Emile M. Scarpelli

Lamb fetal pulmonary fluid. I. Validation and significance of method for determination of volume and volume change.

Extract: An indicator-dilution method is described for measuring fetal pulmonary fluid, FPF, volume (Ve), and volume change with time (Vs) in the lamb fetus in utero. The indicator, albumin, which is the predominant protein of normal FPF, was administered directly to FPF in the form of radio-iodinated human serum albumin (RISA). We have shown that (1) RISA is disbributed homogeneously throughout the FPF compartment, (2) it is not altered within FPF, (3) it does not alter the functional characteristics of FPF, and (4) it remains within the FPF compartment throughout the period of measurement. Ve varies directly with the weight of the fetus so that Ve per kilogram was 31.6–35.6 ml/kg in four of five fetuses. The Ve per kilogram was lower in one fetus at the start of the experiment but increased rapidly to 29.0 ml/kg within 45 min. Thus the relaxation volume of the fetus in utero is in the range of functional residual capacity (FRC) and thoracic gas volume of the air-breathing neonate, which indicates that the pulmonary transformation at birth is, in essence, an isovolumic change in state wherein the fetal liquid-lung becomes the neonatal air-lung. The rate at which FPF is formed (V) is about 1.5 ml/hr-kg; however, the rate may change in so far as both rapid increases and rapid decreases of FPF volume were observed. When breathing movements were induced in the fetus by stimulation of the sciatic nerve, FPF volume decreased rapidly (Vs = −3.0 ml/hr-kg), which indicates that negative intrathoracic pressures promote its resorption. When FPF volume fell transiently or was low initially, there was subsequent rapid restoration of volume to the range of anticipated FRC.Speculation: Validation of a reliable method for measuring Ve and Vs of FPF in utero provides a basis for study of molecular transformations within this compartment during gestation, e.g., our investigation of the fate of FPF phosphatidylcholine in the accompanying report. Since FPF is the analog of the alveolar lining layer of the air-breathing animal, studies of the former (FPF) may give insight into the fluid and molecular dynamics of the latter which, to date, have been quite elusive because the lining layer cannot be sampled directly. Our observation that negative intrathoracic pressure alone seems to promote resorption of FPF under the conditions of our experiments suggests that this may be an important mechanism for the formation of the air-lung at birth. Since relaxation volume of the fetus is practically the same as that of the neonate, we have proposed that alveolar surface tension of the neonate is close to 0.

Lung Surfactants, Counterions, and Hysteresis

The wide hysteresis and low surface tension of lung extracts, as studied on a modified Langmuir-Wilhelmy surface balance, are dependent on the presence of subphase electrolytes. A possible mechanism for the hysteresis and its importance to the exchange of surfactants between the alveolar cell and the alveolar surface film are discussed.

Hemodynamic basis for clinical manifestations of patent ductus arteriosus

Abstract A prosthesis made of silicone rubber has been developed for insertion between the aorta and pulmonary artery of dogs. The size of the communication can be controlled in the closed-chest, unanesthetized animal. The hemodynamic effects of complete acute opening and closing of the shunt have been studied in 35 dogs. The basic hemodynamic changes are related to a decrease in systemic vascular resistance, an increase in pulmonary blood flow, and direct transmission of aortic pressure to the pulmonary artery. When the shunt is opened, there is an immediate decrease in aortic and left ventricular systolic pressure, a rise in pulmonary arterial, left atrial, and left ventricular end-diastolic pressure, an increased stroke volume, and an increased heart rate. A systolic gradient between the left ventricle and the aorta frequently develops when the shunt is opened, and is probably related to the high stroke volume which occurs. The pulmonary arterial pressure tracing shows a triphasic contour when the shunt is open; left ventricular ejection is slightly prolonged, but the right ventricular ejection period is markedly reduced. This explains the paradoxical splitting of the second sound, which is also observed in some patients with patent ductus arteriosus. Systemic blood flow is moderately reduced, but pulmonary blood flow is increased about twofold. Pulmonary diastolic blood flow is markedly increased, so that peripheral pulmonary blood flow becomes much more continuous. During diastole, blood flows perferentially into the low-resistance shunt and pulmonary vascular system, and a marked backflow during diastole occurs in the descending aorta distal to the shunt. The animals varied in their ability to tolerate the shunt. After the initial responses, some dogs showed a gradual increase in aortic stroke volume and left ventricular systolic pressure, and tolerated the shunt well. Others developed a “failure response” that was characterized by a continuing fall in aortic stroke volume and left ventricular systolic pressure, with a rise in left ventricular end-diastolic, left atrial, and pulmonary arterial pressures.

Intrapulmonary foam at birth: an adaptational phenomenon.

Summary: The first inflation and deflation with air of excised lungs of mature fetal lambs and rabbits from the natural liquid-filled state invariably produced foam which was apparent in the trachea when transpulmonary pressure was <0 (lambs) and in terminal lung units (TLU) when monitored by stereomicroscopy (rabbits). Similarly, examination of neonatal lungs of lambs and rabbits that had breathed spontaneously (1 breath to 15 min) revealed bubbles in small airways and in TLU. Volume-pressure diagrams of excised lungs (lambs) revealed relatively low apparent opening pressures, low pressures at maximal volume, and appearance of foam in large airways after withdrawal of a volume of air equivalent to 30% or more of functional residual capacity (FRC) during deflation. The latter is consonant with the presence of bubbles in TLU. Studies of excised lungs indicated that additional foam may be produced during the second inflation. The extent to which subsequent breaths may contribute to foam production could not be determined, but it was apparent that the early neonatal lung (up to 15 min in our studies) is a three-phase system of intrapulmonary foam, free air, and liquid. The phospholipids of fetal pulmonary fluid (FPF) from which foam is produced were incorporated preferentially (in relation to the proteins) into the bubble films.Speculation: Intrapulmonary foam at birth could play an important role in a number of vital adaptations that are known to occur. 1) Bubbles apposing the walls of TLU are air pockets within thin films across which gas exchange would be facilitated beginning with the first breath. 2) Intrapulmonary foam may play a role in maintenance of dilated airways during expiration and at end-expiration when transpulmonary pressures are high. 3) Oxygenation and distention of TLU by foam could be the earliest stimuli for rapid fall of pulmonary vascular resistance. 4) The phospholipids of bubble films could be immediate precursors of the alveolar lining layer that needs to be established quickly at birth. 5) The large thoracic gas volume to FRC ratio of neonatal lungs may be due, in part at least, to intrapulmonary foam. Whereas foam volume and foam production were not quantified in our studies, it appears that the duration of the “foam lung” state and the relative amounts of intrapulmonary foam and free air would depend on FPF volume at the time air breathing is begun and on the rate at which FPF is subsequently absorbed.

pH, temperature, humidity and the dynamic force-area curve of dipalmitoyl lecithin

Both high pH at 25 degrees C and humidity at 37 degrees C prevent DPL films from attaining zero surface tension, whereas humidity at 25 degrees C and high pH at 37 degrees C do not. At 37 degrees C DPL lowered surface tension to zero when spread from organic solvent or when absorbed from aqueous 0.15 M NaCl in the surface balance in which the surface film was exposed to the room air (dry film). Upon saturation of the atmosphere with water vapor in equilibrium with the aqueous phase at 37 degrees C in a closed chamber, DPL lost the ability to produce zero surface tension, and the gamma min of the DPL film increased from zero to 22 dyne/cm. Addition of DPL in chloroform to distilled water before dispersion by sonication did not prevent the effect of the humidity. However, when the chloroform solution of DPL was added to 0.15 M NaCl before sonication, the adsorbed film produced immediately a stable gamma min of zero in a saturated atmosphere, 37 degrees C. In the absence of chloroform, with DPL adsorbed from either distilled water or 0.15 M NaCl, the effect of humidity was reversed either by removing the chamber and returning the wet film to room air or by introducing small quantities of dispersing agents such as cholesteryl palmitate. However, whereas the effect of humidifying the air was reversible indefinitely, the effect of cholesteryl palmitate (zero surface tension, wet or dry film) was irreversible. This means that there are substances or conditions that can assist DPL films in maintaining zero surface tension when such films are exposed to humidity-saturated air at 37 degrees C.

Hepatogenic cyanosis: Arteriovenous shunts in chronic active hepatitis

This report describes a young girl with chronic active hepatitis, cyanosis, andpulmonary arteriovenous fistulas. Measurements of hepatic, cardiovascular, and pulmonary function were obtained during the course of her illness, which were consistent with the pathologic changes found at autopsy. Inasmuch as the cyanosis may be due to both peripheral systemic and pulmonary shunting of blood, presumably secondary to chronic liver disease by still unknown mechanisms, it seems appropriate to designate this condition as “hepatogenic cyanosis”.

Human β-endorphin-like immunoreactivity in the perinatal/neonatal period

R E F E R E N C E S 1. Welsh JW, and May JT: Breast milk and infant infection, Med J Aust 2:66, 1979. 2. Hayes K, Danks DM, Gibas J, and Jack I: Cytomegalovirus in human milk, N Engl J Med 287:177, 1972. 3 Stagno S, Reynolds DW, Pass RF, and Alford CA: Breast milk and the risk of cytomegalovirus infection, N Engl J Med 302:1073, 1980. 4. Yeager AS, Grument FC, Hafleigh EB, Arvin AM, Bradley JS, and Prober CG: Prevention of transfusion-acquired cytomegalovirus infections in newborn infants, J PEDIATR 98:281, 1981. 5. Ballard RA, Drew L, Hufnagle KG, and Riedel PA: Acquired cytomegalovirus infection in preterm infants, Am J Dis Child 133:482, 1979. 6. Barness LA, Dallman PR, Anderson H, Collipp P J, Nichols BL Jr, Walker WA, and Woodruff CW: Human milk banking, Pediatrics 65:854, 1980. 7. Liebhaber M, Lewiston N J, Asquith MT, Olds-Arroyo L, and Sunshine P: Alterations of lymphocytes and of antibody content of human milk after processing, J PEDIATR 91:897, 1977. 8. Bj6rksten B, Burman LG, De Chateau P, Fredrikzon B, Gothefors L, and Herneli O: Collecting and banking human milk: to heat or not to heat? Br Med J 281:765, 1980. 9. Welsh JK, Arsenakis M, Coelen R J, and May JT: Effect of antiviral lipids, heat, and freezing on the activity of viruses in human milk, J Infect Dis 140:322, 1979. 10. Stagno S, Pass RF, Reynolds DW, Moore MA, Nahmias A J, and Alford CA: Comparative study of diagnostic procedures for congenital cytomegalovirus infection, Pediatrics 65:251, 1980.

Cutaneous stimulation and generation of breathing in the fetus.

The generation of spontaneous regular breathing by cutaneous stimulation and by direct electrical stimulation of the sciatic nerve was examined in six previously apneic mature fetal lambs in utero. The fetuses were stable throughout the course of the experiments: PaO2 less than or equal to 27 mm Hg, PaCO2 less than 44 mm Hg, pH 7.29-7.34, blood pressure and heart rate steady and normal. It is shown that electrical stimulation of the fetal skin (66 cps, 4.0 msec, 6 V, 0.77 ma) can be as effective as direct stimulation of the sciatic nerve (66 cps, 4.0 msec, 1.5 V, 0.08 ma) when the higher voltage and current are used. Mechanical cutaneous stimulation also produced spontaneous breathing which, however, was short lived compared with that produced by electrical stimuli. The results are consonant with our concept of activation and recruitment of quiescent respiratory center neurones by somatic sensory stimulation, and they give fundamental support to the clinical observation of others that cutaneous stimulation is effective for the treatment of apnea of prematurity. Speculation Somatic sensory stimuli from the skin may be important determinants of the onset of breathing in the fetus and newborn.

Somatic-Respiratory Reflex and Onset of Regular Breathing Movements in the Lamb Fetus in Utero

Extract: Breathing activity of six mature lamb fetuses (> 135 days of gestation) in utero was monitored from recordings of intraesophageal pressure, intratracheal pressure, and tracheal circumference from a mercury strain gauge before, during, and after stimulation of the central end of a cut sciatic nerve. Stimuli were either low (0.5-2.0 cps) or high (66 cps) frequency, 6-15-V square wave pulses of 0.6-1.25 msec duration. The fetuses remained in utero throughout the experiments in which ambient temperature, paO2, paCO2, arterial pH, mechanical stimulation, and spontaneous respiratory center activity could be ruled out as primary stimuli of the breathing movements observed. In one-third of the trials a “somatic-respiratory reflex” was elicited in which breathing coincided with the period of stimulation: in over 85% of these trials with low frequency stimulation, breathing movements were synchronous with the stimuli; in the rest the synchrony was broken during the period of stimulation. In two-thirds of the trials the “reflex” response was followed by spontaneous regular breathing movements (“onset of regular breathing”) which continued for 1 min to 2 hr 30 min after the stimulation was stopped. Thiopental administration to the ewe (5 mg/kg) seemed to depress respiratory responsivity for about 60 min. Changes of tracheal circumference reflected both transmural pressure gradients and possibly also rhythmic vagal activity associated with breathing.Speculation: The characteristics of the electrical stimuli have been shown in other species to include γ and δ group A and group C afferents, which normally transmit pain, temperature, pressure, touch, and position. Thus, our studies support the idea that somatic sensory stimuli can produce regular breathing at birth. Indeed it is shown that these stimuli are effective even in the absence of other changes in homeostasis that may be associated with the onset of breathing. Since regular breathing movements may be induced consistently, the experimental preparation is ideal for future studies of maturation of the control of breathing during gestation. The “respiratory reflex” that has been described seems to fit the basic definition; this has permitted the formulation of a working hypothesis for the activation and recruitment of quiescent respiratory center neurons, i.e., for the genesis of respiratory center activity.

Lipid monolayers: Surface viscosity of dipalmitoyl lecithin in relation to surface potential and ion binding☆

Abstract The surface potential-surface pressure curve of dipalmitoyl lecithin on 150 m M NaCl at 25°C is identical with that on 75 m M CaCl 2 over the entire film pressure region; at high film pressure, however, the surface viscosity on CaC1 2 is markedly greater than on NaCl. We propose a model of molecular organization in which a lattice is formed from the coalescence of the water structured around the lecithin polar groups in the hydrophilic region below the II interface ; such a lattice is responsible for the surface viscosity but does not influence the surface potential. The greater viscosity effect of CaCl 2 over that of NaCl is probably determined by the influence that the electrolyte exerts on the water structured around the polar surface of the lipid and thus on the extent and strength of the coalescence, and it may not be due to binding of Ca 2+ onto the ionic groups of lecithin.