Pathophysiology of congenital diaphragmatic hernia. III: Exogenous surfactant therapy for the high-risk neonate with CDH.

Exogenous surfactant therapy (EST) in surfactant-deficient premature infants has been shown to improve lung compliance, decrease morbidity, and improve survival. Reports have demonstrated that newborns with congenital diaphragmatic hernia (CDH) have lung compliance, pressure-volume curves, and hyaline membrane formation resembling those changes seen in surfactant deficient premature newborns. We hypothesize that EST may also benefit infants with CDH. All high risk cases of prenatally diagnosed CDH at Children's Hospital of Buffalo from November 1988 to February 1991 were prospectively evaluated for EST. In those families who chose to participate, the surfactant preparation, Infasurf (100 mg/kg), was instilled into the newborn's lungs prior to the first breath. The remainder of the perinatal, neonatal, and surgical care was performed in a routine manner. Three high-risk prenatally diagnosed newborns with left CDH were treated with EST. All showed signs of decreased pulmonary compliance, but could still be adequately oxygenated and ventilated. Surgical correction was performed after stabilization and all required patch closures. Two of the three infants suffered no life-threatening episodes of pulmonary hypertension and all survived. These infants had many known indicators for poor outcome in CDH with an expected survival of less than 20%. We believe that EST in these neonates with CDH contributed to their survival with minimum morbidity. These results suggest that surfactant replacement for the high-risk neonate with CDH warrants further consideration and a randomized clinical trial is being planned.

Extracorporeal enzyme reactors for depletion of phenylalanine in phenylketonuria.

Multitubular enzyme reactors with immobilized enzymes were developed to achieve depletion of circulating substrate by extracorporeal means. To act as prototypes, reactors were prepared with immobilized L-phenylalanine ammonia-lyase, an enzyme that metabolizes phenylalanine to trans-cinnamic acid and ammonia without the need for a coenzyme. We report the first application of phenylalanine ammonia-lyase reactors in an extracorporeal circulation system in a patient with phenylketonuria. A phenylalanine level of 1.82 mmol/L (for the last 6 years) decreased to 1.24 mmol/L after 5.5. hours of treatment, without the enzyme entering the circulation. Total phenylalanine depletion from blood and tissue stores was estimated at 1800 mg. The hemodialysis-like procedure proved to be without side effects, specific for phenylalanine, and suitable in the management of pregnant women with phenylketonuria and late-onset hyperphenylalaninemia. The extracorporeal use of enzyme reactors for temporary enzyme replacement represents a new, safe, and effective therapeutic modality.

Effect of pregnancy on the relationship between concentration and anticoagulant action of heparin.

The anticoagulant effect of heparin, as reflected by the slope of the relationship between heparin concentration and the logarithm of the activated partial thromboplastin time (APTT), was determined in citrated plasma of seven women in the third trimester of pregnancy and in 10 nonpregnant women of comparable age. Factors II, V, and VII to XII, albumin, individual globulins, antithrombin III, fibrinogen, alpha-1-acid glycoprotein, alpha-1-antitrypsin, alpha-2-macroglobulin, prothrombin time, and hematocrit were also determined. Baseline APTT (i.e., APTT without heparin) was 30.2 +/- 3.0 sec (mean +/- SD) in the pregnant women and 29.6 +/- 4.7 sec in the controls (NS). The heparin slope value was 1.68 +/- 0.46 ml/U in the pregnant women and 2.33 +/- 0.49 ml/U in the controls, showing that the anticoagulant effect of heparin is decreased in pregnancy. The prothrombin time was also decreased in pregnancy (19.1 +/- 0.8 vs 23.1 +/- 0.5 sec; P less than 0.01). Pregnancy was associated with a significant increase in the activity of factors VII, VIII, IX, and X and in the concentrations of fibrinogen, alpha-1-globulin, and alpha-1-antitrypsin. The plasma albumin concentration was decreased in the pregnant group. In both the pregnant and nonpregnant women (considered separately), the heparin slope value correlated negatively with factor XI activity (r = -0.85 and -0.71; P less than 0.05). Baseline APTT, which was consistently found to correlate with heparin slope value in previous reports on men and nonpregnant women, also showed such correlation in the nonpregnant group of the present study (r = 0.85; P less than 0.05) but not in the group of pregnant women (r = -0.54; NS). The relative heparin resistance in pregnancy in this investigation is consistent with clinical reports of increased heparin requirements during pregnancy.

Fetomaternal bleeding following diagnostic amniocentesis.

The frequency of diagnostic amniocentesis is increasing. Fetal bleeding and trauma have long been recognized to be complications of amniocentesis. For detection of fetomaternal bleeding, efficacy of modified Kleihauer-Betke staining and alpha-fetoprotein elevation in maternal blood was assessed. Preamniocentesis ultrasound scanning was found useful in reducing the incidence of fetomaternal bleeding and bloody taps. Elevation of alpha-fetoprotein was found to be a more sensitive indicator of fetomaternal bleeding than was modified Kleihauer-Betke staining. The use of alpha-fetoprotein to detect fetomaternal bleeding associated with amniocentesis is suggested for the identification of Rh-negative patients requiring anti-D gamma-globulin to prevent sensitization.

Evaluation of cefoxitin prophylaxis for cesarean section.

Prophylactic cefoxitin was evaluated in 101 patients undergoing cesarean section. A three-dose regimen of either cefoxitin or placebo was administered randomly in a double-blind manner, 46 patients receiving cefoxitin and 55 placebo, with the first dose given after the cord was clamped. In the placebo group, 29% of the patients developed pelvic or wound infection, compared to 4% in the cefoxitin group (P less than 0.003). No patient required re-operation, re-admission, or had a life threatening infection. Ten risk factors for infection were analyzed to help ascertain which patients would benefit from prophylaxis. Cefoxitin, with a broad spectrum of aerobic and anaerobic coverage, was found to be an effective and safe prophylactic agent when given to all patients undergoing cesarean section.

Fetal heart rate variability as an indicator of fetal status.

Numerous studies have shown the clinical usefulness of monitoring fetal heart rate (FHR) variability. Among the disorders associated with decreased FHR variability during labor are fetal asphyxia and acidosis and subsequent distress in the newborn. Among the factors that influence FHR variability are maternal fever, fetal immaturity, so-called fetal sleep, fetal tachycardia, and drug administration to the mother. The nonstress test, which analyzes FHR variability and accelerations of heart rate with fetal movements, may be as useful as the oxytocin challenge test for assessing FHR variability. Doppler ultrasonic cardiography exaggerates the amount of FHR variability. FHR patterns associated with progressive loss of beat-to-beat variability in the absence of maternal drug intake necessitate intervention.