Regional alveolar pressure during periodic flow. Dual manifestations of gas inertia.

We measured pressure excursions at the airway opening and at the alveoli (PA) as well as measured the regional distribution of PA during forced oscillations of six excised dog lungs while frequency (f[2-32 Hz]), tidal volume (VT [5-80 ml]), and mean transpulmonary pressure (PL [25, 10, and 6 cm H2O]) were varied. PA's were measured in four alveolar capsules glued to the pleura of different lobes. The apex-to-base ratio of PA's was used as an index of the distribution of dynamic lung distension. At low f, there was slight preferential distension of the lung base which was independent of VT, but at higher f, preferential distension of the lung apex was found when VT's were small, whereas preferential distension of the lung base was found when VT's approached or exceeded dead space. These VT-related changes in distribution at high frequencies seem to depend upon the branching geometry of the central airways and the relative importance of convective momentum flux vs. unsteady inertia of gas residing therein, which, in this study, we showed to be proportional to the ratio VT/VD*, where VD* is an index of dead space. Furthermore, they imply substantial alteration in the distribution of ventilation during high frequency ventilation as f, VT, and PL vary. The data also indicate that alveolar and airway opening pressure costs per unit flow delivered at the airway opening exhibit weakly nonlinear behavior and that resonant amplification of PA's, which has been described previously for the case of very small VT's, persists but is damped as VT's approach dead space values.

Effect of cholestyramine on the fecal excretion of intravenously administered cholesterol-4-14C and its degradation products in a hypercholesterolemic patient.

The effect of cholestyramine on the fecal excretion of bile acids and neutral sterols was measured in a hypercholesterolemic patient on a low fat, high polyunsaturated fatty acid-containing diet after the intravenous injection of cholesterol-4-(14)C. A significant (16%) lowering of serum cholesterol concentration was accompanied by a 3.2-fold increase in fecal bile acid excretion but no change in neutral sterol output. The increased bile acid loss was adequate to account for the observed fall in serum cholesterol level. The implications of these findings were discussed.

Effect of dietary fat on the fecal excretion of cholesterol and its degradation products in man.

Fecal bile acid and neutral sterol excretion rates were determined in five healthy young men when serum cholesterol changes were induced by isocaloric substitution of an unsaturated (safflower oil) for a saturated fat (butter). The isotope balance method was used after the intravenous injection of cholesterol-4-(14)C. A feces extraction method is presented which permits essentially complete separation of fecal neutral sterols and bile acids. There was a significant increase in the total excretion of the fecal end products of cholesterol metabolism from 966 +/- 42 mg/day on saturated fat to 1147 +/- 45 mg/day on unsaturated fat, and the increase was equally distributed between the neutral sterol and bile acid fractions. With the substitution of dietary fats, regardless of the sequence of their feeding, there was a 28% reduction in serum cholesterol concentration during ingestion of the unsaturated fat. There were reciprocal changes in serum cholesterol levels and fecal steroid excretion with the substitution of one type of fat for the other. The changes in plasma cholesterol content were more than adequately balanced by the reciprocal changes in fecal cholesterol end product excretion. The findings in this study agree with several previous reports in supporting the hypothesis that the hypocholesteremic action of dietary unsaturated fatty acids is associated with an increase in the fecal loss of bile acids and neutral sterols.

Respiratory system impedance from 4 to 40 Hz in paralyzed intubated infants with respiratory disease.

To describe the mechanical characteristics of the respiratory system in intubated neonates with respiratory disease, we measured impedance and resistance in six paralyzed intubated infants with respiratory distress syndrome, three of whom also had pulmonary interstitial emphysema. We subtracted the effects of the endotracheal tube after showing that such subtraction was valid. Oscillatory flow was generated from 4 to 40 Hz by a loudspeaker, airway pressure was measured, and flow was calculated from pressure changes in an airtight enclosure mounted behind the flow source (speaker plethysmograph). After subtraction of the endotracheal tube contribution, resistance ranged from 22 to 34 cmH2O liter-1 s; compliance from 0.22 to 0.68 ml/cmH2O; and inertance from 0.0056 to 0.047 cmH2O liter-1 s2. Our results indicate that, for these intubated infants, the mechanics of the respiratory system are well described as resistance, compliance, and inertance in series. Most of the inertance, some of the resistance, and little of the compliance are due to the endotracheal tube. When the contribution of the endotracheal tube is subtracted, the results are descriptive of the subglottal respiratory system. These data characterize the neonatal respiratory system of infants with respiratory distress syndrome (with or without pulmonary interstitial emphysema) in the range of frequencies used during high frequency ventilation.

Lipids and atherosclerosis.

More than 50 years ago the observation was made that the prevalence of atherosclerosis is unusually low among some of the world's populations. Shortly thereafter came the suggestion that this circumstance is due to the low fat content of their diets and the low cholesterol concentration in their blood. Efforts to apply this thinking for the benefit of human health have taken various turns. The first approach was to recommend a low-fat diet. It was thought that the type of fat in the diet was immaterial and that the dietary cholesterol content made no difference either. Later, it was shown that excellent falls in blood cholesterol could be obtained with high-fat diets if most of the fat was polyunsaturated. Dietary cholesterol was found to play a role, but it must be held at exceptionally low levels before its importance becomes evident. Recently, we have become fearful of excessively high intakes of polyunsaturated fats because no population has consumed such a diet over a long period of time and because of suggestive experimental and epidemiological evidence that the incidence of some forms of cancer may be increased. A low-fat, low-cholesterol diet is the preferred prescription for hyperlipidemia.

Complications of pregnancy and fetal development.

Although the outcome of pregnancy for women with diabetes mellitus has improved in recent years, the infant of the diabetic mother has an increased risk of major clinical problems, particularly in the early neonatal period. These include birth injury due to macrosomia, neonatal hypoglycemia, respiratory distress syndrome, and serious congenital anomalies. Because of the great difficulties encountered during attempts to investigate these problems in clinical research protocols, there is a continuing need to establish appropriate animal models of the diabetic pregnancy. Studies carried out over the past decade, primarily with chemically-induced diabetes have suggested techniques which might be useful. In general, the choice of the animal to be studied will depend on the hypotheses being addressed. For instance, small animals such as rabbits and rats made diabetic with streptozotocin have been successfully used for investigation of fetal lung development. Furthermore, the rat model has been helpful for evaluation of fetal anomalies associated with maldevelopment of the spine and central nervous system. Larger animals, such as the nonhuman primate, are more appropriate for studying placental function and amniotic fluid composition in diabetic pregnancies. The task group on pregnancy and fetal development recommends that animal models of diabetes mellitus be used for a more extensive hormonal and metabolic characterization of diabetic mothers during pregnancy, for investigation of placental physiology with respect to the transfer of substrates from mother to fetus, for systematic and comprehensive study of mechanisms controlling fetal lung development, and for delineation of the pathophysiology of neonatal hypoglycemia. It is further recommended that animal models of spontaneous diabetes such as the BB/W rat be used in future studies dealing with pregnancy and fetal development. Because females with spontaneous diabetes show reduced conception rates, there is a pressing need to enhance the fertility of these animals in order to intensify studies on fetal development.

The hypolipidemic effect of locust bean gum food products in familial hypercholesterolemic adults and children.

Seventeen adults and 11 children, a group of 18 familial hypercholesterolemic (FHC) and 10 normal subjects, were fed products with and without locust bean gum (LBG) (8 to 30 g/day) to assess the hypolipidemic effect of LBG. Identical food products with and without LBG were consumed by two groups (A and B) of arbitrarily assigned patients using a cross-over design. Plasma cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and triglycerides were measured at 2-wk intervals and compared to control feeding periods. In group A, FHC C decreased 10% and LDL-C 11%, normal subjects decreased C 6% and LDL-C 10% (p less than 0.001). In group B, FHC C decreased 17% and LDL-C 19%, normal subjects decreased cholesterol 11%, and LDL-C 6% (p less than 0.001). Cholesterol and LDL-C were lowered in FHC children in both groups. High-density lipoprotein/LDL ratios increased in both groups. The use of food products with LBG in children and adults is a unique approach to treating FHC. LBG food acceptance was good, and there were no significant side effects. LBG in food products appears to be an effective, safe approach to controlling hyperlipidemia.

Lightly hydrogenated soy oil versus other vegetable oils as a lipid-lowering dietary constituent.

Fully refined, bleached, deodorized corn oil and soy oil, and lightly hydrogenated, winterized soy oil were compared for effectiveness in lowering plasma cholesterol. Twenty-four, healthy, young college students were the subjects for the 10-wk studies. At the 300 cal level, the corn oil and unhydrogenated soy oil diets contained approximately 53 g of polyunsaturated and 26 g of saturated fat. The hydrogenated soy oil diet contained 42 and 25 g, respectively. All diets contained approximately 700 mg of cholesterol. Corn oil and unhydrogenated soy oil were equally effective in lowering both total and low density lipoprotein cholesterol. Lightly hydrogenated soy oil was also quite effective, but less so that the more unsaturated oils. Triglycerides were also lowered, but very low density and high density lipoprotein cholesterol concentrations, as well as total high density lipoproteins, were scarcely affected. All of the polyunsaturated fat diets produced small but statistically significant reductions in the cholesterol to protein ratio of all three lipoproteins.

Treatment of type III hyperlipoproteinemia with four different treatment regimens.

The efficacy of clofibrate (CPIB) and nicotinic acid (NA) in the treatment of type III hyperlipoproteinemia was evaluated in 5 male subjects in a randomized cross-over study with clofibrate 1 g b.i.d. and NA 3 g/day (given either b.i.d. or t.i.d.). Following a baseline period of 6 weeks, each drug was given for 12 weeks with samples for lipid and lipoprotein determinations obtained at 6, 9, and 12 weeks. Both clofibrate and NA resulted in a significant reduction from baseline of total cholesterol (23% and 28%), VLDL cholesterol (49% and 56%), total triglycerides (40% and 43%), and VLDL triglycerides (46% and 48%), as well as a significant increase in HDL cholesterol (22% and 28%) and HDL/LDL ratio (31% and 62%). The HDL/LDL ratio was higher on NA than clofibrate (0.47 +/- 0.19 vs. 0.38 +/- 0.09, P less than 0.05). Four subjects were continued in the study and treated sequentially with NA 3.0 g/day (alternate to the previous schedule) and gemfibrozil 1.2 g/d in divided doses. Each of the 4 regimens resulted in a significant change from baseline of each of the measured lipid and lipoprotein determinations except LDL cholesterol. Comparison among the treatment regimens revealed no differences except for significantly higher HDL cholesterol and HDL/LDL ratio with NA given t.i.d.

Response to a cholesterol-lowering diet: efficacy is greater in hypercholesterolemic subjects even after adjustment for regression to the mean.

PURPOSE: To define how much regression to the mean confounds apparent responsiveness in subgroup analyses, and to test, using techniques that remove regression to the mean, whether hypercholesterolemic subjects are more likely to respond to diet. PATIENTS AND METHODS: Data collected on 812 men and women participating in the Minnesota Coronary Survey Dietary Trial who had at least 2 total cholesterol measurements on a high-saturated-fat diet and 1 cholesterol measurement on a low-saturated-fat diet were analyzed for the effects of initial serum cholesterol and regression toward the mean on measurement of diet responsiveness. RESULTS: If regression towards the mean is not taken into account, dietary responsiveness in patients with mean cholesterol levels of 280 mg/dL was -25%, whereas dietary responsiveness in subjects with mean serum cholesterol levels of 156 mg/dL was -5%. After regression toward the mean was taken into account, subjects with high initial serum cholesterol levels had an 18% reduction in serum cholesterol levels whereas subjects with lower levels had an 11% reduction. Even after regression toward the mean is accounted for, subjects with high serum cholesterol levels were significantly more diet-responsive (p < 0.005). CONCLUSION: The efficacy of a cholesterol-lowering diet for individuals can be overestimated or underestimated if only single measurements are used to determine response. Subjects with hypercholesterolemia, even after adjustment for regression towards the mean, are more diet-responsive than subjects with lower cholesterol levels. Dietary therapy should remain the first step in the treatment of hypercholesterolemia, and should also be effective in reducing cholesterol levels in the population at large.

Comparison of effectiveness of thyrotropin-suppressive doses of D- and L-thyroxine in treatment of hypercholesterolemia.

In an attempt to compare the cholesterol-lowering effects of equivalent doses of D- and L-thyroxine, 10 euthyroid, hypercholesterolemic subjects were treated with graded doses of each medication in a cross-over design using thyrotropin suppression following thyrotropin-releasing hormone administration as the end-point. The mean thyrotropin-suppressive dose of D-thyroxine was 2.4 +/- 0.66 mg per day, which resulted in mean reductions of 10 percent in total plasma cholesterol, 10 percent in plasma low-density lipoprotein cholesterol, and 11 percent in plasma high-density lipoprotein cholesterol. The mean thyrotropin-suppressive dose of L-thyroxine was 135 +/- 46 micrograms per day, which resulted in mean reductions of 7 percent in total plasma cholesterol, 6 percent in plasma low-density lipoprotein cholesterol, and 14 percent in plasma high-density lipoprotein cholesterol. The reductions in total, low-density, and high-density cholesterol achieved with D-thyroxine were not significantly different from those achieved with L-thyroxine. Neither medication produced a significant increase in heart rate or ventricular ectopy as determined by Holter monitoring. These data do not support the belief that D-thyroxine has a preferential cholesterol-lowering effect in humans when compared with equivalent doses of L-thyroxine. In addition, both D- and L-thyroxine reduced plasma high-density lipoprotein cholesterol.

High-frequency ventilation in premature infants with lung disease: adequate gas exchange at low tracheal pressure.

The technique of high-frequency ventilation (HFV) was used in ten infants with severe respiratory distress syndrome and five infants with pulmonary interstitial emphysema (PIE). The mean frequency used was 12 Hz (720/min). Peak tracheal pressure for the infants with respiratory distress syndrome was 28 +/- 4 (SD) cm H2O on conventional ventilation, and 22 +/- 4 cm H2O on HFV (P less than .05). For the infants with PIE, peak tracheal pressure decreased from 38 +/- 11 to 24 +/- 5 cm H2O (P less than .05). Mean tracheal pressure was the same for the two types of ventilation. No adverse clinical or pathologic side effects were seen. Clinical and radiologic improvements were seen in the infants with PIE after initiation of HFV. It is believed that these improvements in the patients with PIE were secondary to the decrease in tracheal pressure and that HFV may have a role in treatment of preexisting barotrauma and its prevention. These studies contribute to the preliminary data necessary before controlled trials of HFV in infants with respiratory distress syndrome and PIE can be carried out.

Hemodynamic response to high-frequency ventilation in infants following cardiac surgery.

The hemodynamic response to high-frequency ventilation was compared with conventional ventilation in six infants following cardiac surgery. While undergoing high-frequency ventilation, adequate gas exchange was maintained in all infants. High frequency ventilation allowed a reduction of peak ventilatory pressure at the airway opening by 19%, and peak tracheal pressure by 42%. No clinically important changes in heart rate, systemic and pulmonary arterial pressure, cardiac index, or systemic and pulmonary vascular resistance were noted when high-frequency ventilation was compared with conventional ventilation.

Improved neonatal survival following multiple doses of bovine surfactant in very premature neonates at risk for respiratory distress syndrome.

To determine whether multiple doses of bovine surfactant would improve neonatal mortality in very premature neonates, we conducted two multicenter controlled trials under identical protocols; the results were combined for analysis. Four hundred and thirty neonates born between 23 and 29 weeks gestation and weighing 600 to 1250 g at birth were assigned randomly at birth to receive either 100 mg of phospholipids/kg of Survanta, a modified bovine surfactant (n = 210), or a sham air placebo (n = 220) within 15 minutes of birth. Neonates who developed respiratory distress syndrome and required mechanical ventilation with at least 30% oxygen could be given up to three more doses in the first 48 hours after birth. Dosing was performed by investigators not involved in the clinical care of the neonates; nursery staff were kept blinded as to the treatment assignment. Cause of death was determined by a panel of three independent, board-certified neonatologists after blindly reviewing case report forms and autopsy reports. Fewer Survanta-treated neonates died of any cause (11.4% vs 18.8%, P = .031), died of respiratory distress syndrome (1.9% vs 15.6%, P less than .001), and either died or developed bronchopulmonary dysplasia due to respiratory distress syndrome (39.5% vs 49.1%, P = .044). The incidence of respiratory distress syndrome was also lower in Survanta-treated neonates (28.0% vs 56.9%, P less than .001), and the Survanta-treated neonates' oxygenation and ventilatory status were improved significantly at 72 hours. Survanta-treated neonates were also at lowered risk of developing pulmonary interstitial emphysema (23.3% vs 36.9%, P = .002) and other forms of pulmonary air leaks (9.6% vs 20.8%, P .002).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular risk factor change--1973-74 to 1980-82: the Minnesota Heart Survey.

Reductions in population risk factor levels, including blood pressure, blood cholesterol, and cigarette smoking may be associated with the observed decline in cardiovascular disease (CVD) mortality rates. However, few recent population-based comparisons of risk trends are available. To evaluate changes in these risk characteristics in the recent period, data were compared from two surveys performed in the same metropolitan area using similar methods. The Lipid Research Clinic (LRC) Prevalence Study surveyed a population sample of 4185 adults aged 25-59 in 1973-74. The Minnesota Heart Survey (MHS) surveyed a population sample of 2914 adults of the same age in the same metropolitan area in 1980-82. The average systolic and diastolic blood pressures were significantly lower in the 1980-82 survey averaging 1.5/3.8 mmHg for men and 1.6/2.8 mmHg for women. The use of anti-hypertensive medications increased significantly over the period while the prevalence of hypertension was similar. Significant declines in mean serum cholesterol were also observed in 1980-82, averaging 3.3 mg/dl for men and 5.5 mg/dl women. The prevalence of regular cigarette smoking in men was also lower in 1980-82, 36.3 vs 42.1% in 1973-74. Women had a lower prevalence of smoking (38.8-35.6%) but the average woman smoker increased consumption of cigarettes while the average man did not. These observations suggest that population risk defined by these characteristics is declining which may explain part of recent Minnesota trends in CVD mortality and could have a favorable effect on future disease patterns.

Effect of clofibrate and colestipol singly and in combination on plasma lipids and lipoproteins in type III hyperlipoproteinemia.

The effects of colestipol, clofibrate, and a combination of these two drugs on plasma lipid and lipoprotein values were evaluated in seven subjects with type III hyperlipoproteinemia. When compared to baseline, colestipol administration resulted in a significant decrease in LDL-cholesterol (146 v 99, P less than 0.01) and a significant increase in VLDL-triglycerides (260 v 399, P less than 0.05). The increases in total triglycerides (346 v 462, P = 0.09) and VLDL-C (117 v 155, P = 0.17) noted with colestipol were not statistically significant. Clofibrate administration increased HDL-C (37 v 46, P less than 0.05), and lowered VLDL-C (117 v 56, P less than 0.05), VLDL-triglycerides (260 v 144, P less than 0.05) and total triglycerides (346 v 218, P less than 0.01). The combined regimen was more effective than clofibrate in lowering total and LDL-cholesterol, and no other significant differences were noted.

Variation among neonatal intensive care units in narcotic administration.

OBJECTIVES: To compare rates of narcotic administration for medically treated neonates in different neonatal intensive care units (NICUs) and to compare treated and untreated neonates to assess whether narcotics provided advantages or disadvantages for short-term outcomes, such as cardiovascular stability (ie, blood pressure and heart rate), hyperbilirubinemia, duration of respiratory support, growth, and the incidence of intraventricular hemorrhage. STUDY DESIGN: The medical charts of neonates weighing less than 1500 g, admitted to 6 NICUs (A-F), were abstracted. Neonates who had a chest tube or who had undergone surgery were excluded from the study, leaving the records of 1171 neonates. We modeled outcomes by linear or logistic regression, controlling for birth weight (<750, 750-999, and 1000-1499 g) and illness severity (low, 0-9; medium, 10-19; high, > or =20) using the Score for Neonatal Acute Physiology (SNAP), and adjusted for NICU. RESULTS: Narcotic use varied by birth weight (<750 g, 21%; 750-999 g, 13%; and 1000-1499 g, 8%), illness severity (low, 9%; medium, 19%; and high, 37%), day (1, 11%; 3, 6%; and 14, 2%), and NICU. We restricted analyses to the 1018 neonates who received mechanical ventilation on day 1. Logistic regression, adjusting for birth weight and SNAP, confirmed a 28.6-fold variation in narcotic administration (odds ratios, 4.1-28.6 vs NICU A). Several short-term outcomes also were associated with narcotic use, including more than 33 g of fluid retention on day 3 and a higher direct bilirubin level (6.8 micromol/L higher [0.4 mg/dL higher], P = .03). There were no differences in weight gain at 14 and 28 days or mechanical ventilatory support on days 14 and 28. Narcotic use was not associated with differences in worst blood pressure or heart rate or with increased length of hospital stay. CONCLUSIONS: Our study found a 28.6-fold variation among NICUs in narcotic administration in very low-birth-weight neonates. We were unable to detect any major advantages or disadvantages of narcotic use. We did not assess iatrogenic abstinence syndrome or long-term outcomes. These results indicate the need for randomized trials to rationalize these widely differing practices.

Preferential axial flow during high-frequency oscillations: effects of gas density.

Allen et al. (J. Clin. Invest. 76: 620-629, 1985) reported that regional phasic lung distension during high-frequency oscillations (HFO) is substantially and systemically heterogeneous when both frequency (f) and tidal volume (VT) are large. They hypothesized that this phenomenon was attributable to central airway geometry and preferential axial flow induced therein by the momentum flux of the inspiratory gas stream. According to that hypothesis, the observed distribution of phasic lung distension would depend on the ratio VT/VD* (where VD* is an index of anatomic dead space), independent of gas density (rho), when f is scaled in proportion to lung resonant frequency, fo. To test this hypothesis, we used the methods of Allen et al. (ibid.) to study six excised dog lungs during HFO (f = 2-32 Hz; VT = 5-80 ml) using gases of different densities. Alveolar pressure excursions (PA) were measured as rho spanned a 12-fold range using He, air, and SF6. The apex-to-base and right-to-left ratios of PA were used as indexes of regional heterogeneity of phasic lung distension. For each gas at low f, distension of the lung base was favored slightly independent of VT, but at higher f distension of the lung apex was favored when VT was small, whereas distension of the lung base was favored when VT was large. In addition, we observed substantial right-to-left differences in apical lobes during oscillation at high f not seen before.(ABSTRACT TRUNCATED AT 250 WORDS)

Heterogeneity of mean alveolar pressure during high-frequency oscillations.

Mean alveolar pressure may exceed mean airway pressure during high-frequency oscillations (HFO). To assess the magnitude of this effect and its regional heterogeneity, we studied six excised dog lungs during HFO [frequency (f) 2-32 Hz; tidal volume (VT) 5-80 ml] at transpulmonary pressures (PL) of 6, 10, and 25 cmH2O. We measured mean pressure at the airway opening (Pao), trachea (Ptr), and four alveolar locations (PA) using alveolar capsules. Pao was measured at the oscillator pump, wherein the peak dynamic head was less than 0.2 cmH2O. Since the dynamic head was negligible here, and since these were excised lungs, Pao thus represented true applied transpulmonary pressure. Ptr increasingly underestimated Pao as f and VT increased, with Pao - Ptr approaching 8 cmH2O. PA (averaged over all locations) and Pao were nearly equal at all PL's, f's, and VT's, except at PL of 6, f 32 Hz, and VT 80 ml, where (PA - Pao) was 3 cmH2O. Remarkably, mean pressure in the base exceeded that in the apex increasingly as f and VT increased, the difference approaching 3 cmH2O at high f and VT. We conclude that, although global alveolar overdistension assessed by PA - Pao is small during HFO under these conditions, larger regional heterogeneity in PA's exists that may be a consequence of airway branching angle asymmetry and/or regional flow distribution.