Liquid ventilation during early development: theory, physiologic processes and application

Clinical statistics indicate that extrauterine viability becomes increasingly compromised at earlier gestational ages. It is generally accepted that this trend is largely due to the immaturity of the pulmonary system. Investigators have attributed the high degree of instability during the perinatal period of the preterm infant to incomplete biochemical development of the lung. Whereas disruption in biochemical development results in alveolar surfactant deficiency, elevated interfacial tension, alveolar instability, and inadequate pulmonary gas exchange, it is possible that incomplete development of other components within the pulmonary as well as other organ systems may also influence ultimate extrauterine viability of the preterm neonate. However, until recently, little was known in this regard as conventional gas ventilation techniques have been unsuccessful in supporting a stable animal preparation for controlled experimental investigation of physiologic processes before approximately 85% gestation. In the early 1970s, the concept of liquid ventilation was applied to the preterm and newborn animal. Since this time, technological advances in liquid delivery systems have established this experimental approach as a viable means to support the preterm infant during the transition from the liquid-filled intrauterine to gas-filled extrauterine environment. Reduction of surface tension, improvement in lung mechanics, effective pulmonary gas exchange, acid-base balance, improved distribution of pulmonary blood flow, and cardiovascular stability in the liquid ventilated preterm animal support the use of this alternative method of ventilation as a valuable experimental tool and potential clinical therapeutic modality during early development. The evolution of this approach is presented in this article.     

Comparison of gas and liquid ventilation: clinical, physiological, and histological correlates.

To differentiate the effects of gas and liquid ventilation on cardiopulmonary function during early development, we compared the clinical, physiological, and histological profiles of gas- and liquid-ventilated preterm lambs (n = 16; 108-116 days gestation). Immediately after cesarean section delivery, ventilation commenced using gas delivered by a volume ventilator (n = 9) or liquid perfluorochemical (n = 7) delivered by a mechanically assisted liquid ventilation system. Pulmonary gas exchange, acid-base status, vital signs, and respiratory compliance were assessed during the 3-h protocol; sections of the lungs were obtained for histological analyses when the animals were killed. Six of nine gas-ventilated lambs expired from respiratory failure before 3 h, with the remaining animals experiencing severe respiratory insufficiency, pneumothoraces, and cardiovascular deterioration. Six of seven liquid-ventilated lambs survived with good gas exchange and cardiovascular stability and without fluorothorax; one experienced ventricular fibrillation before 1 h and expired despite pulmonary stability. Respiratory compliance was significantly greater in the liquid- than in the gas-ventilated lambs. Histological analyses of gas-ventilated lungs demonstrated nonhomogeneous lung expansion, with thick-walled gas exchange spaces containing proteinaceous exudate, hemorrhage, and hyaline membranes. In contrast, liquid-ventilated lungs appeared clear, with thin-walled and uniformly expanded gas exchange spaces that were free of hyaline membranes and luminal debris. Morphometric analyses demonstrated that surface area and gas exchange index were greater in the liquid- than in the gas-ventilated lambs. These results indicate that elimination of surface active forces by liquid ventilation during early development provides more effective gas exchange with less barotrauma compared with gas ventilation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Partial liquid ventilation improves gas exchange and increases EELV in acute lung injury

Gas exchange is improved during partial liquidventilation with perfluorocarbon in animal models of acute lung injury.The specific mechanisms are unproved. We measured end-expiratory lung volume (EELV) by null-point body plethysmography in anesthetized sheep.Measurements of gas exchange and EELV were made before and after acutelung injury was induced with intravenous oleic acid to decrease EELVand worsen gas exchange. Measurements of gas exchange and EELV wereagain performed after partial liquid ventilation with 30 ml/kg ofperfluorocarbon and compared with gas-ventilated controls. Oxygenationwas significantly improved during partial liquid ventilation, and EELV(composite of gas and liquid) was significantly increased, comparedwith preliquid ventilation values and gas-ventilated controls. Weconclude that partial liquid ventilation may directly recruitconsolidated alveoli in the lung-injured sheep and that this may be onemechanism whereby gas exchange is improved.

     

Compliance, blood gases, and acid-base balance in guinea pigs artificially ventilated with different IPPV patterns

In order to estimate optimum parameters for artificial ventilation of adult guinea pigs, the effect of four hours intermittent positive pressure ventilation (IPPV) was studied using different tidal volumes (VT), respiratory frequencies (f), and minute volumes (Ve). Total compliance was measured by placing the animal in a whole body plathysmograph, the arterial blood gases, pH and base excess by catheterizing the carotid artery. In Series I 9 guinea pigs were ventilated at parameters adapted to the spontaneous breathing pattern (VT = 2 ml, f = 70 breaths.min-1). This ventilatory pattern resulted in severe disorders in compliance, gas exchange, and acid-base balance. In Series II 3 different VT (2, 6, 10 ml) were studied by changing f so that Ve was kept constant. The results demonstrated a favourable effect of slow and deep ventilation upon lung mechanics and oxygenation. In Series III 3 different Ve (300, 250, 200 ml.min-1) were tested using a constant VT = 10 ml. Optimum parameters for artificial ventilation of adult guinea pigs were: VT = 10 ml and f = 20 breath--min-1 which resulted in stable compliance, good O2-saturation, normocapnia and normal acid-base balance.     

Panting and acid-base regulation in heat stressed birds

1. Studies in respiratory physiology and acid-base balance of panting birds exposed to high Tas show that flying as well as nonflying birds can use the respiratory system simultaneously for gas exchange and evaporative cooling. 2. The present study proves that well acclimated hand-reared birds can effectively regulate a normal CO2 level and acid-base status in arterial blood, when exposed to extremely high temperatures (50-60 degrees C). 3. In many birds practising simple or "flush-out" panting, the dead space can be reduced to a volume which is estimated to be approx 15% the volume of the respiratory tract. 4. These two modes of ventilation, shallow and high-rate, restricted to the nonrespiratory surfaces, may ensure the avoidance of CO2-washout and limit lung ventilation to the volumes needed for oxygen consumption. 5. This view supports earlier theories, suggesting the existence of physiological shunt mechanisms which operate during thermal panting in birds.     

Effect of Surfactant and Partial Liquid Ventilation Treatment on Gas Exchange and Lung Mechanics in Immature Lambs: Influence of Gestational Age

Objectives

Surfactant (SF) and partial liquid ventilation (PLV) improve gas exchange and lung mechanics in neonatal RDS. However, variations in the effects of SF and PLV with degree of lung immaturity have not been thoroughly explored.

Setting

Experimental Neonatal Respiratory Physiology Research Unit, Cruces University Hospital.

Design

Prospective, randomized study using sealed envelopes.

Subjects

36 preterm lambs were exposed (at 125 or 133-days of gestational age) by laparotomy and intubated. Catheters were placed in the jugular vein and carotid artery.

Interventions

All the lambs were assigned to one of three subgroups given: 20 mL/Kg perfluorocarbon and managed with partial liquid ventilation (PLV), surfactant (Curosurf®, 200 mg/kg) or (3) no pulmonary treatment (Controls) for 3 h.

Measurements and Main Results

Cardiovascular parameters, blood gases and pulmonary mechanics were measured. In 125-day gestation lambs, SF treatment partially improved gas exchange and lung mechanics, while PLV produced significant rapid improvements in these parameters. In 133-day lambs, treatments with SF or PLV achieved similarly good responses. Neither surfactant nor PLV significantly affected the cardiovascular parameters.

Conclusion

SF therapy response was more effective in the older gestational age group whereas the effectiveness of PLV therapy was not gestational age dependent.     

Growth and development of the term and premature pig-tailed macaque (Macaca nemestrina): Cardiovascular and respiratory changes during the first 3 weeks of life

Growth and development of the infant pigtailed macaque (Macaca nemestrina) over the first 3 weeks of life have been characterized by the variables of body weight, blood pressure, heart rate, ventilation, blood gas tensions, and lung mechanics. The effects of prematurity on postnatal developmental trends were assessed at gestational ages of 135–145 days (0.80 of term) and 150–155 days (0.91 of term). There was no indication that cesarean section, restraint, or instrumentation had any significant influence on the measurements. Gestational age at delivery had no effect on the minute ventilation per kilogram body weight, the hematocrit, or the heart rate; however, body weight, tidal volume, respiratory frequency, arterial gas tensions, blood pressure, and lung compliance did vary with gestational age at delivery. Postnatal maturational changes in these variables were similar between term and premature animals. The data for infant macaques and newborn humans were compared. The newborn macaque appears to be an excellent model of human developmental trends (and/or disease state) over the first 3 weeks of life, though some potentially important differences have been found.     

Continuous tracheal gas insufflation during partial liquid ventilation in juvenile rabbits with acute lung injury.

To examine the hypothesis that combined treatment with tracheal gas insufflation (TGI) and partial liquid ventilation (PLV) may improve pulmonary outcome relative to either treatment alone in acute lung injury (ALI), saline lavage lung injury was induced in 24 anesthetized, ventilated juvenile rabbits that were then randomly assigned to receive (n = 6/group) 1) conventional mechanical ventilation (CMV) alone, 2) continuous TGI at 0.5 l/min, 3) PLV with perfluorochemical liquid, and 4) combined TGI and PLV (TGI + PLV), and subsequently ventilated with minimized pressures and tidal volume (Vt) to keep arterial Po(2) (Pa(O(2))) >100 Torr and arterial Pco(2) (Pa(CO(2))) at 45-60 Torr for 4 h. Gas exchange, lung mechanics, myeloperoxidase, IL-8, and histomorphometry [including expansion index (EI)] were assessed. The CMV group showed no improvement in lung mechanics and gas exchange; all treated groups had significant increases in compliance, Pa(O(2)), ventilation efficacy index (VEI), and EI, and decreases in PaCO(2), oxygenation index, physiological dead space-to-Vt ratio (Vd/Vt), myeloperoxidase, and IL-8, relative to the CMV group. TGI resulted in lower peak inspiratory pressure, Vt, Vd/Vt, and greater VEI vs. PLV group; PLV resulted in greater compliance, Pa(O(2)), and EI vs. TGI. TGI + PLV resulted in decreased peak inspiratory pressure, Vt, Vd/Vt, and increased VEI compared with TGI, improved compliance and EI compared with PLV, and a further increase in Pa(O(2)) and oxygenation index and a decrease in PaCO(2) vs. either treatment alone. These results indicate that combined treatment of TGI and PLV results in improved pulmonary outcome than either treatment alone in this animal model of ALI.     

Effects of diverse regimes of artificial respiration on the course of experimental toxic pulmonary edema

In acute experiments on cats with closed chest the author studied the influence of artificial ventilation of increased frequency or volume on the pulmonary edema degree, foam formation intensity, pulmonary gas exchange and the animals survival in experimental pulmonary edema caused by intravenous infusion of mixture fatty acids. It was shown, that artificial ventilation of increased frequencies or volumes in pulmonary edema reduces the increase of the pulmonary coefficient and edema liquid quantity at the beginning of edema and it does not become stronger in following stages. Artificial ventilation of increased regimes decreases the foam formation, increases survival of the animals, delays the arterial pressure decrease, improves the pulmonary gas exchange. Artificial ventilation of increased frequency is more effective then ventilation of increased volume decreases foam formation and improves gas exchange in the lungs.     

Physiological evaluation of a new quantitative SPECT method measuring regional ventilation and perfusion.

We have developed a new quantitative single-photon-emission computed tomography (SPECT) method that uses (113m)In-labeled albumin macroaggregates and Technegas ((99m)Tc) to estimate the distributions of regional ventilation and perfusion for the whole lung. The multiple inert-gas elimination technique (MIGET) and whole lung respiratory gas exchange were used as physiological evaluations of the SPECT method. Regional ventilation and perfusion were estimated by SPECT in nine healthy volunteers during awake, spontaneous breathing. Radiotracers were administered with subjects sitting upright, and SPECT images were acquired with subjects supine. Whole lung gas exchange of MIGET gases and arterial Po(2) and Pco(2) gases was predicted from estimates of regional ventilation and perfusion. We found a good agreement between measured and SPECT-predicted exchange of MIGET and respiratory gases. Correlations (r(2)) between SPECT-predicted and measured inert-gas excretions and retentions were 0.99. The method offers a new tool for measuring regional ventilation and perfusion in humans.     

Normal physiological values for conscious pigs used in biomedical research

Although the domestic pig is rapidly becoming an animal of choice in certain areas of biomedical research requiring a large animal model, effective utilization of the species is often encumbered by a lack of reference values for common functional variables. To address this problem, normal data for over 100 physiologic or related variables were collected from conscious chronically instrumented animals that were maintained under near basal conditions. Included were measurements of body composition, fluid volumes, blood physical and biochemical characteristics, blood gas and acid-base status, plasma hormone levels, energy metabolism, renal function, hemodynamics and pulmonary function. Most porcine values were similar to those collected under comparable conditions from humans. Compared to adult man, however, pigs had higher values for extracellular space, plasma volume, arterial pH, plasma bicarbonate, cardiac output, arterial pressure, expired ventilation, heat production, and core temperature, and lower values for red cell volume, hemoglobin level, plasma osmotic and oncotic pressure, arterial O2 content, renal blood flow and glomerular filtration rate. Many of these deviations were due to immaturity. Nevertheless, we have found pigs to be an excellent large animal model for a variety of functional studies.     

Pulmonary gas-exchange analysis by using simultaneous deposition of aerosolized and injected microspheres

Numerical methods for determining end-capillarygas contents for ventilation-to-perfusion ratios were first developedin the late 1960s. In the 1970s these methods were applied to validate distributions of ventilation-to-perfusion ratios measured by the multiple inert-gas-elimination technique. We combined numerical gasanalysis and fluorescent-microsphere measurements of ventilation andperfusion to predict gas exchange at a resolution of~2.0-cm³ lung volume in pigs.Oxygen, carbon dioxide, and inert gas exchange were calculated in551-845 compartments/animal before and after pulmonaryembolization with 780-µm beads. Whole lung gas exchange was estimatedfrom the perfusion- and ventilation-weighted end-capillary gascontents. Before lung injury, no significant difference existed betweenmicrosphere-estimated arterial PO₂and PCO₂ and measured values. Afterlung injury, the microsphere method predicted a decrease in arterialPO₂ but consistently underestimatedits magnitude. Correlation between predicted and measured inert gasretentions was 0.99. Overestimation of low-solubility inert gasretentions suggests underestimation of areas with low ventilation-to-perfusion ratios by microspheres after lung injury. Regional deposition of aerosolized and injected microspheres is a validmethod for investigating regional gas exchange with high spatial resolution.

     

Effects of acute temperature changes on aerial and aquatic gas exchange, pulmonary ventilation and blood gas status in the South American lungfish, Lepidosiren paradoxa

Lungfish (Dipnoi) are probably sister group relative to all land vertebrates (Tetrapoda). The South American lungfish, Lepidosiren paradoxa, depends markedly on pulmonary gas exchange. In this context, we report on temperature effects on aquatic and pulmonary respiration, ventilation and blood gases at 15, 25 and 35 degrees C. Lung ventilation increased from 0.5 (15 degrees C) to 8.1 ml BTPS kg(-1) min(-1) (35 degrees C), while pulmonary O(2)-uptake increased from 0.06 (15 degrees C) to 0.73 ml STPD kg(-1) min(-1) (35 degrees C). Meanwhile aquatic O(2)-uptake remained about the same ( approximately 0.01 ml STPD kg(-1) min(-1)) at all temperatures. Concomitantly, the pulmonary gas exchange ratio (R(E)) rose from 0.11 (15 degrees C) to 0.62 (35 degrees C), because a larger fraction of total CO(2) output became eliminated by the lung. Accordingly, PaCO(2) rose from 13 (15 degrees C) to 37 mm Hg (35 degrees C), leading to a significant decrease of pHa at higher temperature (pHa=7.58-15 degrees C; 7.33-35 degrees C). The acid-base status of L. paradoxa was characterized by a generally low pH (7.4-7.5), high bicarbonate level (20-25 mM) and PaO(2) ( approximately 80 mm Hg). The increased dependence on the lung at higher temperature parallels data for amphibians. Further, the effects of bimodal gas exchange on temperature-dependent acid-base regulation closely resemble those of anuran amphibians.     

Lung protein leaks in ventilated lambs: effects of gestational age

To study the protein permeability properties of the ventilated premature lung, we delivered groups of eight lambs at 122 and 135 days gestational age and ventilated the lambs equivalently. The lambs at 122 days gestational age had been treated with natural sheep surfactant at birth, and both groups of lambs had similar pH and blood gas values to 3 h of age. Three groups of lambs at 146 days gestational age also were studied for comparison; four lambs were ventilated to normalized PCO2 values, four lambs were ventilated equivalently to the premature lambs with supplemental CO2 used to normalize PCO2 values, and four lambs were treated with natural surfactant and ventilated similarly to the preterm lambs. The percent recovery into an alveolar wash and lung tissue of 131I-albumin given by intravascular injection and of 125I-albumin given into the airways was measured in each animal after killing at 3 h of age. Full-term lambs had a small bidirectional leak of albumin to and from the alveoli and lung tissue. The recovery of intravascular 131I-albumin in the alveolar wash was 5.8- and 4.1-fold higher in lambs at 122 and 135 days gestational age, respectively, than in full-term lambs. The loss of 125I-albumin from the airways and alveoli also increased as gestational age decreased. The bidirectional flux of albumin to and from the alveoli increased as gestational age decreased in the prematurely delivered and ventilated lambs.     

Frequency and amplitude effects during high-frequency vibration ventilation in dogs

High-frequency external body vibration, combined with constant gas flow at the tracheal carina, was previously shown to be an effective method of ventilation in normal dogs. The effects of frequency (f) and amplitude of the vibration were investigated in the present study. Eleven anesthetized and paralyzed dogs were placed on a vibrating table (4-32 Hz). O2 was delivered near the tracheal carina at 0.51.kg-1.min-1, while mean airway pressure was kept at 2.4 +/- 0.9 cmH2O. Table vertical displacement (D) and acceleration (a), esophageal (Pes), and tracheal (Ptr) peak-to-peak pressures, and tidal volume (VT) were measured as estimates of the input amplitude applied to the animal. Steady-state arterial PCO2 (PaCO2) and arterial PO2 (PaO2) values were used to monitor overall gas exchange. Typically, eucapnia was achieved with f greater than 16 Hz, D = 1 mm, a = 1 G, Pes = Ptr = 4 +/- 2 cmH2O, and VT less than 2 ml. Inverse exponential relationships were found between PaCO2 and f, a, Pes, and Ptr (exponents: -0.69, -0.38, -0.48, and -0.54, respectively); PaCO2 decreased linearly with increased displacement or VT at a fixed frequency (17 +/- 1 Hz). PaO2 was independent of both f and D (393 +/- 78 Torr, mean +/- SD). These data demonstrate the very small VT, Ptr, and Pes associated with vibration ventilation. It is clear, however, that mechanisms other then those described for conventional ventilation and high-frequency ventilation must be evoked to explain our data. One such possible mechanism is forcing of flow oscillation between lung regions (i.e., forced pendelluft).     

Factors in the development of arterial hypoxemia in middle-aged and elderly people

Partial pressure of oxygen and carbon dioxide in alveolar air and arterial blood, lung diffusion capacity and its components, ventilation parameters, ventilation-perfusion ratio were determined in healthy people aged 60-89 (45 subjects) and aged 20-31 (19 subjects, controls). In elderly and old people PO2 in arterial blood was found to decrease with increasing alveolar-arterial PO2 gradient. In other words, arterial hypoxemia was determined by the disturbance in gas exchange between alveolar air and blood of lung capillaries. The diffusion capacity of lung decreased at the expense of membrane factor. Its age-related dynamics was mainly due to a decrease in the pulmonary diffusion surface occurring because of improper coordination of ventilation and perfusion in the lungs. The discrepancy of pulmonary ventilation and perfusion proved to be the leading factor of arterial hypoxemia in late ontogenesis.     

Regulation of breathing at birth

The factors which regulate the transition to lung gas exchange in the newborn are not well understood. The transition begins within seconds of birth with the newborn's first breath and is largely complete by 30 min of age at which time breathing is continuous, and arterial blood gas tensions and pH approach stable newborn values. Experiments indicate that sensory stimulation caused by cutaneous cooling or sciatic nerve stimulation can result in the initiation of breathing within seconds. Thus, massive sensory stimulation of the newborn caused by labour and delivery probably plays an important role in promoting the rapid onset of lung ventilation. Any delay in the onset of lung gas exchange causes a rise in arterial PCO2 and fall in pH which would stimulate breathing probably via stimulation of the central chemoreceptors. Since an impairment of CO2 elimination is usually observed after birth, a rise in arterial PCO2 likely stimulates breathing in the newborn. However, this impairment is transient and is usually corrected within 30 min to 2 h of age. Recent experiments suggest that placental perfusion inhibits the fetal central respiratory system and that this effect may be mediated by a placentally-produced respiratory inhibitor. Thus, withdrawal of a respiratory inhibitor from the circulation may play an important role in maintaining breathing in the newborn after sensory stimulation wanes and arterial PCO2 returns to normal fetal levels.     

Pulmonary gas exchange and acid-base state at 5,260 m in high-altitude Bolivians and acclimatized lowlanders.

Pulmonary gas exchange and acid-base state were compared in nine Danish lowlanders (L) acclimatized to 5,260 m for 9 wk and seven native Bolivian residents (N) of La Paz (altitude 3,600-4,100 m) brought acutely to this altitude. We evaluated normalcy of arterial pH and assessed pulmonary gas exchange and acid-base balance at rest and during peak exercise when breathing room air and 55% O2. Despite 9 wk at 5,260 m and considerable renal bicarbonate excretion (arterial plasma HCO3- concentration = 15.1 meq/l), resting arterial pH in L was 7.48 +/- 0.007 (significantly greater than 7.40). On the other hand, arterial pH in N was only 7.43 +/- 0.004 (despite arterial O2 saturation of 77%) after ascent from 3,600-4,100 to 5,260 m in 2 h. Maximal power output was similar in the two groups breathing air, whereas on 55% O2 only L showed a significant increase. During exercise in air, arterial PCO2 was 8 Torr lower in L than in N (P < 0.001), yet PO2 was the same such that, at maximal O2 uptake, alveolar-arterial PO2 difference was lower in N (5.3 +/- 1.3 Torr) than in L (10.5 +/- 0.8 Torr), P = 0.004. Calculated O2 diffusing capacity was 40% higher in N than in L and, if referenced to maximal hyperoxic work, capacity was 73% greater in N. Buffering of lactic acid was greater in N, with 20% less increase in base deficit per millimole per liter rise in lactate. These data show in L persistent alkalosis even after 9 wk at 5,260 m. In N, the data show 1) insignificant reduction in exercise capacity when breathing air at 5,260 m compared with breathing 55% O2; 2) very little ventilatory response to acute hypoxemia (judged by arterial pH and arterial PCO2 responses to hyperoxia); 3) during exercise, greater pulmonary diffusing capacity than in L, allowing maintenance of arterial PO2 despite lower ventilation; and 4) better buffering of lactic acid. These results support and extend similar observations concerning adaptation in lung function in these and other high-altitude native groups previously performed at much lower altitudes.     

A perfluorochemical loss/restoration (L/R) system for tidal liquid ventilation

Tidal liquid ventilation is the transport of dissolved respiratory gases via volume exchange of perfluorochemical (PFC) liquid to and from the PFC-filled lung. All gas-liquid surface tension is eliminated, increasing compliance and providing lung protection due to lower inflation pressures. Tidal liquid ventilation is achieved by cycling fluid from a reservoir to and from the lung by a ventilator. Current approaches are microprocessor-based with feedback control. During inspiration, warmed oxygenated PFC liquid is pumped from a fluid reservoir/gas exchanger into the lung. PFC fluid is conserved by condensing (60-80% efficiency) vapor in the expired gas. A feedback-control system was developed to automatically replace PFC lost due to condenser inefficiency. This loss/restoration (L/R) system consists of a PFC-vapor thermal detector (+/- 2.5%), pneumatics, amplifiers, a gas flow detector (+/- 1%), a PFC pump (+/- 5%), and a controller. Gravimetric studies of perflubron loss from a flask due to evaporation were compared with experimental L/R results and found to be within +/- 1.4%. In addition, when L/R studies were conducted with a previously reported liquid ventilation system over a four-hour period, the L/R system maintained system perflubron volume to within +/- 1% of prime volume and 11.5% of replacement volume, and the difference between experimental PFC loss and that of the L/R system was 1.8 mL/hr. These studies suggest that the PFC L/R system may have significant economic (appropriate dosing for PFC loss) as well as physiologic (maintenance of PFC inventory in the lungs and liquid ventilator) impact on liquid ventilation procedures.