Long-term follow-up of premature infants treated with prophylactic, intratracheal recombinant human CuZn superoxide dismutase.

OBJECTIVE: To examine the long-term effects of treatment with recombinant human CuZn superoxide dismutase (rhSOD) in infants enrolled previously in two placebo-controlled trials. STUDY DESIGN: Records for 46 (88%) infants were examined, with 19 infants having received either single or multiple intratracheal (i.t.) doses of placebo, 12 having received a single i.t. dose of rhSOD, and 15 having received multiple i.t. doses of rhSOD. Mean age at follow-up was 28 months corrected age. Records were examined for neurologic dysfunction, developmental delay, and any significant medical disorders. RESULTS: Four placebo infants (21%) had evidence of neurodevelopmental abnormalities and four infants developed asthma. Four single-dose rhSOD infants (33%) had neurodevelopmental abnormalities and two infants developed asthma. One multiple-dose rhSOD infant had evidence of neurodevelopmental abnormalities and one developed asthma. No other differences were found between the placebo and rhSOD groups. CONCLUSION: Preliminary data suggest that rhSOD is safe and not associated with any long-term adverse effects. Further results will depend on the results of multicenter trials of rhSOD in preterm infants.

Safety and pharmacokinetics of multiple doses of recombinant human CuZn superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome.

OBJECTIVES: To examine the safety and pharmacokinetics of multiple intratracheal (IT) doses of recombinant human CuZn superoxide dismutase (rhSOD) in premature infants with respiratory distress syndrome who are at risk for developing bronchopulmonary dysplasia (BPD). Methods. Thirty-three infants (700 to 1300 g) were randomized and blindly received saline, 2.5 mg/kg or 5 mg/kg rhSOD IT within 2 hours of surfactant administration. Infants were treated every 48 hours (as long as endotracheal intubation was required) up to 7 doses. Serial blood and urine studies, chest radiographs, neurosonograms, SOD concentration and activity measurements, and tracheal aspirate (TA) inflammatory markers were assessed throughout the 28-day study. RESULTS: SOD concentrations in serum (0.1 [0.05/0.15] microg/mL-geometric mean with lower/upper confidence intervals), tracheal aspirates (TA) (0.2 [0.1/0.3] microg/mL) and urine (0.3 [0.2/0.4] microg/mL) were similar at baseline in all 3 groups and did not change significantly in the placebo group. In the rhSOD treatment groups, SOD concentrations were increased on day 3 and did not change significantly thereafter over the 14-day dosing period (also measured on days 5, 7, and 13). SOD concentrations averaged 0.4 [0.3/0.5] microg/mL in serum, 0.8 [0.6/1.2] microg/mL in TA and 1.1 [1.0/1.3] microg/mL in urine for the low-dose group and 0.6 [0.5/0.7] microg/mL in serum, 1.1 [0.9/1.5] microg/mL in TA, and 2.2 [1.6/2.9] microg/mL in urine for the high-dose group over the 14-day dosing period. Enzyme activity directly correlated with SOD concentration and rhSOD was active even when excreted in urine. TA markers of acute lung injury (neutrophil chemotactic activity, albumin concentration) were lower in the rhSOD agroups compared with placebo. No significant differences in any clinical outcome variable were noted between groups. CONCLUSIONS: These data indicate that multiple IT doses of rhSOD increase the concentration and activity of the enzyme in serum, TA and urine, reduce TA lung injury markers and are well-tolerated. Further clinical trials examining the efficacy of rhSOD in the prevention of BPD are warranted.

Safety and pharmacokinetics of recombinant human superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome.

OBJECTIVE: As a first step in the evaluation of recombinant human CuZn superoxide dismutase (rhSOD) in the prevention of neonatal lung injury, safety and pharmacokinetics of intratracheally (IT) administered rhSOD were studied. METHODS: Twenty-six preterm infants weighing 750 to 1250 g with respiratory distress syndrome were studied in three sequential groups (placebo, 0.5, and 5 mg/kg). Placebo or rhSOD was administered IT 30 minutes after the first surfactant dose. Serial blood and urine studies, rhSOD levels, tracheal aspirate fluid (TAF) markers of acute inflammation, radiographs, and ultrasounds were performed over the 28-day study period. RESULTS: Serum SOD concentrations were similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.1 to 0.2 microgram/mL). In the 0.5-mg/kg group, levels were highest at 12 hours (geometric mean 0.7, upper-lower limit 0.5 to 0.8 microgram/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were highest at 6 hours (geometric mean 3.0, upper-lower limit 2.3 to 4.0 micrograms/mL) and returned to baseline by day 4. Concentrations of SOD in TAF were also similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.2 to 0.3 microgram/mL). There were no significant increases in the placebo group, but levels in the 0.5-mg/kg group were highest when first sampled at 24 hours (geometric mean 1.1, upper-lower limit 0.8 to 1.4 micrograms/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were also highest when sampled at 24 hours (geometric mean 1.4, upper-lower limit 0.9 to 2.1 micrograms/mL) and returned to baseline by day 4. Urine levels were highest at 12 hours in both the 0.5-mg/kg (geometric mean 1.3, upper-lower limit 1.0 to 1.7 micrograms/mL) and 5-mg/kg infants (geometric mean 6.4, upper-lower limit 3.9 to 10.4 micrograms/mL) and decreased significantly by day 2 to 3. rhSOD activity assays (serum, TAF, and urine) demonstrated that the enzyme still possessed significant activity. No adverse effects of rhSOD were found. TAF neutrophil chemotactic activity and albumin concentrations, important acute lung injury markers, were significantly lower in the high-dose rhSOD group compared with the other groups. CONCLUSIONS: Data suggest that a single IT dose of rhSOD results in significant increases in both concentration and activity of the antioxidant in serum, TAF, and urine for 2 to 3 days. The enzyme appears to be well tolerated, and TAF inflammatory markers are reduced after administration. This has important implications in rhSOD trials to prevent acute and chronic lung injury in preterm neonates.

A semipermeable skin dressing for extremely low birth weight infants.

Skin breakdown and high fluid requirements are common problems in extremely low birth weight infants that may be reduced by application of a semipermeable skin dressing (SPD). An SPD was applied to 39 study infants who weighed < 1000 gm (control subjects, n = 37) to determine whether it would protect the skin and decrease fluid requirements. Randomization occurred before 12 hours of life and SPD was applied to the chest, abdomen, and back. Sixty-one infants survived the first 14 days. Skin remained nonerythematous, intact, and undamaged under the dressing, whereas uncovered skin sustained significant breakdown in both groups. No significant differences were found in fluid or electrolyte status. Although the SPD did not affect fluid requirements, the significant improvement in skin integrity under the SPD may justify its use in premature infants with delicate skin.

The "88% saturation test": a simple lung function test for young children.

OBJECTIVE: The 88% saturation test (88%-SAT) was developed as an alternative to standard spirometry for those young children unable to perform standard forced expiratory maneuvers. In adults, this test revealed rapid desaturation in those persons with a history of asthma when compared with healthy control subjects. Similar findings in children were tested. SETTING: Tertiary care hospital. PATIENTS: Thirty-three former premature infants (28.3 +/- 2.3 weeks gestation), aged 5 to 7 years, who were participating in a follow-up study, were enrolled in this study. DESIGN: The study compared the 88%-SAT with standard spirometry and respiratory health characteristics ascertained through a parental questionnaire. The 88%-SAT consists of continuous measurement of hemoglobin saturation by pulse oximetry (SaO2) while the subject breathes a nonhumidified 12% oxygen and nitrogen mixture for 10 minutes or until SaO2 decreases to 88%, whichever occurs first. Abnormal 88%-SAT was defined as a decrease of SaO2 to 88% within the 10-minute period, and abnormal spirometry was defined using standardized values. RESULTS: Of the 20 children who successfully completed both spirometry and the 88%-SAT, 10 had normal spirometry results and did not desaturate to 88%, and 5 had abnormal spirometry and 88%-SAT results. Four children did not desaturate during the 88%-SAT, but had abnormal spirometry results, and one child had abnormal 88%-SAT results, but normal spirometry. Ten additional children completed the 88%-SAT, but not standard spirometry. Three children were unable to complete either test. Of those 30 children tested, 7 (23%) had a history of reactive airways disease, and all 7 had abnormal 88%-SAT results. The 88%-SAT had greater sensitivity (100% vs 75%) and specificity (87% vs 63%) than spirometry in identifying children with known reactive airways disease. The mean McCarthy general cognitive index (GCI) of the group performing both spirometry and the 88%-SAT (n = 20) achieved a mean (+/- SD) GCI of 96.2 +/- 16.7, and the group (n = 30) that completed the 88%-SAT had a mean (+/- SD) GCI of 75.2 +/- 26.3 (chi 2 P < .012). The 10 children able to perform only the 88%-SAT had a mean GCI (+/- SD) of 72.8 +/- 26.9, and the 3 children unable to perform either test had a mean GCI (+/- SD) of 63 +/- 11. CONCLUSIONS: Our data suggest that the 88%-SAT may be more effective than spirometry for identifying reactive airways disease in young, uncooperative, or developmentally delayed children. The dry air of the hypoxic inspired gas may function as an airway challenge, leading to decreased oxygenation in patients with reactive airways.

High-frequency jet ventilation and surfactant treatment of newborns with severe respiratory failure.

Twenty-eight newborn infants (birthweight, 2.4 +/- 1.1 kg; gestational age, 34.6 +/- 6.1 weeks) with respiratory distress syndrome (RDS), meconium aspiration syndrome, or pneumonia who deteriorated in spite of optimal conventional mechanical ventilation (CMV) and exogenous surfactant therapy were treated with high-frequency jet ventilation (HFJV) and continued surfactant therapy. For enrollment, infants had to have a limited response to surfactant therapy and conventional ventilation, and meet clinical criteria that confirmed clinical deterioration and severity of illness. Study infants had received exogenous calf lung surfactant extract (CLSE) and conventional ventilation prior to the start of HFJV at 46.3 +/- 8.2 hours of age. Patients initially responded to HFJV alone with significant improvement in several respiratory variables, but deteriorated subsequently and receive additional doses of exogenous surfactant on HFJV. Exogenous surfactant and HFJV resulted in significant and sustained improvement in several respiratory variables. Only ten patients deteriorated to meet criteria for a second surfactant dose on HFJV, and two patients received a third dose. Twenty-five of the 28 patients studied survived (89%). No patients received extracorporeal membrane oxygenation or were discharged home on oxygen. The results of this pilot study suggest that the combination of HFJV and exogenous surfactant replacement may be effective in treating infants with more severe respiratory failure, and indicate the need for more extensive controlled investigations.

Nasal continuous positive airway pressure facilitates extubation of very low birth weight neonates.

A prospective randomized trial was performed in 58 neonates comparing nasal continuous positive airway pressure (NCPAP) vs oxyhood following extubation of neonates weighing less than 1 kg. All neonates had been ventilated for the treatment of respiratory distress syndrome for at least 24 hours and weighed less than 1 kg at the time of extubation. Clinical criteria for elective extubation included improving pulmonary status, fraction of inspired oxygen (FIO2) less than or equal to 0.35, mean airway pressure less than or equal to 7 cm H2O, ventilator rate less than or equal to 20 breaths per minute, and weight at least 80% of birth weight. Informed consent was obtained and neonates were randomized to NCPAP or oxyhood following extubation. Success was defined as remaining free of additional ventilatory support for at least 5 days. Failure criteria included FIO2 greater than or equal to 0.60 to maintain pulse oximetry greater than or equal to 93%, PaCO2 greater than or equal to 60 mm Hg, pH less than or equal to 7.23, or moderate to severe apnea. Results demonstrate that 22 (76%) of 29 neonates were successfully extubated to NCPAP while only 6 (21%) of 29 were successfully extubated to oxyhood (P less than .0001). There were no differences in baseline characteristics between the two groups. Of the 23 neonates who failed oxyhood, 21 were then given a trial of NCPAP and 58% (12/21) remained extubated. Data indicate that using selected clinical criteria for elective extubation of neonates weighing less than 1 kg, NCPAP facilitates successful extubation.

Left main coronary artery obstruction. Follow-up of thirty patients with and without surgery.

Thirty patients, 20 males and 10 females, having a 50% or greater obstruction of the left main coronary artery, were evaluated. Their ages ranged from 40 to 71 years (mean 53.8 years). All patients had angina pectoris, the duration of which varied from 2 months to 20 years (mean 5.4 years). Twenty-four patients (80%) had accelerated angina pectoris; 17 (56.7%) had prior myocardial infarction, and 27 (90%) were found to have coexisting three-vessel disease and abnormal left ventricular contraction. There were no deaths or serious arrhythmias related to cardiac catheterization procedures. In the 11 unoperated patients 5 (45%) died within the first year of follow-up; however, all except one death occurred in patients with diffuse distal coronary artery disease technically unsuitable for surgery. Among the six survivors four were considered surgical candidates. These four patients have continued to have symptoms of angina pectoris with a mean follow-up period of 17.5 months (16 to 20 months). In the 19 patients who underwent aortocoronary saphenous vein bypass grafting, there was one immediate postoperative death (surgical mortality 5.3%) and one late death. The 17 survivors in the surgical group have a mean follow-up period of 17.3 months (8 to 31 months); 13 of them have clinically improved with 6 being totally free of angina pectoris. Thus, mortality is extremely high in those with poor distal vasculature technically unsuitable for surgery, but mortality is relatively low in patients who have technically bypassable lesions whether treated surgically or medically. Although saphenous vein bypass grafting appears to be more effective in providing clinical improvement, asymptomatic left main coronary obstruction may not justify surgical therapy.

Hemodynamic features of prolapsing and nonprolapsing left atrial myxoma.

In the course of the evaluation of five patients with left atrial myxoma, it was noted that the movement of the myxoma was related to specific changes in left atrial hemodynamics. Prolapsing tumors, Type I, move from the left ventricle to the left atrium in early systole and from the left atrium to the left ventricle in early diastole, thereby causing prominent c and v waves accompanied by a rapid y descent. Nonprolapsing tumors, Type II, remain in the left atrium during the entire cardiac cycle, impeding flow across the mitral valve. In these latter cases, the y descent is slow and indistinguishable from that caused by mitral valvular stenosis. The cineangiocardiograms and echocardiograms corroborate these two types of hemodynamic observations. The particular value of direct echocardiographic examination of the left atrium prior to cardiac catheterization was evident in two of the three patients with nonprolapsing tumors. Since the hemodynamic pattern of nonprolapsing left atrial myxoma resembles that of mitral valvular stenosis, it is stressed that echocardiography should have an important place in precatheterization assessment of patients with mitral valve disease. If left atrial myxoma is suspected clinically or on the basis of echocardiographic findings, regardless of the pressure curve contours, transseptal cardiac catheterization should be avoided and the left atrium visualized by pulmonary angiography levophase.