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.

Changes in endothelial cell and smooth muscle cell integrin expression during closure of the ductus arteriosus: an immunohistochemical comparison of the fetal, preterm newborn, and full-term newborn rhesus monkey ductus.

Anatomical closure of the ductus arteriosus requires normally quiescent luminal endothelial cells and medial smooth muscle cells to migrate into the subendothelial space forming intimal mounds that eventually coalesce and occlude the vessel's lumen. The migration of endothelial cells and smooth muscle cells requires the presence of integrin receptors that interact with the surrounding matrix. We used immunohistochemical staining to examine the repertoires of integrins expressed by endothelial cells and smooth muscle cells during postnatal closure of the ductus arteriosus in full-term and preterm rhesus monkeys. In the fetal ductus, luminal endothelial cells have a limited repertoire of integrins. During postnatal ductus closure, luminal endothelial cells, of both term and preterm monkeys, change their phenotype and express the full repertoire of integrins found on growing capillary endothelial cells (alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, alpha 6 beta 1, alpha v beta 1, alpha 6 beta 4, and alpha v beta 5). Similarly, during ductus closure, smooth muscle cells of both term and preterm monkeys expand their integrin repertoire to include the alpha 5 beta 1 and alpha v beta 3 integrins; these two integrins have been shown to be essential for smooth muscle cell migration in vitro. These changes in integrin profile occur at the same time the endothelial and smooth muscle cells invade their neighboring compartments. In contrast, preterm monkeys with a persistently patent ductus lumen fail to develop these changes in integrin expression and fail to develop neointimal mounds. No evidence of intimal thickening occurs in the absence of changes in integrin expression. Therefore, endothelial cells and smooth muscle cells change phenotypes to produce the intimal thickening required for ductus closure.

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.

Intracranial pressure and cerebral perfusion pressure in clinically normal equine neonates.

Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) were determined in 8 clinically normal neonatal foals. After the foals oriented themselves and nursed the mares, they were sedated as necessary, and local anesthesia was provided for making the skin incisions. Using a technique similar to that used in human beings, an indwelling subdural catheter was placed to measure ICP. Carotid artery catheterization was used to measure arterial blood pressure. Cerebral perfusion pressure was calculated as the difference between mean arterial blood pressure and ICP. Intracranial pressure and CPP readings were taken twice during each 24-hour period, starting at 6 hours of age and continuing through 72 hours of age. Mean (+/- SD) ICP were 5.83 +/- 1.82, 8.81 +/- 2.06, and 9.55 +/- 1.55 mm of Hg (range, 2 to 15 mm of Hg), and mean CPP were 80.19 +/- 10.34, 75.30 +/- 10.86, and 76.80 +/- 12.59 mm of Hg (range, 50 to 109 mm of Hg) for each of the first three 24-hour periods after birth, respectively. All 8 foals had physical and neurologic examinations, CSF analysis, and computerized axial tomography evaluations. The foals manifested normal behavior during the interval of measurements, and adverse effects of the procedure were not detected during the monitoring period. Establishment of normal values for ICP and CPP are important to clinicians who have the opportunity to apply this technique for monitoring and evaluating neonatal foals with signs of CNS dysfunction.

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.

Prenatal exposure to epidermal growth factor attenuates respiratory distress syndrome in rhesus infants.

Treatment of nonhuman primate fetuses with epidermal growth factor (EGF) results in histologic and biochemical maturation of their lungs. To determine whether these effects improve lung function postnatally, we studied premature rhesus infants delivered at 78% of gestation after in utero treatment with EGF (n = 5) or placebo (n = 5). Indices of lung function during the 4 d of postnatal care included fractional concentration of inspired oxygen, peak inspiratory pressure, ventilator rate, mean airway pressure, arterial to alveolar oxygen tension ratio, and ventilation index. Statistically significant differences were noted in the time courses of these variables between EGF- and placebo-treated infants. The direction of the differences indicated that the EGF-treated infants had less severe lung disease. Surfactant apoprotein A concentration and lecithin to sphingomyelin ratio were both significantly higher in the amniotic fluid of the EGF-treated group, indicating advanced biochemical maturation in this group of animals. Whereas birth weight was not affected by EGF exposure, adrenal and gut weights, standardized for body weight, were increased significantly. Histologic studies showed advanced cellular maturation with increased parenchymal airspace and decreased parenchymal tissue space in the EGF-treated group compared with the control group. We conclude that prenatal exposure to EGF stimulates biochemical and histologic maturation of the lung and markedly attenuates the clinical severity of respiratory disease in this model of simian respiratory distress syndrome.

Brain injury and protective effects of hypothermia using triphenyltetrazolium chloride in neonatal rat.

Colorless 2,3,5-triphenyltetrazolium chloride (TTC) is reduced by enzymes in functioning mitochondria to a red-colored compound, and has been used to differentiate areas of viable tissue from areas of infarction in adult animals. TTC was used to study the central nervous system protective effects of hypothermia on the neonatal rat exposed to hypoxia and ischemia. The effect of hypothermia on survival and weight gain was also determined. Seven-day-old Wistar rats with right carotid artery ligation were exposed to 3 hours of 8% oxygen and maintained at either 37 degrees C (n = 22) or 30 degrees C (n = 18). The survivors were sacrificed 2 days later and brain slices exposed to TTC. These slices were photographed and the percentage of damage to the right brain was estimated gravimetrically from the stained and unstained areas of enlarged images. The mean weight gains were 4.2 +/- 1.2 gm in the 30 degrees C group and -1.0 +/- 2.8 gm in the 37 degrees C group (P < .001). The survival in the 37 degrees C group was 77% and in the 30 degrees C group 100% (P < .025). The mean percentage damage to the right side of the brain in the 37 degrees C group was 45.5% (range: 0-87.5%); there was no detectable damage in any of the 30 degrees C group pups (P < .0001). In our study, TTC proved to be a rapid and simple method for assessing central nervous system injury in the neonatal rat. This study also confirms that moderate hypothermia is protective against hypoxic-ischemic brain injury.

Intratracheal administration of pulmonary vasodilator agents.

We compared intravenous and intratracheal administration of histamine (0.4 and 1.6 micrograms/kg, respectively) and nitroglycerin (5.0 and 20.0 micrograms/kg, respectively) in seven hypoxemic 2 week old lambs, during right lung only perfusion, to see if intratracheal administration could limit their vasodilator action to the pulmonary vessels. The hemodynamic variables: pulmonary artery pressure (Ppa), left atrial pressure (Pla), pulmonary blood flow per kilogram (Q/kg), and aortic pressure (Pao) were measured at baseline and in each experimental state, then pulmonary vascular resistance (PVR) and systemic vascular input resistance (SVR) were determined. We found that intravenous histamine showed some pulmonary vasodilator selectivity in that it caused a 19% decrease of Ppa from baseline (P less than 0.002), a 23% decrease of PVR from baseline (P less than 0.002), and an 8% decrease of SVR from baseline (P less than 0.05). Intratracheal histamine produced smaller effects, decreasing Ppa by 11% from baseline (P less than 0.02), and PVR by 14% from baseline (P less than 0.02), while SVR was unaffected. Intravenous nitroglycerin decreased cardiac output by 16% from baseline (P less than 0.02), and also decreased SVR by 8% while producing a small increase in PVR. Intratracheal nitroglycerin caused a similar 17% (P less than 0.01) decrease in cardiac output, and again an increased PVR but a decreased SVR. This study confirms that histamine has some intrinsic pulmonary vasodilator selectivity. Furthermore, the data suggest that intratracheal administration may accentuate pulmonary selectivity by lessening systemic effects. Nitroglycerin, on the other hand, had untoward hemodynamic effects in the presence of hypoxia.

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.

Age-dependent effects of sodium nitroprusside and dopamine in lambs.

Vasodilators and cardiotonic agents are frequently used in hypoxemic newborn infants with persistent pulmonary hypertension. We studied the effects of sodium nitroprusside and dopamine on hypoxia-induced pulmonary hypertension in seven newborn (0-3 d) and seven young (10-14 d) lambs under chloralose anesthesia. Pulmonary blood flow, pulmonary arterial pressure, systemic arterial pressure, and left atrial pressure were measured during the experimental states of hypoxia, hypoxia plus nitroprusside, and hypoxia plus both nitroprusside and dopamine. Pulmonary and systemic arterial pressure and cardiac output all decreased significantly when hypoxemic newborn lambs were given nitroprusside; in contrast, when hypoxemic young lambs were given nitroprusside, cardiac output did not change, whereas both pulmonary and systemic arterial pressure decreased significantly. Calculated pulmonary vascular resistance was unchanged in the newborn lambs but fell in the young lambs, implying that active pulmonary vasodilation by nitroprusside occurred only in the latter group. Systemic vascular resistance was not significantly affected by nitroprusside in either group. The addition of dopamine resulted in qualitatively similar changes in both groups of lambs, with increased pulmonary blood flow and no significant change in pulmonary or systemic arterial pressures. Maturation in vascular smooth muscle responsiveness to nitrovasodilators may explain the age-related differences that we found in lambs, and could also account for the variable clinical responses to vasodilators observed in hypoxemic human infants.

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.

Bilateral renal dysplasia with nephron hypoplasia in a foal.

Bilateral renal dysplasia and nephron hypoplasia was diagnosed in a Quarter Horse foal with clinical signs of lethargy, convulsions, and diarrhea. Laboratory evaluation revealed anemia, hypoproteinemia, leukopenia, hyponatremia, hypochloremia, and hyposmolality. The foal also had high concentrations of serum creatinine, BUN, and phosphorus. Evaluation of urinary indices revealed a high ratio of urinary gamma-glutamyl-transferase activity to concentration of creatinine, as well as a high fractional clearance ratio of sodium and potassium. Intravenous treatment with saline solution (0.9% NaCl) and antimicrobials provided only temporary resolution of some of the abnormalities. Diagnosis was partly established by histologic evaluation of renal tissue obtained via an ultrasonographically guided biopsy and was confirmed at necropsy. Pathologic changes in the kidney were unique in that the size of the kidneys, along with the appearance and number of glomeruli, were essentially normal despite marked hypoplasia of nephron tubules in the medulla.

Effect of blood sampling site on measurements of bilirubin-albumin binding.

Significant arterio-venous concentration gradients in metabolites such as lactate could result in sampling site differences in bilirubin binding measurements. Therefore, total bilirubin and apparent unbound bilirubin concentrations were determined on paired capillary and arterial serum samples from ten neonates with hyaline membrane disease. There were no significant arterial versus capillary differences in bilirubin binding in these infants. However, a small, statistically significant but clinically irrelevant, difference in total bilirubin concentration was found. Consistent blood sampling sites should be used for laboratory tests where arterial, venous, and capillary results differ or could conceivably differ.

Neuropathologic documentation of prenatal brain damage.

Neuropathologic evidence of prenatal brain damage, chiefly in cerebral white matter, was found in 25% of infants who died at 7 days of age or less, with a total of ten preterm (16%) and 12 term (48%) infants among the 89 subjects studied. Few clinical features distinguished infants with prenatal injury from those without such injuries. Apgar scores were low, seizures were rare, and acute intracranial hemorrhage occurred equally often in both groups. Few pregnancies were entirely normal, but hydramnios was the only factor that occurred more often in prenatally injured infants, a statistically significant difference only among term infants. Oligohydramnios was not associated with prenatal brain injury. Unless fetal/maternal abnormalities in late gestation are identified and corrected, improved neonatal care will increase survival for prenatally damaged infants and the incidence of cerebral palsy may rise.