Extracorporeal membrane oxygenation exposes infants to the plasticizer, di(2-ethylhexyl)phthalate.

OBJECTIVES: To determine the exposure to, and evaluate the potential toxicity from, the plasticizer, di(2-ethylhexyl)phthalate (DEHP) during extracorporeal membrane oxygenation (ECMO) therapy. DESIGN: Protocol 1 consisted of a prospective comparison of three ECMO circuit designs in vitro. Protocol 2 consisted of a prospective, comparative clinical study evaluating DEHP plasma concentrations in ECMO vs. non-ECMO patients with respiratory failure. SETTING: Neonatal intensive care unit at The Children's National Medical Center, Washington, DC. PATIENTS: In protocol 2, 28 consecutive term infants were referred for ECMO therapy. Eighteen infants required ECMO; ten control patients received conventional ventilation and improved without ECMO. INTERVENTIONS: In protocol 1, three ECMO circuit designs were primed in vitro with normal saline, albumin, and human blood, which was maintained at 37 degrees C and recirculated at 400 mL/min for 48 hrs. Plasma samples were obtained at time 0, 1 hr, and every 6 hrs. In protocol 2, ventilatory and cardiovascular management of the patients in the study was conducted by the attending physician. Patients were placed on ECMO when they met the institutional criteria for ECMO therapy. Daily plasma concentrations for DEHP were collected until 3 days after decannulation from bypass in the ECMO group. Control patients were sampled daily until extubation. Evidence of cardiac, liver, or lung toxicity was evaluated by Chest Radiographic Scores, liver function studies, and echocardiograms obtained on day 1, day 3, and the day of decannulation in the ECMO group, or at the time of extubation in the control group. Sedation, blood product transfusions as indicated, antibiotics, and hyperalimentation were administered to all patients. MEASUREMENTS AND MAIN RESULTS: All DEHP plasma concentrations were measured by gas chromatography. In protocol 1, three circuits were studied: circuit A (small surface area); circuit B (larger surface area); and circuit C (surface area of A but with heparin-bonded tubing in the circuit). DEHP leached from circuit A at 0.32 +/- 0.12 microgram/ mL/hr, compared with 0.57 +/- 0.14 microgram/mL/hr from circuit B (p < .05). This amount of DEHP extrapolates in the ECMO patient to a potential exposure of 20 to 70 times that exposure from other medical devices or procedures, such as transfusions, dialysis, or short-term cardiopulmonary bypass. Circuit C showed almost no leaching from the circuit; DEHP concentrations decreased at a rate of 0.2 +/- 0.04 microgram/mL/ hr. In protocol 2, DEHP was undetected in the control patients. DEHP concentrations in ECMO patients were greater in the early course of ECMO. However, most patients cleared this compound from the plasma before decannulation. In contrast to the in vitro results in protocol 1, the average highest concentration at any time on bypass was 8.3 +/- 5.7 micrograms/mL or 2 mg/kg. CONCLUSIONS: DEHP leaches from ECMO circuits, with potential exposure concentrations related to the surface area of the tubing in the ECMO circuit. Heparin bonding of the tubing eliminates this risk. Although significant concentrations of DEHP leach from the nonheparin-bonded circuits over time, our in vivo studies showed that the DEHP plasma concentrations were less than the previously reported values and do not correlate with any observable short-term toxicity. This compound may be either efficiently metabolized by the newborn, or redistributed into various tissues. Although signs of toxicity were not found in this study, long-term complications from chronic exposure to DEHP have not been determined.

Inhaled nitric oxide in term infants with hypoxemic respiratory failure.

OBJECTIVE: To determine whether inhaled nitric oxide (NO) administered during conventional mechanical ventilation could produce improvements in oxygenation and reduce the incidence of meeting extracorporeal membrane oxygenation (ECMO) criteria in infants with hypoxemia. DESIGN: Prospective, randomized, controlled trial. Enrolled infants were assigned to conventional treatment with or without adjunctive inhaled NO. Control infants meeting failure criteria (partial pressure of arterial oxygen (PaO2)<80 mm Hg (10.7 kPa)) were allowed to cross over. Caregivers were not masked to group assignment. SETTING: Neonatal intensive care units at the University of Alabama Hospital and the Children's Hospital of Alabama, October 1993 to May 1994. PATIENTS: Newborn infants, both term and near-term, with PaO2 less than 100 mm Hg (13.3 kPa) who were receiving mechanical ventilation with 100% oxygen. Exclusion criteria included major congenital anomalies, diaphragmatic hernia, profound asphyxia, and significant bleeding. INTERVENTIONS: Inhaled NO was initiated in the NO group at a dose of 20 to 40 ppm and advanced stepwise to 80 ppm if PaO2 remained less than 100 mm Hg (13.3 kPa). OUTCOME MEASURES: Primary outcome variables were treatment failure and meeting of ECMO criteria before crossover. Improvement in oxygenation and ultimate use of ECMO or high-frequency oscillatory ventilation were secondary outcome variables. RESULTS: Seventeen neonates with hypoxemia were enrolled; 16 had echocardiographic evidence of pulmonary hypertension, and eight had extrapulmonary shunting. At 1 hour of treatment, two infants in the NO group responded with increases in PaO2 of more than 100 mm Hg (13.3 kPa); after crossover, two had increases in PaO2 of more than 10 mm Hg (1.3 kPa) and one control infant had an increase in PaO2 of more than 10 mm Hg (1.3 kPa). All control infants met failure criteria and crossed over to receive NO; two had increases in PaO2 of more than 10 mm Hg (1.3 kPa) with NO treatment. Despite initial responses, all subjects in both groups eventually met failure criteria. There were no differences between groups in primary outcome variables. CONCLUSIONS: Although inhaled NO produced a transient improvement in oxygenation in some infants, it did not reduce the incidence of meeting ECMO criteria in this population.

Purification of lumazine proteins from Photobacterium leiognathi and Photobacterium phosphoreum: bioluminescence properties.

Bright strains of the marine bioluminescent bacterium Photobacterium leiognathi produce a "lumazine protein" in amounts comparable to that previously found in Photobacterium phosphoreum. New protocols are developed for the purification to homogeneity of the proteins from both species in yields up to 60%. In dimmer strains the amounts of lumazine protein in extracts are less, and also there is an accompanying shift of the bioluminescence spectral maximum to longer wavelength, 492 nm. Both types of lumazine proteins have identical fluorescence spectra, with maxima at 475 nm, so it is suggested that, whereas lumazine protein is the major emitter in bright strains, there is a second emitter also present with a fluorescence maximum at longer wavelength. The two species of lumazine protein have the same 276 nm/visible absorbance ratio, 2.2, but differ in visible maxima: P. phosphoreum, 417 nm; P. leiognathi, 420 nm. For the latter the bound lumazine has epsilon 420 = 10 100 M-1 cm-1, practically the same as in free solution. The two lumazine proteins also differ quantitatively in their effect on the in vitro bioluminescence reaction, i.e., at blue shifting the bioluminescence spectrum or altering the kinetics. The P. phosphoreum lumazine protein is more effective with its homologous luciferase or with P. leiognathi luciferase than is the lumazine protein from P. leiognathi. These differences may have an electrostatic origin.