Color M-mode propagation velocity, but not its ratio to early diastolic inflow velocity, changes throughout gestation in normal human fetuses.

OBJECTIVES: Color M-mode propagation velocity (Vp) is a measure of diastolic function in adults and, when combined with early diastolic inflow velocity (E), the ratio E/Vp reflects ventricular filling pressure. Early detection of diastolic compromise may benefit fetal patients at risk for developing heart failure. The objectives of this study were to measure values for Vp and inflow peak E in a group of normal fetuses, to analyze age-dependent alterations in these measurements, and to evaluate the interobserver and intraobserver variability of the measurements. METHODS: Thirty-two normal fetuses at between 20 and 35 weeks' gestation underwent echocardiography. Color M-mode Vp was measured from the four-chamber view for the right (RV) and left (LV) ventricles, and mitral and tricuspid inflow velocities were determined by pulsed-wave Doppler ultrasound. The values obtained were compared with previously reported findings in adults. RESULTS: Adequate tracings were obtainable in 23 patients for the RV and 29 for the LV. Mean Vp values for the RV (15.3 +/- 3.2 cm/s) and LV (20.8 +/- 5.6 cm/s) were lower than normal adult values, and Vp values were significantly lower for the RV than the LV (P < 0.001). Applying Bazett's heart rate correction, values for RV (23.4 +/- 4.8 cm/s) and LV (31.9 +/- 8.7 cm/s) remained lower than normal adult values. There was a linear correlation of Vp with gestational age for the RV (R = 0.69, P < 0.001), and the ratio of E/Vp corrected for heart rate for the RV (1.51 +/- 0.26) remained constant throughout gestation. Interobserver bias was high but intraobserver bias low, at 19 and 1.1%, respectively. CONCLUSIONS: Vp is lower in fetal than in adult life. Vp for the RV changes in a manner indicative of improving diastolic function throughout normal gestation, providing insight into the alterations in diastolic function with gestation that contribute to increases in cardiac output. The use of Vp to assess diastolic function disturbance in fetuses is feasible, but high interobserver variability is problematic.

Hemodynamic effects of positive end-expiratory pressure during partial liquid ventilation in newborn lambs.

BACKGROUND/PURPOSE: The aim of this study was to compare the effect of positive end-expiratory pressure (PEEP) application on hemodynamics, lung mechanics, and oxygenation in the intact newborn lung during conventional ventilation (CV) and partial liquid ventilation (PLV) at functional residual capacity (FRC). CV or PLV modes of ventilation do not affect hemodynamics nor the optimum PEEP for oxygenation. METHODS: Seven newborn lambs (1 to 3 days old) were instrumented to measure pulmonary hemodynamics and airway mechanics. Each lamb was used as their own control to compare different modes of ventilation (CV followed by PLV) under graded variations of PEEP (4, 8, 12, and 16 cm H(2)O) on the influence on pulmonary blood flow and pulmonary vascular resistance. RESULTS: There was a significant drop in pulmonary blood flow (PBF) from baseline (PEEP of 4 cm H(2)O on CV, 1,229 +/- 377 mL/min) in both modes of ventilation on a PEEP of 16 cm H(2)O (CV, 750 +/- 318 mL/min v PLV, 926 +/- 396 mL/min, respectively; P <.05). Peak inspiratory pressure (PIP) was higher on PLV at PEEP states of 4 cm H(2)O (16.5 +/- 1.3 cm H(2)O to 10.6 +/- 2.1 cm H(2)O; P <.05) and 8 cm H(2)O (18.8 +/- 2.2 cm H(2)O to 15.1 +/- 2.6 cm H(2)O; P <.05) when compared with CV. Conversely, PIP required to maintain the pCO(2) was lower on PLV at PEEP states of 12 (22.5 +/- 3.6 cm H(2)O to 24.2 +/- 3.8 cm H(2)O; P <.05) and 16 cm H(2)O (27.0 +/- 1.6 cm H(2)O to 34.0 +/- 5.9 cm H(2)O; P <.05). CONCLUSIONS: Hemodynamically, CO is impaired at a PEEP above 12 cm H(2)O in intact lungs. PFC at FRC does provide an advantage in lung mechanics more than 10 to 12 cm H(2)O of PEEP by decreasing the amount PIP needed to achieve the similar levels of gas exchange and minute ventilation, implying a reduced risk for barotrauma with chronic ventilation. Thus, selection of the appropriate level of PEEP appears to be important if PLV is to be utilized at FRC. The best strategy for PLV, including the selection of PEEP, remains to be determined.

Form and function of fetal and neonatal pulmonary arterial bifurcations.

Bifurcation is a basic form of vascular connection. It is composed of a parent vessel of diameter d(0), and two daughter vessels, d(1) and d(2), where d(0) > d(1) >/= d(2). Optimal values for the bifurcation area ratio, beta = (d(1)(2) + d(2)(2))/d(0)(2), and the junction exponent, x, in d(0)(x) = d(1)(x) + d(2)(x), are postulated to be universal in nature. However, we have hypothesized that the perinatal pulmonary arterial circulation is an exception. Arterial diameters were measured in pulmonary vascular casts of a fetal lamb (140 days gestation/145 days term) and a neonatal lamb (1 day old). The values for beta and x were evaluated in 10,970 fetal and 846 neonatal bifurcations sampled from the proximal and intermediate arterial regions. Mean values and confidence intervals (CI) for the fetus were beta = 0.890 (0.886-0.895 CI) and x = 1.75 (1.74-1.76 CI); and for the newborn were beta = 0.913 (0.90-0.93 CI) and x = 1. 79 (1.75-1.82 CI). These values are significantly different from Murray's law (beta > 1, x = 3) or the West-Brown-Enquist law (beta = 1, x = 2). Therefore, perinatal pulmonary bifurcation design appears to be distinctive and exceptional. The decreasing cross-sectional area with branching leads to the hemodynamic consequence of shear stress amplification. This structural organization may be important for facilitating vascular development at low flow rates; however, it may be the origin of unstable reactivity if elevated blood flow and pressure occurs.

Effects of correction of hypocalcemia on cardiac function in the newborn lamb.

The effect of correction of hypocalcemia on cardiac function in the neonate is unclear. Therefore, we evaluated changes in hemodynamic variables and cardiac contractility in a hypocalcemic neonatal lamb model. Baseline serum ionized hypocalcemia was induced via chelation with intravenous EGTA. Cardiac contractility, measured as end-systolic elastance, did not change with correction of hypocalcemia in this model. In contrast, the variable dP/dt(max), a load-dependent index of contractility, showed an increase with calcium administration while the end-diastolic volume decreased, suggesting that diastolic function or early systolic function had changed. Systemic vascular resistance, cardiac output, and heart rate did not change significantly with correction of hypocalcemia. The results of this study suggest that in our newborn lamb model, cardiac contractility is insensitive to ionized calcium and may reflect cardiac immaturity, but that there may be an effect of calcium administration on diastolic or early systolic function.

Role of nitric oxide in cardiovascular responses to endotoxemia in neonatal lambs.

To determine whether systemic cardiovascular responses to gram-negative endotoxemia are mediated by nitric oxide, we evaluated time-dependent changes in contractility and hemodynamics in a neonatal sheep model subjected to nitric oxide synthesis inhibition with L-Name (Nomega-nitro-L-arginine methyl ester). Four groups were studied: control (C), endotoxin (E), endotoxin L-Name where the nitric oxide synthase inhibitor was given prior to endotoxin (ELN), and a control L-Name group pretreated with L-Name (CLN). The contractility, measured as end-systolic elastance (Ees), increased transiently in the E group and then returned to baseline. In contrast, Ees declined over time in the ELN group. In terms of peripheral hemodynamics, both the E and ELN groups demonstrated significant progressive decreases in blood pressure and vascular resistance. The results of this study suggest that nitric oxide contributes to the newborn contractile response of the heart to endotoxin, but does not appear to mediate the systemic vascular relaxation response.

Role of arterial design on pulse wave reflection in a fractal pulmonary network.

A novel interpretation of pulmonary arterial input impedance was evaluated for the lung as a fractal vascular network. We hypothesized that local sources of reflection introduce trends of global reflection into the input impedance spectra. These trends are related to the network topology, geometry, and design according to Rb = Rdx, where Rb is the branching ratio, Rd is the diameter ratio, and x is the fractal dimension quantifying design. Simulations using values of Rd and x, which were derived morphometrically, confirmed two patterns of global reflection: a continuous trend attributed to a single effective site of reflection caused by frequency-dependent sources of impedance contrast and a discrete trend arising from a longitudinal distribution of frequency-independent sources of reflection. The continuous trend depended only on the network parameter Rd, whereas the discrete trend depended on Rd and x. Our results indicate that the impedance-matching properties of a deterministic pulmonary fractal network encode arterial geometry and topology via function and that typical values of Rd and x for the pulmonary circulation facilitate shear stress amplification in its peripheral vessels. Thus, inasmuch as shear forces may be involved in the endothelial mechanisms for pathological, or physiological, vascular remodeling, broadband input impedance analysis may reveal interactions between network organization and vascular function.

Irreversibility of birth-related changes in the pulmonary circulation.

We hypothesized that establishing conditions of hypoxia and fluid filling of the airways in lungs of newborns would reproduce the high levels of pulmonary vascular resistance (PVR) observed in the fetal state. We assessed the hemodynamics of the left pulmonary circulation of 1- to 3-day-old lambs during a variety of airway states while attempting to reestablish fetal conditions. Eleven animals were studied during both normoxemia and hypoxemia in a baseline airway state with a positive end-expiratory pressure (PEEP) of 4 cm H2O, and in experimental airway states, of atelectasis, and fluid filling to 15 and 30 mL/kg and with PEEP of 12 cm H2O. PVR increased while pulmonary blood flow decreased with all airway state changes as compared to baseline, suggesting a passive mechanism for these changes. With the addition of hypoxemia there was a further increase in PVR in all states accompanied by an increase in pulmonary blood flow, indicating that active vasoconstriction was responsible for the increase in PVR. The combined effects of hypoxemia and fluid filling, designed to approximate the fetal state, increased PVR to only 20-30% of fetal values. Thus, additional factors appear to be important in maintaining the high PVR of the fetal state. We speculate that ventilation of the lungs at birth irreversibly alters these factors.

Escherichia coli endotoxin depresses left ventricular contractility in neonatal lambs.

We evaluated the effects of Escherichia coli endotoxin on the peripheral vascular hemodynamics and myocardial function of the newborn lamb to understand how gram-negative endotoxemia can lead to cardiovascular collapse in newborn infants. Fifteen lambs, 0-3 d old, were acutely instrumented with a micromanometer-tipped catheter and two pairs of ultrasonic crystals to measure left ventricular (LV) pressure and LV anterior-posterior and septal-free wall dimensions, a fluid-filled catheter for monitoring aortic pressure, and an electromagnetic flow probe to measure systemic blood flow. Cardiovascular performance was evaluated by measuring or deriving the following variables: mean arterial blood pressure (MABP), LV pressure, heart rate, stroke volume, systemic vascular resistance, LV dp/dt, end-diastolic area, arterial elastance, and end-systolic elastance (the slope of the end-systolic pressure-area relationship) as an index of contractility independent of loading conditions and heart rate. Once instrumented, nine lambs received endotoxin, 0.5 mg/kg i.v., and six animals, serving as controls, received a saline infusion. Of the endotoxin-treated lambs, five survived the duration of the study (120 min from the beginning of the endotoxin infusion), and four died by 90 min from the beginning of the endotoxin infusion. No significant changes in any of the cardiovascular variables occurred in the control group. A significant decrease in MABP was seen in all endotoxin-treated animals by 45 min after the beginning of the endotoxin infusion. MABP decreased by 52% from baseline in the survivors and 38% in the nonsurvivors. In the survivors, the MABP stabilized with saline boluses, whereas in the nonsurvivors MABP continued to decrease until death.(ABSTRACT TRUNCATED AT 250 WORDS)

Modeling methodology for vascular input impedance determination and interpretation.

The significance of pulse wave reflections in the pulmonary vascular system is elaborated using a new method to determine the broadband frequency response of input impedance up to frequencies of 100 Hz. A simple data model, based on the signal construct of a wavelet, is used to generalize and reconcile the common approaches to vascular frequency response estimation so that an accurate response can be calculated from physiological waveforms. Input impedance interpretation is accomplished using a structural and functional modeling methodology. To identify internal structural system properties, the methodology of inverse scattering is used to relate observed pulse wave echoes in the frequency response to a longitudinal distribution of reflection sites of anatomic significance. To identify functional interactions with pulmonary vascular wave mechanics, a time series analysis methodology is proposed to describe vascular interactions using a generalized principle of superposition. The methods of determination and interpretation are applied to a sample pressure-flow data set from the pulmonary circulation of a lamb experiencing vascular-ventilatory interaction. The example suggests that the frequency response is consistent with a discrete longitudinal distribution of reflection sites that may be affected by the ventilator.

The influence of pulsatile perfusion on the vascular properties of the newborn lamb lung.

It is not known how the mode of flow alters the resistance properties of the newborn pulmonary circulation. Therefore, we compared the pressure responses of the perfused left pulmonary circulation of 16 newborn lambs with step changes in either pulsatile or steady flow. The slope of the pressure-flow curve differed significantly according to mode of perfusion. The slope of the pressure-flow curve was 0.125 +/- 0.115 mm Hg.mL-1.kg.min for pulsatile flow and 0.484 +/- 0.350 mm Hg.mL-1.kg.min for steady flow perfusion (p less than 0.05). The intercept pressure at zero flow was similar for both modes of flow, being 21.3 +/- 4.9 mm Hg for pulsatile flow compared with 23.8 +/- 11.3 mm Hg for steady flow perfusion. All perfusions with either mode of flow demonstrated flow-dependent decreases in pulmonary vascular resistance. However, the decreases in resistance were greater for pulsatile than for steady flow perfusion. In addition, the steady-perfused lungs demonstrated a significantly greater left lung wet/dry weight ratio than either the left lungs of pulsatile-perfused animals or the intact left lungs of 13 control animals not undergoing experimental perfusion (p less than 0.05). Thus, the mode of flow appears to play a major role in modulating the magnitude and distribution of pulmonary vascular resistance. This factor must be considered when interpreting the physiologic significance of hemodynamic experiments.

Hemodynamic responses to angiotensin II in the newborn lamb.

Angiotensin II is known to increase both pulmonary and systemic arteriolar tone in adult animals. Its influence on these vascular beds shortly after birth is less well understood. Therefore, we studied the effects of infusions of angiotensin II (0.1 microgram/kg/min) on pulmonary and systemic hemodynamics in 13 anesthesized newborn lambs. Systemic vascular resistance increased significantly from a mean of 0.079 +/- 0.03 to 0.094 +/- 0.04 mm Hg/ml/min during angiotensin II infusion while the mean pulmonary vascular resistance was unchanged at 0.024 +/- 0.01 mm Hg/ml/min. Interestingly, cardiac output increased significantly by 18.9% during angiotensin II infusion. During hypoxemia produced by ventilating with 10-12% oxygen, the responses to angiotensin II infusion were similar to those obtained during normoxia. The absence of an effect on pulmonary vascular resistance and the increase in cardiac output were not predicted based on results reported for older animals. The mechanisms responsible for these age-related differences are unknown. Our findings have implications regarding the potential clinical use of angiotensin II as a modulator of blood pressure in the hypotensive newborn.

Effect of pulmonary hypertension on lung compliance in newborn lambs.

We studied the effects of increased pulmonary arterial pressure and vascular resistance on lung compliance in 12 anesthetized newborn lambs. Lung compliance was unaffected by large changes in pulmonary artery pressure and pulmonary vascular resistance (80% increase) that were induced by either hypoxia or acidosis. We conclude that contraction of the pulmonary vascular smooth muscle in normal newborn lambs does not affect the stiffness of the lung in the parenchymal regions undergoing volume change during ventilation.

Increased right ventricular afterload alters left ventricular function in newborn lambs.

The effects of acutely increased right ventricular afterload induced by mechanical constriction of the main pulmonary artery or with alveolar hypoxia on function of the left ventricle were assessed in six and nine lambs, respectively (aged 1 to 3 days). Mechanical constriction of the main pulmonary artery in newborn lambs compromised left ventricular function with significant decreases in systemic blood flow and the peak first derivative of left ventricular pressure when considered simultaneously and as single variables. In contrast, alveolar hypoxia augmented left ventricular function with significant increases in systemic blood flow and the peak first derivative of left ventricular pressure when considered simultaneously or as single variables. Interaction appears to exist between the right and left ventricles during the newborn period. The mechanically increased afterload may have compromised left ventricular function by altering its end-diastolic size, inotropic state, or both. On the other hand, the augmented left ventricular function in the presence of hypoxia may have been due to an increase in inotropic background. The clinical implications in some infants with pulmonary hypertension and left ventricular dysfunction are raised.

Normocarbic hyperventilation fails to induce pulmonary vasodilation.

The pulmonary vasodilator effect of increased rate of mechanical ventilation, with and without respiratory alkalosis, was studied in chronically instrumented newborn lambs. Pulmonary hypertension was first induced by ventilating with a hypoxic gas mixture. Subsequent respiratory alkalosis caused significant decreases in pulmonary arterial pressure and pulmonary vascular resistance. When normocarbia was re-established by adding carbon dioxide to the inspired gas, with the ventilator rate being held constant, the pressure and resistance returned to the baseline hypertensive state. Therefore, mechanical factors, either direct or indirect, appear to be of minor importance in the mechanism of pulmonary vasodilation secondary to frequency-induced hyperventilation.

Changes in the auditory brainstem response associated with intravenous infusion of unconjugated bilirubin into infant rhesus monkeys.

The auditory brainstem response (ABR) was monitored in nine infant rhesus monkeys during the intravenous infusion of 50-168 mg/kg of unconjugated bilirubin. Sulfisoxazole (200 mg/kg) was sometimes given near the end of or just before the bilirubin infusion if no obvious ABR change had yet occurred. Five of the animals were term gestation, four were preterm, and they ranged from 1 to 40 days of age at the time of study. The three oldest term animals, studied at 20, 35 and 40 days of age, respectively, showed variable changes in the ABR waves during bilirubin infusion and these changes were not altered further by sulfisoxazole administration. The other two term infants, studied at 1 and 6 days of age, respectively, showed sulfisoxazole enhanced ABR wave latency increase and amplitude reduction followed by loss of the ABR. Both of these animals became apneic following ABR loss and eventually died. The ABR reappeared in one animal prior to death. Minimal gross and microscopic changes were present in the brain of the 6-day-old animal at autopsy. The four preterm animals all had a progressive wave amplitude decrease followed by loss of the ABR with bilirubin alone. These preterm animals were sacrificed shortly after the ABR loss with only one showing yellow staining of the basal ganglia at autopsy. The infant rhesus monkey may be a useful paradigm for bilirubin-induced ototoxicity as manifested by potentially reversible ABR changes. The changes are dependent on gestational and chronological age of the animal and appear to occur in the peripheral eighth nerve or cochlea as well as in brainstem pathways.

"Shock lung" resulting from perfusion of canine lungs with stored bank blood.

An in situ lung perfusion model was used to study the impact of stored bank blood, with or without dacron wool filtration, on morphologic and functional derangement in canine lungs. Autologous blood was stored 24 hours or 21 days in ACD solution and then passed through standard recipient set filters before perfusion through the left lower lung lobes of dogs equipped to have pressure and gas tensions monitored from pulmonary artery, vein and bronchus. In an additional group of dogs, 21-day stored blood was additionally filtered through dacron-wool prior to lung perfusion. Pulmonary vascular resistance increased markedly for lungs perfused with stored blood, whether or not dacron-wool filtered, as compared with lungs perfused with fresh blood. Effective compliance decreased in both groups of lungs perfused with stored blood, and arteriovenous oxygen gradients decreased significantly in these groups as compared with fresh blood-perfused lungs. As an index of congestion, wet/dry lung weight ratios increased for both groups perfused with stored blood which also showed gross and microscopic evidence of pulmonary edema. As a measure of microaggregated blood debris, screen filtration pressure determinations were not significantly different in fresh or stored canine blood in ACD. We conclude from observations of these canine lung perfusions that pulmonary anatomic and functional injury can result from the use of stored bank blood which may be modified, but not eliminated, by depth filtration. We infer that microaggregated blood debris is not the primary noxious factor in stored canine blood, and a toxic serum-borne factor may be implicated.