Jay M. Milstein

Increased Indomethacin Dosing for Persistent Patent Ductus Arteriosus in Preterm Infants: A Multicenter, Randomized, Controlled Trial

OBJECTIVE We conducted a multicenter, randomized, controlled trial to determine whether higher doses of indomethacin would improve the rate of patent ductus arteriosus (PDA) closure. STUDY DESIGN Infants (<28 weeks gestation) who received a conventional, prophylactic 3-dose course of indomethacin were eligible if they had continued evidence of persistent ductus patency on an echocardiogram obtained before the third prophylactic indomethacin dose. Infants (n = 105) were randomized to receive an extended 3-day course of either low-dose (0.1 mg/kg/d) or higher-dose (0.2 or 0.5 mg/kg/d) indomethacin. An echocardiogram was obtained 24 hours after the last dose of study drug. RESULTS Despite increasing serum indomethacin concentrations by 2.9-fold in the higher-dose group, we failed to detect a significant decrease in the rate of persistent PDA (low = 52%; higher = 45%, P = .50). The higher-dose group had a significantly higher occurrence of serum creatinine >2 mg/100 mL (low = 6%, higher = 19%, P < .05) and moderate/severe retinopathy of prematurity (ROP) (low = 15%, higher = 36%, P < .025). The incidence of moderate/severe ROP was directly related to the poststudy indomethacin concentrations (odds ratio = 1.75, confidence interval: 1.15-2.68, P < .01). CONCLUSION Increasing indomethacin concentrations above the levels achieved with a conventional dosing regimen had little effect on the rate of PDA closure but was associated with higher rates of moderate/severe ROP and renal compromise.

Near-infrared spectroscopy as a screening tool for patent ductus arteriosus in extremely low birth weight infants.

Background: Patent ductus arteriosus (PDA) is frequent and potentially pathologic in preterm infants. A simple bedside tool to screen for ductal patency would assist in the care of extremely low birth weight (ELBW) infants. Objective: To investigate the utility of near-infrared spectroscopy (NIRS) in identifying ELBW infants who would benefit from early echocardiography. Methods: Tissue oxygen saturation (StO2) was measured by NIRS in the lungs, brain, skeletal muscle and kidney of 20 ELBW infants. Comparisons were made between the StO2 in these organs and the need for intervention for a PDA. All studies were performed within the first 4 days of life. Similar measurements were performed following treatment with indomethacin in nine of the patients. Results: The StO2 of skeletal muscle (left deltoid) and kidney differed between the infants who were treated for PDA and those who were not (p = 0.01 for both). As a screen for a PDA requiring intervention, deltoid StO2 had sensitivity 77% and specificity 83%, and kidney StO2 had sensitivity 85% and specificity 83%. Following treatment with indomethacin, the low StO2 in the deltoid and kidney increased toward the range seen in patients who did not require treatment of a PDA. Inter- and intra-observer variability ranged from minimal to high. Conclusion: This pilot study of a portable NIRS device shows encouraging efficacy in identifying ELBW infants who were likely to benefit from early echocardiography and subsequent intervention to close a PDA. Further study is warranted.

Duplication of the cervical esophagus: a case report and review of the literature

This report describes a newborn with a cervical esophageal duplication cyst, a rare developmental anomaly of the neck. Only a few cases of this cystic entity have been described in the literature to date. This case is unique in that the patient had an air-fluid level within the lesion as a result of communication of the duplication cyst with the native esophagus.

A case of segmental paternal isodisomy of chromosome 14

Abstract. Uniparental disomy of chromosome 14 (UPD 14) results in one of two distinct abnormal phenotypes, depending upon the parent of origin. This discordance may result from the reciprocal over-expression and/or under-expression of one or more imprinted genes. We report a case of segmental paternal isodisomy for chromosome 14 with features similar to those reported in other paternal disomy 14 cases. Microsatellite marker analysis revealed an apparent somatic recombination event in 14q12 leading to proximal biparental inheritance, but segmental paternal uniparental isodisomy distal to this site. Analysis of monochromosomal somatic cell hybrids containing either the paternally inherited or the maternally inherited chromosome 14 revealed no deletion of the maternally inherited chromosome 14 and demonstrated the presence of paternal sequences from D14S121 to the telomere on both chromosomes 14. Thus, the patient has paternal isodisomy for 14q12-14qter. Because the patient shows most of the features associated with paternal disomy 14, this supports the presence of the imprinted domain(s) distal to 14q12 and suggests that the proximal region of chromosome 14 does not contain imprinted genes that contribute significantly to the paternal UPD 14 phenotype.

Pulmonary vasodilator action of tolazoline.

Summary: The pulmonary vasodilator action of tolazoline in newborn lambs was shown to be mediated via histamine receptors. Maximal changes in pulmonary vascular resistance, ΔPVR, were calculated as percents of the base line value, %ΔPVR. The mean %ΔPVR after tolazoline, 1 mg/kg, was −25 ± 4% for eight lambs. Four lambs then received the histamine H1 receptor antagonist, diphen-hydramine, and the mean %ΔPVR due to tolazoline was — 12 ± 4%. Four lambs received the H2 receptor antagonist, metiamide, and the mean %ΔPVR due to tolazoline was −18 ± 5%. After both H1 and H2 antagonists, the mean %ΔPVR due to tolazoline was +6 ± 8%. Therefore, both histamine H1 and H2 receptors were involved in the vasodilator response to tolazoline.Speculation: If the pulmonary vasodilator action of tolazoline is mediated by histamine receptors in human infants, as it is in newborn lambs, it may be possible to select a more specific therapeutic agent for infants with pulmonary vasospasm. Histamine, 2-mcthylhistamine, a specific H1 agonist, or 4-methylhistaminc, a specific H2 agonist, may be such agents in certain situations.

Searching for Circles of Meaning and Using Spiritual Experiences to Help Parents of Infants With Life-Threatening Illness Cope

One of the major challenges parents can face is learning that their child has a life-threatening illness. A phenomenological study was completed to identify which interactions with health care providers were and were not helpful. Parents discussed what it was like to have an infant with a life-threatening illness and what helped them to cope. Parents indicated that they benefited from identifying “circles of meaning,” or ways in which their infant touched another life. Parents appreciated hearing from health care providers that they felt close to their infant. This sense of connection allowed parents to reconstruct a semblance of meaning in the midst of a life-altering event. Parents were also influenced by intuitive and spiritual experiences associated with their infant’s illness. Parents should be encouraged to reflect on spiritual moments and to identify how their critically ill infant influenced the lives of other family members, friends, and health care professionals.

Burnout assessment in house officers: Evaluation of an intervention to reduce stress

Background: Medical house officers are at increased risk for stress related symptoms leading to professional burnout. Aims: Measure burnout in house officers and establish whether utilization of a psychotherapeutic tool individually by physicians reduces symptoms characteristic of burnout. Method: Two groups of pediatric house officers at the University of California Davis Health System completed a Maslach Burnout Survey (MBS) at the beginning and end of a three-month period in 2003. An Intervention group (7 of 15 enrolled) was trained in the use of a self-administered psychotherapeutic tool. Outcome Measures were MBS scores and a qualitative interview of intervention group members. Results: There were no significant differences between the two groups, prior to the study or over time. Qualitative interviews revealed that subjects experience stressors in relation to their professional activities, but already utilize some elements of the tool and were too busy to implement the entire tool systematically. Conclusions: Pediatric trainees did not seem to manifest burnout symptoms based upon the MBS; interviews suggested that some do experience significant stress, although manifestations and responses were varied, some may be at risk. Methods identifying individuals at risk for burnout, and interventions to cope with stress may be valuable to their training.

Escherichia coli endotoxin depresses left ventricular contractility in neonatal lambs

ABSTRACT: We evaluated the effects of Escherichia coli endotoxin on the peripheral vascular hemodynamics and myocardial function of the newborn lamb to understand how gram-negative endotoxemia can lead to cardiovascular collapse in newborn infants. Fifteen lambs, 0–3 d old, were acutely instrumented with a micromanometer-tipped catheter and two pairs of ultrasonic crystals to measure left ventricular (LV) pressure and LV anterior-posterior and septal-free wall dimensions, a fluid-filled catheter for monitoring aortic pressure, and an electromagnetic flow probe to measure systemic blood flow. Cardiovascular performance was evaluated by measuring or deriving the following variables: mean arterial blood pressure (MABP), LV pressure, heart rate, stroke volume, systemic vascular resistance, LV dp/dt, end-diastolic area, arterial elastance, and end-systolic elastance (the slope of the end-systolic pressure-area relationship) as an index of contractility independent of loading conditions and heart rate. Once instrumented, nine lambs received endotoxin, 0.5 mg/kg i.v., and six animals, serving as controls, received a saline infusion. Of the endotoxin-treated lambs, five survived the duration of the study (120 min from the beginning of the endotoxin infusion), and four died by 90 min from the beginning of the endotoxin infusion. No significant changes in any of the cardiovascular variables occurred in the control group. A significant decrease in MABP was seen in all endotoxin-treated animals by 45 min after the beginning of the endotoxin infusion. MABP decreased by 52% from baseline in the survivors and 38% in the nonsurvivors. In the survivors, the MABP stabilized with saline boluses, whereas in the nonsurvivors MABP continued to decrease until death. In the survivors, end-systolic elastance remained stable, and, despite changes in afterload, LV dp/dt also remained stable throughout the study. In the nonsurvivors, the end-systolic elastance and LV dp/dt exhibited a progressive decline until death, with the changes in the end-systolic elastance preceding the changes in LV dp/dt. End-diastolic area and stroke volume remained stable during the study in both groups of endotoxin-treated animals, decreasing in the nonsurvivors just before death. Because the changes in end-systolic elastance and LV dp/dt clearly preceded the decreases in end-diastolic area and stroke volume in the nonsurvivors, we conclude that the myocardial depression in the nonsurvivors was primarily due to depressed myocardial contractility, not decreased preload.

A rare lethal combination of premature closure of the foramen ovale and d-transposition of the great arteries with intact ventricular septum

We report an infant who presented with cyanosis after birth and was unresponsive to all resuscitative efforts. Emergent echocardiogram showed d-transposition of the great arteries (d-TGA) with an intact ventricular septum. Attempts to perform a bedside balloon atrial septostomy failed due to inability to traverse the atrial septum. Autopsy revealed d-TGA with intact atrial and ventricular septa and patent ductus arteriosus. Though no survivors have been reported for this rare lethal combination of lesions thus far in the literature, we speculate that recent advances in fetal treatment may soon be applicable to infants with this condition.

Increased systemic vascular resistance in neonates with pulmonary hypertension

The time necessary for aortic diastolic pressure to decrease to 50 percent of an initially selected value after dissipation of the dicrotic notch (T 1/2) was determined in newborn infants with and without pulmonary hypertension. The mean T 1/2 was 671 +/- 167 msec in seven infants with clinical evidence of pulmonary hypertension and documented right to left ductus arteriosus shunting; 849 +/- 243 msec in nine infants with clinical evidence of pulmonary hypertension but no documented right to left ductus arteriosus shunting; and 457 +/- 66 msec in eight infants with hyaline membrane disease and no clinical evidence of pulmonary hypertension or a patent ductus arteriosus. The mean T 1/2 values in the former two groups were significantly different from that in the group with no pulmonary hypertension (P less than 0.01). An evaluation of factors affecting T 1/2 leads to the conclusion that the patients with pulmonary hypertension had increased systemic vascular resistance as well. This finding has important diagnostic, etiologic and therapeutic implications.