gradient. Follow-up catheterization at 23 +/- 4 months in six patients (one patient declined restudy) showed a persistent decrease in LVOT gradient (53 +/- 13 vs. 16 +/- 11 mm Hg), left ventricular systolic pressure (149 +/- 16 vs. 108 +/- 14 mm Hg) and pulmonary capillary wedge pressure (18 +/- 2 vs. 12 +/- 4 mm Hg) versus preimplantation values. CONCLUSIONS: Permanent DCP is an effective therapy for selected pediatric patients with HOCM. Rapid atrial rates and intrinsic atrioventricular conduction, as well as congenital mitral valve abnormalities, may preclude effective pacing in certain patients.

Development and validation of an LC-MS-MS method for the determination of terfenadine in human plasma.

A sensitive LC-MS-MS method capable of quantifying terfenadine at levels down to 100 pg ml-1 in human plasma is reported. The method was validated over a linear range from 0.1 to 5.0 ng ml-1 using a liquid-liquid extraction with a deuterium-labelled internal standard. The between-run precision and accuracy of the calibration standards were 2.6-6.0% RSD and -2.0 to +2.2% relative error (RE). The between-run and within-run precision and accuracy of quality control samples (0.3, 1.5 and 3.5 ng ml-1) were 1.0-5.9% RSD and +1.7 to +6.3% RE. This method was applied to the analysis of human plasma samples.

Determination of nicotine and cotinine in human plasma by liquid chromatography-tandem mass spectrometry with atmospheric-pressure chemical ionization interface.

Here we report a sensitive liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method capable of quantifying nicotine down to 1 ng/ml and cotinine to 10 ng/ml from 1.0 ml of human plasma. The method was validated over linear ranges of 1.0-50.0 ng/ml for nicotine and 10.0-500.0 ng/ml for cotinine, using deuterated internal standards. Compounds were simply extracted from alkalinized human heparinized plasma with methylene chloride, reconstituted into a solution of acetonitrile, methanol and 10 mM ammonium acetate (53:32:15, v/v) after the organic phase was dried down, and analyzed on the LC-MS-MS, which is a PE Sciex API III system equipped with a Keystone BDS Hypersil CI8 column and atmospheric pressure chemical ionization (APCI) interface. The between-run precision and accuracy of the calibration standards were < or = 6.42% relative standard deviation (R.S.D.) and < or = 11.8% relative error (R.E.) for both nicotine and cotinine. The between-run and within-run precision and accuracy of quality controls, (2.5, 15.0, 37.5 ng/ml for nicotine and 25.0, 150.0, 375.0 ng/ml for cotinine), were < or = 6.34% R.S.D. and < or = 7.62% R.E. for both analytes. Sample stabilities in chromatography, in processing and in biological matrix were also investigated. This method has been applied to pharmacokinetic analysis of nicotine and cotinine in human plasma.

Pediatric use of intravenous amiodarone: efficacy and safety in critically ill patients from a multicenter protocol.

OBJECTIVE: The purpose of this study was to analyze the efficacy and safety of intravenous amiodarone in young patients with critical, drug-resistant arrhythmias. BACKGROUND: Intravenous amiodarone has been investigated in adults since the early 1980s. Experience with the drug in young patients is limited. A larger pediatric study group was necessary to provide responsible guidelines for the drug's use before its market release. METHODS: Eight centers obtained institutional approval of a standardized protocol. Other centers were approved on a compassionate use basis after contacting the primary investigator (J.C.P). RESULTS: Forty patients were enrolled. Standard management in all failed. Many patients had early postoperative tachyarrhythmias (25 of 40), with early successful treatment in 21 (84%) of 25. Twelve patients had ventricular tachyarrhythmias: seven had successful therapy, and six died, none related to the drug. Eleven patients had atrial tachyarrhythmias: 10 of 11 had immediate success, but 3 later died. Fourteen patients had junctional ectopic tachycardia, which was treated with success (sinus rhythm or slowing, allowing pacing) in 13 of 14, with no deaths. Three other patients had supraventricular tachycardias, with success in two and no deaths. The average loading dose was 6.3 mg/kg body weight, and 50% of patients required a continuous infusion. Four patients had mild hypotension during the amiodarone bolus. One postoperative patient experienced bradycardia requiring temporary pacing. There were no proarrhythmic effects. Deaths (9 [23%] of 40) were not attributed to amiodarone. CONCLUSIONS: Intravenous amiodarone is safe and effective in most young patients with critical tachyarrhythmia. Intravenous amiodarone can be lifesaving, particularly for postoperative junctional ectopic tachycardia, when standard therapy is ineffective.

Stereospecific determinations of (+/- )-DU-124884 and its metabolites (+/- )-KC-9048 in human plasma by liquid chromatography.

(+)-DU-124884 is a 5-HT1-like receptor agonist under investigation for drug development. A sensitive, stereospecific LC method was developed for the analysis of (+)-DU-124884, its optical isomer (-)-DU-124884 and their N-dealkylated metabolites, (+/- )-KC-9048, in human plasma. A plasma sample was treated with triethylamine in methanol and the proteins were precipitated by acetonitrile. The supernatant was evaporated to dryness under nitrogen. The analytes and internal standard (acebutolol) formed diastereomers with (S)-(+)-1-(1-naphthyl)ethyl isocyanate immediately. The diastereomers formed were extracted into diethyl ether. They were completely resolved from each other and from matrix peaks on a Microsorb silica column with a mobile phase of methanol-chloroform-hexane (8:12:80, v/v/v) in a run time of 26 min. Detection was by fluorescence with excitation wavelength at 320 nm and emission wavelength at 440 nm. The linearity range is 0.1-200 ng ml-1 (r > 0.99). The limit of quantitation is 0.1 ng ml-1 and the detection limit is 0.02 ng ml-1 (signal-to-noise ratio = 3). The interday precision and accuracy of quality control samples were 5.5-7.6% RSD (relative standard deviation) and 0 to+4% bias for (+)-DU-124884, 5.5-7.9% RSD and 0 to +4% bias for (-)-DU-124884, 4.5-6.5% RSD and -7 to 0% bias for (+)-KC-9048 and 4.5-7.5% RSD and -7 to 0% bias for (-)-KC-9048. Consistent recovery from different lots of human plasma, parallelism of the method, stabilities of on-system, reinjection, bench-top, freeze-thaw cycles and sample storage were established.

Cardiovascular effects of cocaine in neonates exposed prenatally.

This blinded cross-sectional study was to determine whether chronic cocaine exposure in utero produces abnormalities in left ventricular function (shortening fraction), heart rate, rhythm, and conduction in term neonates. Three groups of neonates were evaluated by two-dimensional echo Doppler and 24 hour Holter monitor, with studies initiated in the first 24 hours of life. Group A (n = 32) neonates had a positive history of chronic maternal cocaine use in pregnancy (MCU+) and a positive neonatal urine cocaine test (NUC+). Group B (n = 23) neonates were MCU+ but NUC-. Group C (n = 32) neonates were MCU- and NUC-. Measured parameters were compared statistically by analysis of variance. p < 0.05 was regarded as significant. Echocardiography showed no significant difference between groups A, B, and C for left ventricular shortening fraction. Holter monitor likewise revealed no significant difference between groups in minimal, maximal, and average heart rate, or in the incidence of supraventricular and ventricular arrhythmias greater than 20 beats/h in the 24-hour period. None of the patients had atrioventricular or bundle branch block. It is possible that the developmental state of the newborn heart makes it less responsive to the adverse effects of cocaine.

Development and validation of an LC/MS/MS method for the determination of L-hyoscyamine in human plasma.

A sensitive and specific LC/MS/MS method for the determination of L-hyoscyamine was developed and validated over the linearity range 20-500 pg ml-1 with 1.0 ml of plasma using scopolamine as the internal standard. The API III-Plus LC/MS/MS was operated under the multiple reaction monitoring mode using the atmospheric pressure chemical ionization technique. The instrument parameters were optimized to obtain 1.8 min run time with baseline separation of the internal standard from L-hyoscyamine. The between-run precision and accuracy of the calibration standards were 1.2 to 5.0% RSD and -4.5 to +2.5% relative error (RE). The within-run precision and accuracy of quality controls (60, 150 and 350 pg ml-1) were 1.9-3.4% RSD and -3.3 to +5.1% RE. Stability of L-hyoscyamine in human plasma and processed samples has been established.

Tilt table evaluation for control pediatric patients: comparison with symptomatic patients.

This study was designed to evaluate pediatric control patients during head-up tilt in comparison with symptomatic neurocardiogenic syncope patient head-up tilt responses. Twenty-three pediatric control (c) patients (13 females, 10 males; 11.9 +/- 3.1 years) were tested with head-up tilt (HUT) and compared with 66 symptomatic (s) patients. Baseline drug-free HUT (cHUT-1), a second drug-free HUT (cHUT-2), and a final HUT with isoproterenol infusion (cHUT-3) were each performed at 80 degrees tilt angle for 30 min or until positive. For comparison, 66 symptomatic patients (41 females, 25 males; 13.6 +/- 2.5 years) underwent drug-free HUT (sHUT-1); negative responders during sHUT-1 underwent follow-up HUT with isoproterenol (sHUT-2). HUT data were compared for both groups at both 30 and 20 min tilt duration. Twelve control patients (52%) had a symptomatic response during cHUT-1 at 18 +/- 8 min. During cHUT-2, 5 of 23 patients were positive at 13 +/- 5 min; each had previously tested positive during cHUT-1. Two patients, each positive in cHUT-1 and cHUT-2, refused cHUT-3. The only patient testing positive during cHUT-3 was test positive in cHUT-1 but negative for cHUT-2. In comparison, 43 of 66 (65%) symptomatic patients tested positive during drug-free sHUT-1 at 11 +/- 6 min. Subsequently, 20 of the 23 negative patients underwent HUT with isoproterenol (sHUT-2), with 8 of 20 testing positive. Thus, 51 of 66 symptomatic patients (77%) were called "true positives."(ABSTRACT TRUNCATED AT 250 WORDS)