Monitoring cardiovascular function in infants with chronic lung disease of prematurity.

In addition to persistent airways disease, survivors of premature birth with chronic lung disease are at risk of cardiovascular sequelae, including pulmonary hypertension, systemic hypertension, left ventricular hypertrophy, and exercise intolerance. The major treatment of pulmonary hypertension is supplemental oxygen, but drugs such as calcium channel blockers may also be required. The use of inhaled nitric oxide for its long term management is being investigated

K+-channel blockade inhibits shear stress-induced pulmonary vasodilation in the ovine fetus.

To determine whether K+-channel activation mediates shear stress-induced pulmonary vasodilation in the fetus, we studied the hemodynamic effects of K+-channel blockers on basal pulmonary vascular resistance and on the pulmonary vascular response to partial compression of the ductus arteriosus (DA) in chronically prepared late-gestation fetal lambs (128-132 days gestation). Study drugs included tetraethylammonium (TEA; Ca2+-dependent K+-channel blocker), glibenclamide (Glib; ATP-dependent K+-channel blocker), charybdotoxin (CTX; preferential high-conductance Ca2+-dependent K+-channel blocker), apamin (Apa; low-conductance Ca2+-dependent K+-channel blocker), and 4-aminopyridine (4-AP; voltage-dependent K+-channel blocker). Catheters were inserted in the left pulmonary artery (LPA) for selective drug infusion and in the main pulmonary artery, aorta, and left atrium to measure pressure. An inflatable vascular occluder was placed around the DA. LPA flow was measured with an ultrasonic flow transducer. Animals were treated with saline, high- or low-dose TEA, Glib, Apa, CTX, CTX plus Apa, or 4-AP injected into the LPA. DA compression caused a time-related decrease in pulmonary vascular resistance in the control, Glib, Apa, CTX, CTX plus Apa, and low-dose TEA groups but not in the high-dose TEA and 4-AP groups. These data suggest that pharmacological blockade of Ca2+- and voltage-dependent K+-channel activity but not of low-conductance Ca2+- and ATP-dependent K+-channel activity attenuates shear stress-induced fetal pulmonary vasodilation.

Effects of inhaled nitric oxide on pulmonary edema and lung neutrophil accumulation in severe experimental hyaline membrane disease.

To determine the effects of inhaled NO (iNO) on pulmonary edema and lung inflammation in experimental hyaline membrane disease (HMD), we measured the effects of iNO on pulmonary hemodynamics, gas exchange, pulmonary edema, and lung myeloperoxidase (MPO) activity in extremely premature lambs (115 d of gestation, 0.78 term). In protocol 1, we measured the effects of iNO (20 ppm) on lung vascular endothelial permeability to 125I-labeled albumin (indexed to blood volume using 57Cr-tagged red blood cells) during 1 h (n = 10) and 3 h (n = 14) of conventional mechanical ventilation with FiO2 = 1.00. In comparison with controls, iNO improved pulmonary hemodynamics and gas exchange, but did not alter lung weight-to-dry weight ratio or vascular permeability to albumin after 1 or 3 h of mechanical ventilation. To determine whether low dose iNO (5 ppm) would decrease lung neutrophil accumulation in severe HMD, we measured lung MPO activity after 4 h of mechanical ventilation with or without iNO (protocol 2). Low dose iNO improved gas exchange during 4 h of mechanical ventilation (PaO2 at 4 h: 119 +/- 35 mm Hg iNO versus 41 +/- 7 mm Hg control, p < 0.05), and reduced MPO activity by 79% (p < 0.05). We conclude that low dose iNO increases pulmonary blood flow, without worsening pulmonary edema, and decreases lung neutrophil accumulation in severe experimental HMD. We speculate that in addition to its hemodynamic effects, low dose iNO decreases early neutrophil recruitment and may attenuate lung injury in severe HMD.

Effects of oxygen and exogenous L-arginine on EDRF activity in fetal pulmonary circulation.

To determine whether L-arginine, the precursor of endothelium-derived relaxing factor (EDRF), increases vasodilator activity in the fetal pulmonary circulation, we studied its effects on basal pulmonary vascular tone and on pulmonary vasodilation stimulated by oxygen and acetylcholine (ACh) in chronically prepared late-gestation fetal lambs. L-Arginine infusion (30-300 mg over 10 min) into the left pulmonary artery (LPA) increased blood flow (18-57%) without changing pulmonary artery pressure. To determine whether O2-induced vasodilation involves EDRF and is augmented by L-arginine treatment, we infused L-arginine or NG-nitro-L-arginine (L-NNA), an inhibitor of EDRF synthesis, while increasing fetal PO2 6 Torr by delivering 100% O2 to the ewe for 120 min. In controls, LPA blood flow progressively increased from 106 +/- 13 ml/min (baseline) to 257 +/- 34 ml/min (peak) at 40 min of increased PO2 (P < 0.05, baseline vs. peak) but steadily returned toward baseline during the next hour. Treatment with L-NNA markedly attenuated O2-induced pulmonary vasodilation (P < 0.05 vs. control). L-Arginine infusion did not augment or sustain the O2-induced vasodilator response. We also examined whether L-arginine could sustain pulmonary vasodilation to ACh, another EDRF-dependent stimulus, and found that the EDRF substrate neither potentiated nor sustained the ACh response. We conclude that: in the fetal lung 1) exogenous L-arginine is a fetal pulmonary vasodilator, 2) increased PO2 augments EDRF activity in the fetal lung, and 3) supplemental L-arginine does not sustain either O2- or ACh-induced vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Fat-soluble vitamins in infants identified by cystic fibrosis newborn screening.

Fat-soluble vitamin status was assessed in 36 infants diagnosed with cystic fibrosis by newborn screening in the Colorado Program. At the time of diagnosis of cystic fibrosis, 36% of infants were hypoalbuminemic, 21% had vitamin A deficiency, 35% had vitamin D deficiency, and 38% had vitamin E deficiency. None had vitamin K deficiency. Supplementation with pancreatic enzymes, a multiple vitamin preparation, and additional vitamin E was associated with normalization of serum albumin, retinol, and 25-hydroxyvitamin D and negative PIVKA testing at age 6 and 12 months. Several patients remained vitamin E deficient, but this was felt to be due to poor compliance. Biochemical evidence of fat-soluble vitamin deficiency is common before age 3 months in infants with CF and responds to supplementation in the first year of life.

Fat-soluble-vitamin status during the first year of life in infants with cystic fibrosis identified by screening of newborns.

We investigated the fat-soluble-vitamin status during the first year of life in 36 infants with cystic fibrosis (CF) consecutively identified by screening of newborns. At initial evaluation (at age 51.0 +/- 26.7 d) 36% of patients were hypoalbuminemic, 21% had low serum retinol, 35% had low serum 25-hydroxyvitamin D. 38% had low serum alpha-tocopherol and low ratios of serum vitamin E to total lipids, and none had elevated protein in vitamin K absence (PIVKA). Hypoalbuminemia was more common in breast-fed than in formula-fed infants. Seventy-two-hour fecal fat excretion correlated inversely with serum alpha-tocopherol. Treatment with oral pancreatic enzyme supplements, a multiple vitamin, and additional vitamin E was associated with normalization of serum albumin, retinol, and 25-hydroxyvitamin D and negative PIVKA at age 6 and 12 mo. Approximately 10% of patients remained vitamin E deficient. Biochemical evidence of fat-soluble-vitamin deficiencies is common before age 3 mo in patients with CF and, except for vitamin E, these deficiencies corrected with standard therapy.