J. Craig Jackson

Partial liquid ventilation with perflubron in premature infants with severe respiratory distress syndrome

Background The intratracheal administration of a perfluorocarbon liquid during continuous positive-pressure ventilation (partial liquid ventilation) improves lung function in animals with surfactant deficiency. Whether partial liquid ventilation is effective in the treatment of infants with severe respiratory distress syndrome is not known. Methods We studied the efficacy of partial liquid ventilation with perflubron in 13 premature infants with severe respiratory distress syndrome in whom conventional treatment, including surfactant therapy, had failed. Partial liquid ventilation was initiated by instilling perflubron during conventional mechanical ventilation to a volume approximating the functional residual capacity. Infants were considered to have completed the study if they received partial liquid ventilation for at least 24 hours. Results Ten infants received partial liquid ventilation for 24 to 76 hours. In the other three infants, partial liquid ventilation was discontinued within four hours in fa...

Breech extraction of low-birth-weight second twins:Can cesarean section be justified?

The outcomes of 54 breech-extracted second twins weighing between 750 and 2000 gm were compared with the outcomes of their siblings and of 43 sets of twins delivered by cesarean section for malpresentation. Vaginally delivered first twins had fewer days of mechanical ventilation and oxygen therapy than their breech-extracted siblings (p = 0.004). There were no significant differences in any measures of neonatal outcome when breech-extracted twins were compared with second twins delivered by cesarean section. We conclude that routine cesarean section is not justified for nonvertex second twins expected to weigh less than 2000 gm.

Changes in hyaluronan deposition during early respiratory distress syndrome in premature monkeys.

ABSTRACT: Increased deposition of hyaluronan (HA) is part of the early response to fibrogenic stimulus in the lung exposed to bleomycin injury and has been associated with increased lung water in adult animals. Early respiratory distress syndrome (RDS) in premature infants is characterized by increased lung water, and late sequelae include fibrosis or bronchopulmonary dysplasia. We hypothesized that increased MA in the alveolar interstitium would be associated with increasingly severe RDS in prematurely delivered monkeys and that modes of therapy that affect severity of disease such as treatment with high-frequency oscillatory ventilation or exogenous surfactant would decrease this response. Thirty-four Macaca nemestrina monkeys were delivered at 134 ± 1 d (term = 168 d) and randomized to high-frequency oscillatory ventilation or conventional mechanical ventilation from birth. Sixteen of these animals received surfactant. At 6 h of age, the right lower lung was frozen in situ during inflation to 30 cm H2O (approximately 2940 Pa) and then dehydrated and processed for microscopy. The presence and severity of RDS were evaluated by clinical and morphologic criteria. HA concentrations in lung extracts increased with progressively severe RDS (p = 0.0003). Treatment with high-frequency oscillatory ventilation decreased the lung injury score (1.69 ± 0.7 compared with 2.5 ± 0.9, p = 0.05), but changes in lung HA concentration did not reach significance (37.9 ± 22.7 compared with 44.8 ± 22.6). Surfactant treatment decreased lung HA concentration (29.6 ± 19.0 μg/wet lung) compared with non-surfactant-treated animals (54.7 ± 20.2 μg/g wet lung, p = 0.0009). Two fetal animals (144 and 163 d gestation) and seven additional premature animals ventilated for up to 96 h were compared with the animals killed at 6 h. HA concentrations increased with length of mechanical ventilation and severity of illness in these animals. HA was localized in freeze-dried lung sections using a biotinylated probe. Lung sections were blindly scored for the distribution of HA staining, and these scores were positively correlated with HA concentration measurements (r = 0.75, p < 0.0001). The quantity of HA in alveolar microvasculature correlated with severity of RDS (r = 0.68, p = 0.0004). We conclude that 1) HA concentration in RDS lungs of prematurely delivered infant monkeys is increased relative to normal lungs at 6 h, 2) increased HA is localized predominantly to the perivascular space of lung vasculature, and 3) this response is decreased by surfactant treatment.

Perfluorochemical liquid-enhanced adenoviral vector distribution and expression in lungs of spontaneously breathing rodents.

Perfluorochemical (PFC) liquids have been shown to improve gas exchange and lung compliance in models of lung injury. We reasoned they may also be useful as a vehicle for gene transfer by improving transgene distribution throughout the lung as well as increasing total transgene expression. We have developed a model for PFC liquid use in spontaneously breathing rodents that obviates the need for intubation and ventilation. Intratracheal instillation of the adenoviral vector Adlac-Z resulted in patchy distribution of beta-galactosidase (beta-gal) activity as demonstrated using X-gal histochemistry. In contrast, in rats instilled with Adlac-Z followed by instillation of PFC liquid, more uniformly distributed and increased beta-gal activity was observed. Activity in distal airway and alveolar epithelium was particularly increased. Quantitative measure of beta-gal activity in lung homogenates demonstrated a 3- to 6-fold increase in total activity in lungs of rats receiving Adlac-Z and PFC liquid compared to animals receiving Adlac-Z alone. These studies show that PFC liquids can enhance both the distribution and the total amount of transgene expressed following adenoviral-mediated vector transfer to lungs during spontaneous breathing. Use of PFC liquids may increase the efficacy of gene transfer strategies for treatment of cystic fibrosis and other lung diseases.

Effects of surfactant therapy on outcome of infants with birth weights of 600 to 750 grams

Replacement therapy with exogenous surfactant has been studied for both prevention and treatment of respiratory distress syndrome. Although reports demonstrate improved survival rates for surfactant-treated infants with RDS, the impact of this therapy on outcome of extremely low birth weight infants is unknown. TM Previous studies have not reported outcome after surfactant treatment for the subset of premature infants who are born at ELBWs and who are at the highest risk for complications of prematurity. We report the outcome of infants born with birth weights between 600 and 750 gm who underwent prospective random selection to receive either surfactant or placebo as part of a multidose prevention study.

Efficacy of thromboresistant umbilical artery catheters in reducing aortic thrombosis and related complications

Previous in vitro and in vivo reports suggest that catheters constructed of polyurethane with heparin bonded to the surface (HB-PU) are less thrombogenic than catheters made of polyvinyl chloride (PVC). A randomized trial sufficiently large (power 80%) to detect a reduction in the incidence of umbilical artery (UA) catheter complications, including aortic thrombus formation, from 45% to 20% was conducted in 125 infants. The infants were monitored for complications possibly related to the use of a UA catheter, such as systemic hypertension and abnormalities of lower extremity perfusion. The presence of aortic thrombi was assessed by ultrasound study 3.5 +/- 1.2 (SD) days and 11.1 +/- 2.3 days after insertion of the catheter. The use of HB-PU umbilical catheters did not lead to a significant reduction in the incidence of complications and aortic thrombi compared with the use of PVC catheters. The lack of reduction may have been related to the prolonged duration of catheter use in both groups. A much larger study would have been required to detect a smaller, but perhaps clinically significant, reduction in catheter-associated complications.

Multicenter comparative study of conventional mechanical gas ventilation to tidal liquid ventilation in oleic acid injured sheep.

We performed a multicenter study to test the hypothesis that tidal liquid ventilation (TLV) would improve cardiopulmonary, lung histomorphological, and inflammatory profiles compared with conventional mechanical gas ventilation (CMV). Sheep were studied using the same volume-controlled, pressure-limited ventilator systems, protocols, and treatment strategies in three independent laboratories. Following baseline measurements, oleic acid lung injury was induced and animals were randomized to 4 hours of CMV or TLV targeted to “best PaO2” and PaCO2 35 to 60 mm Hg. The following were significantly higher (p < 0.01) during TLV than CMV: PaO2, venous oxygen saturation, respiratory compliance, cardiac output, stroke volume, oxygen delivery, ventilatory efficiency index; alveolar area, lung % gas exchange space, and expansion index. The following were lower (p < 0.01) during TLV compared with CMV: inspiratory and expiratory pause pressures, mean airway pressure, minute ventilation, physiologic shunt, plasma lactate, lung interleukin-6, interleukin-8, myeloperoxidase, and composite total injury score. No significant laboratories by treatment group interactions were found. In summary, TLV resulted in improved cardiopulmonary physiology at lower ventilatory requirements with more favorable histological and inflammatory profiles than CMV. As such, TLV offers a feasible ventilatory alternative as a lung protective strategy in this model of acute lung injury.

Postnatal changes in lung phospholipids and alveolar macrophages in term newborn monkeys

In order to better understand the postnatal sequence of surfactant secretion and establishment of the alveolar macrophage (AM) population in newborn primates, healthy Macaca nemestrina monkeys were sacrificed during fetal life at term gestation (n = 5), or at 2 days (n = 5) or 3-4 weeks (n = 5) after term vaginal delivery. Excised lung tissue and left lung lavage were analyzed for phospholipid (PL) content, surface active material (SAM) extract, PL components, surface activity, pressure-volume characteristics, and AM number. Compared to term fetal animals, 2 day old term newborn monkeys were found to have a several-fold increase in lavage PL and SAM, and this was associated with greater maximal lung volume and drier lungs, but not improved deflation stability. During the subsequent 3-4 weeks of life, a 42% reduction in lung tissue stores of PL and SAM, and an 87% reduction in lavage PL and SAM were noted. Despite these major changes in quantity, there were relatively minor changes in the composition of the PL synthesized and released. The reduced quantity of SAM in the 3-4 week old animals led to a small decline in deflation stability. The several-fold increase in lavage PL and SAM during the first 2 days of life was accompanied by a 33-fold increase in AM; there was an additional 4-fold increase in AM number by 3-4 weeks of age. The abundance of lavage surfactant at 2 days of age may play a role in the influx of AM.

Gravitational effects on volume distribution in a model of partial and total liquid ventilation

To estimate regional lung volume during ventilation with liquids (e. g. perfluorochemicals, PFC) we developed a multi-compartment mathematical model of a lung and thorax. The height of the fluid column and the fluids density determine alveolar pressure (PA). The weight of thoracic contents above any given gravitational plane influences pleural pressure (PPL). Transpulmonary pressure (PTP=PA&MINUS;PPL) and compliance of the lung and chest wall permit estimation of volumes. The results indicate the lung inflates almost uniformly during total liquid ventilation despite a substantial vertical PA gradient. Inflation uniformity is due to the offsetting vertical PPL gradient created by the added weight of the PFC and sustained by the relative rigidity of the chest wall. During partial liquid ventilation our model indicates that the combination of uniform PA with a large vertical gradient in PPL leads to a vertical PTP gradient and therefore relative over-inflation of the top of the lung. This effect increases with increasing PFC dose and with lung height.

Acute changes in vasoactive lipid mediators in experimental hyaline membrane disease

Endothelial release of the arachidonate derivative PGI2 may be increased in response to cyclic lung stretching. We therefore sought to determine if the stable metabolite of PGI2, 6-keto-PGF1 alpha, would be found in increased quantities in primates ventilated with conventional mechanical ventilation (CMV) compared to treatment with high frequency oscillatory ventilation (HFOV). We also sought to determine if other membrane-derived vasoactive substances such as LTC4, PAF and TXB2 would be elevated in plasma and lung tissue of animals developing hyaline membrane disease (HMD) and if the levels would correlate with the severity of the respiratory distress. Twenty prematurely delivered monkeys were treated with either CMV or HFOV from the first breath after Cesarean delivery until sacrifice at 6 h of age. We found a significant increase from birth to 5 min and from 5 min to 5 h in 6-keto-PGF1 alpha, and a significant increase from 5 min to 5 h in TXB2. We found a significant decline from cord blood to 5 min of LTC4, without further change by 5 h. PAF was present in all plasma samples but showed no upward or downward trend. There was no difference in the 5-h plasma level or in the lung homogenate level of any of the lipid mediators between the two types of assisted ventilation. There was no correlation between any lipid mediator level and severity of the HMD, as measured by gas exchange, radiographic or histologic criteria, when assessed by each ventilator group alone or with both groups combined. We conclude that the immediate postnatal increases in TXB2 and PGI2 and decrease in LTC4 are not altered substantially by use of HFOV.