Frederick C. Morin

INHALED NITRIC OXIDE AND PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

Background Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension. Methods In a prospective, multicenter study, 58 full-term infants with severe hypoxemia and persistent pulmonary hypertension were randomly assigned to breathe either a control gas (nitrogen) or nitric oxide (80 parts per million), mixed with oxygen from a ventilator. If oxygenation increased after 20 minutes and systemic blood pressure did not decrease, the treatment was considered successful and was continued at lower concentrations. Otherwise, it was discontinued and alternative therapies, including extracorporeal membrane oxygenation, were used. Results Inhaled nitric oxide successfully doubled systemic oxygenation in 16 of 30 infants (53 percent), whereas conventional therapy without inhaled nitric oxide increased oxygenation in only 2 of 28 infants (7 percent). Long-term therapy with inhaled nitric oxide sustained systemic oxygenation in 75 percent of the infants who had initial improvement. Extracorporeal membrane oxygenation was required in 71 percent of the control group and 40 percent of the nitric oxide group (P=0.02). The number of deaths was similar in the two groups. Inhaled nitric oxide did not cause systemic hypotension or increase methemoglobin levels. Conclusions Inhaled nitric oxide improves systemic oxygenation in infants with persistent pulmonary hypertension and may reduce the need for more invasive treatments.

Perfluorocarbon-associated gas exchange (partial liquid ventilation) in respiratory distress syndrome: a prospective, randomized, controlled study.

ObjectiveTo determine the efficacy of perfluorocarbon-associated gas exchange (partial liquid ventilation) in respiratory distress syndrome. DesignProspective, randomized, controlled study. SettingState University of New York at Buffalo, School of Medicine and Biomedical Sciences. SubjectsEleven premature lambs with respiratory distress syndrome, delivered by cesarean section. InterventionsFive lambs were supported by conventional mechanical ventilation alone. Six lambs were switched to perfluorocarbon-associated gas exchange after 60 to 90 mins of conventional mechanical ventilation. Perfluorocarbon-associated gas exchange was accomplished by instilling a volume of liquid perfluorocarbon equivalent to normal functional residual capacity (30 mL/kg) into the trachea, performing 3 to 4 mins of tidal liquid ventilation, and at end-expiration, with liquid functional residual capacity of 30 mL/kg remaining in the lung, reconnecting the animal to the volume ventilator for gas tidal volumes. Measurements and Main ResultsSerial arterial blood gases and lung mechanics were measured. While receiving conventional ventilation, all animals developed progresssive hypoxemia, hypercarbia, and acidosis. However, in the perfluorocarbon-associated gas exchange group, within 5 mins of the initiation of perfluorocarbon-associated gas exchange, mean Pao2 increased four-fold, from 59 ± 6 torr (7.9 ± 0.8 kPa) during conventional ventilation to 250 ± 28 torr (33.3 ± 3.7 kPa; p<.05) during perfluorocarbon-associated gas exchange, and this increase was sustained at 60 mins of perfluorocarbnon-associated gas exchange (268 ± 38 torr; 35.7 ± 5.1 kPa; p<.05). Mean Paco2 decreased progressively from 62 ± 4 torr (8.3 ± 0.5 kPa) during conventional ventilation to 38 ± 3.3 torr (5.1 ± 0.4 kPa) at 60 mins of perfluorocarbon-associated gas exchage (p<.05). Mean pH concomitantly increased. Dynamic compliance increased three-fold within 15 mins of instituting perfluorocarbon-associated gas exchange, from 0.31 ± 0.02 mL/cm H2O during conventional ventilation to 0.90 ± 0.11 mL/cm H2O during perfluorocarbon-associated gas exchange, and this increase was sustained at 60 mins of perfluorocarbon-associated gas exchange (p<.05). Mean peak expiratory flow and mean expiratory resistance were essentially unchanged during perfluorocarbon-associated gas exchange as compared with conventional ventilation in the same group. ConclusionsWe conclude that perfluorocarbon-associated gas exchange, which employs liquid functional residual capacity and gas tidal volumes delivered by a conventional ventilator can facilitate oxygenation and CO2 removal, and dramatically improve lung mechanics in the premature lamb with respiratory distress syndrome. (Cirt Care Med 1993; 21:1270–1278)

Pathophysiology of congenital diaphragmatic hernia II: The fetal lamb CDH model is surfactant deficient

The high mortality for congenital diaphragmatic hernia (CDH) has been attributed to a combination of pulmonary hypoplasia and pulmonary hypertension. We hypothesize that a surfactant deficiency may in part be contributing to the pathophysiology of CDH. This study documents the functional, quantitative, and qualitative aspects of the surfactant status of the alveolar air-liquid interface and the type II pneumocyte in the fetal lamb CDH model. Ten lamb fetuses (gestational age, 80 days) had a CDH created via a left thoracotomy and then were allowed to continue in utero development until term. Three litter mates and three nonoperated time-dated fetuses served as controls. At term, pressure-volume curves were performed to measure pulmonary compliance and total lung capacity. Alveolar lavage was then performed to measure the quantitative and the qualitative aspects of pulmonary surfactant. Finally, isolation of type II pneumocytes allowed quantification of phospholipid synthesis. When compared with controls (N = 6), the CDH lambs (N = 5) had significantly smaller lungs (P = .009), decreased total lung capacity (P less than .001) and compliance (P less than .001), reduced total lavaged phospholipids (P = .006), and decreased percent phosphatidylcholine (P = .02). CDH lambs also had increased total lavaged proteins (P = .05) and higher minimum dynamic surface tension (P less than .001). A surfactant deficiency may be contributing to the pathophysiology of CDH. Surfactant replacement therapy in premature infants has been shown to improve lung compliance, decrease morbidity, and improve survival. Exogenous surfactant may also benefit infants with CDH.

Pathophysiology of congenital diaphragmatic hernia III: Exogenous surfactant therapy for the high-risk neonate with CDH

Exogenous surfactant therapy (EST) in surfactant-deficient premature infants has been shown to improve lung compliance, decrease morbidity, and improve survival. Reports have demonstrated that newborns with congenital diaphragmatic hernia (CDH) have lung compliance, pressure-volume curves, and hyaline membrane formation resembling those changes seen in surfactant deficient premature newborns. We hypothesize that EST may also benefit infants with CDH. All high risk cases of prenatally diagnosed CDH at Childrens Hospital of Buffalo from November 1988 to February 1991 were prospectively evaluated for EST. In those families who chose to participate, the surfactant preparation, Infasurf (100 mg/kg), was instilled into the newborns lungs prior to the first breath. The remainder of the perinatal, neonatal, and surgical care was performed in a routine manner. Three high-risk prenatally diagnosed newborns with left CDH were treated with EST. All showed signs of decreased pulmonary compliance, but could still be adequately oxygenated and ventilated. Surgical correction was performed after stabilization and all required patch closures. Two of the three infants suffered no life-threatening episodes of pulmonary hypertension and all survived. These infants had many known indicators for poor outcome in CDH with an expected survival of less than 20%. We believe that EST in these neonates with CDH contributed to their survival with minimum morbidity. These results suggest that surfactant replacement for the high-risk neonate with CDH warrants further consideration and a randomized clinical trial is being planned.

Treatment of persistent pulmonary hypertension in the newborn lamb by inhaled nitric oxide

We previously showed that fetal lambs whose ductus arteriosus is ligated prenatally will have persistent pulmonary hypertension at birth. We investigated the effect of inhaled nitric oxide on the pulmonary circulation in this animal model. The ductus arteriosus of six fetal lambs was ligated at 126 days of gestation. The lambs were delivered and studied at 136 days of gestation. Mechanical ventilation was maintained at a fraction of inspired oxygen of 0.80. Nitric oxide gas was administered at five different concentrations (6, 12, 25, 50, and 100 ppm) for 5-minute periods separated by 10-minute periods of ventilation without nitric oxide. Inhaled nitric oxide caused dose-dependent decreases in pulmonary arterial pressure and vascular resistance and dose-dependent increases in pulmonary blood flow without affecting systemic arterial pressure. Thus pulmonary arterial pressure decreased from equal to aortic pressure to less than aortic pressure. At the highest dose, mean pulmonary arterial pressure decreased by 27% +/- 2%, pulmonary blood flow increased by 86% +/- 6%, and pulmonary vascular resistance decreased by 59% +/- 4%. Nitric oxide also caused dose-dependent increases in systemic arterial oxygen tension and in the saturation of hemoglobin with oxygen. Partial pressure of arterial oxygen increased from 43 +/- 16 mm Hg at baseline to 185 +/- 72 mm Hg at the highest dose; saturation increased from 74% +/- 8% to 96% +/- 2%. In our model of persistent pulmonary hypertension of the newborn, inhaled nitric oxide selectively dilates the pulmonary circulation, thereby improving systemic arterial oxygenation. Nitric oxide is a promising new treatment of persistent pulmonary hypertension of the newborn.

Partial liquid ventilation in premature lambs with respiratory distress syndrome: Efficacy and compatibility with exogenous surfactant

OBJECTIVE To determine the efficacy of partial liquid ventilation (PLV) by means of a medical-grade perfluorochemical liquid, perflubron (LiquiVent), in premature lambs with respiratory distress syndrome (RDS). Further, to determine the compatibility of perflubron with exogenous surfactant both in vitro and in vivo during PLV. DESIGN Prospective, randomized, controlled study, with in vitro open comparison. SUBJECTS Twenty-two premature lambs with RDS. INTERVENTIONS In vitro assays were conducted on three exogenous surfactants before and after combination with perflubron. We studied four groups of lambs, which received one of the following treatment strategies: conventional mechanical ventilation (CMV); surfactant (Exosurf) plus CMV; PLV; or surfactant plus PLV. MEASUREMENTS AND MAIN RESULTS In vitro surface tension, measured for three exogenous surfactants, was unchanged in each animal after exposure to perflubron. Lung mechanics and arterial blood gases were serially measured. All animals treated with PLV survived the 5 hours of experiment without complication; several animals treated with CMV died. During CMV, all animals had marked hypoxemia and hypercapnia. During PLV, arterial oxygen tension increased sixfold to sevenfold within minutes of initiation, and this increase was sustained; arterial carbon dioxide tension decreased to within the normal range. Compliance increased fourfold to fivefold during PLV compared with CMV. Tidal volumes were increased during PLV, with lower mean airway pressure. Resistance was similar for both CMV and PLV; there was no difference with surfactant treatment. CONCLUSIONS We conclude that PLV with perflubron improves lung mechanics and gas exchange in premature lambs with RDS, that PLV is compatible with exogenous surfactant therapy, and that, as a treatment for RDS in this model, PLV is superior to the surfactant studied.

Ligating the ductus arteriosus before birth remodels the pulmonary vasculature of the lamb.

ABSTRACT: The clinical syndrome of persistent pulmonary hypertension of the newborn includes a developmentally abnormal pulmonary microvasculature which contains excessive amounts of muscle and which cannot adapt to air breathing in the perinatal period. Surgical ligation of the ductus arteriosus of the fetal lamb has produced a physiologic model of pulmonary hypertension of the newborn. The aim of the present investigation is to determine whether surgical ligation of the ductus arteriosus in fetal sheep produces anatomic changes in the pulmonary blood vessels. The pulmonary vasculature of seven neonatal lambs that underwent surgical ligation of the ductus arteriosus from 6 to 17 d before birth was compared to that of five control lambs with a patent ductus arteriosus without fetal surgery and three control lambs with a patent ductus arteriosus that underwent sham surgery. Quantitative microscopic analysis of the barium gelatin-filled peripheral pulmonary vascular bed revealed an increase in the proportion of partially and fully muscularized pulmonary arteries at the level of the terminal bronchiole and within the acinus (p<0.0001). This finding demonstrates that medial muscle develops in areas of the distal pulmonary vascular bed where it is normally absent. Periadventitial fibrosis surrounding intraacinar pulmonary arteries was also present. No change in the number of small intraacinar arteries was detected. This structural remodeling of the peripheral pulmonary vascular bed was initiated in utero by ductus arteriosus occlusion. Prenatal closure of the ductus arteriosus for 6 to 17 d in fetal lambs produces anatomic changes in small pulmonary arteries of the newborn lamb. These anatomic changes are similar to pathologic alterations reported in human neonates dying with idiopathic persistent pulmonary hypertension of the newborn.

Pulmonary arterial contractility in neonatal lambs increases with 100% oxygen resuscitation.

The optimal Fio2 during neonatal resuscitation is a subject of controversy. The effect of exposure to high levels of inspired oxygen on pulmonary arterial (PA) contractility is not known. We studied differences in PA vasoreactivity in term lambs initially ventilated with 21% or 100% oxygen, followed by continued ventilation using oxygen as needed for 24 h, or ventilated with 100% oxygen for 24 h and room air breathing 1-d-old lambs. Term lambs were delivered by cesarean section, intubated, and ventilated with 21% (21%Res) or 100% oxygen (100%Res) for the first 30 min of life. Subsequently, the ventilator Fio2 was adjusted to maintain a Pao2 between 45 and 65 mm Hg for 24 h. Five lambs were ventilated continuously with 100% oxygen (100%24h). Six spontaneously breathing newborn lambs (RA Spont) were studied for comparison. Lambs were killed at 24 h of life and PA rings were isolated and contracted with norepinephrine (NE) and KCl and some were relaxed with A23187 and SNAP in tissue baths. NE and KCl induced contractions were highest in PA isolated from 100%24h lambs, and were significantly higher in 100%Res lambs than PA from 21%Res lambs. Contraction responses in PA from RA Spont lambs were similar to 21%Res lambs. Relaxations to A23187 and SNAP were similar among all ventilated groups. PA contractility to NE and KCl is increased following both brief (30 min) and prolonged (24 h) exposure to 100% oxygen during mechanical ventilation. In contrast, normoxic resuscitation and ventilation do not increase PA contractility.

Pulmonary hemodynamics in neonatal lambs resuscitated with 21%, 50%, and 100% oxygen.

The effect of resuscitation with varying levels of O2 on pulmonary hemodynamics at birth is not well known. We hypothesized that the decrease in pulmonary vascular resistance (PVR) and subsequent response to pulmonary vasoconstrictors and vasodilators will differ following resuscitation with 21%, 50%, or 100%O2 for 30 min at birth in normal term lambs. Lambs at 141 d gestation were delivered by cesarean section and ventilated with 21% (21% Res; n = 6), 50% (50% Res; n = 6), or 100% O2 (100% Res; n = 7) for 30 min followed by ventilation with 21% O2 in all three groups. A greater decrease in PVR was seen with 50% and 100% O2 ventilation than with 21% O2 (0.21 ± 0.02, 0.21 ± 0.02, and 0.34 ± 0.05 mm Hg/mL/min/kg, respectively). Subsequent pulmonary vasoconstriction to hypoxia (10% O2) and the thromboxane analog U46619 (0.5 and 1 μg/kg/min) was similar in all three groups. After inducing a stable elevation in PVR with U46619, impaired pulmonary vasodilation to inhaled NO (59 ± 4, 65 ± 4, and 74 ± 5% of baseline PVR with 21, 50, and 100%Res, respectively) and acetylcholine infusion (67 ± 8, 75 ± 6, and 87 ± 4% of baseline PVR with 21, 50, and 100%Res, respectively) and rebound pulmonary hypertension following their withdrawal were observed in the 100%Res group. We conclude that, while ventilation with 100% O2 at birth results in a greater initial decrease in PVR, subsequent pulmonary vasodilation to NO/acetylcholine is impaired.

Perfluorocarbon-associated gas exchange improves pulmonary mechanics, oxygenation, ventilation, and allows nitric oxide delivery in the hypoplastic lung congenital diaphragmatic hernia lamb model

OBJECTIVES To determine the efficacy of perfluorocarbon-associated gas exchange and the effects of inhaled nitric oxide during perfluorocarbon-associated gas exchange in the congenital diaphragmatic hernia lamb model. DESIGN Prospective, nonrandomized, controlled, nonhuman trial. SETTING Animal research facility. SUBJECTS Fetal lambs of 16 time-dated pregnant ewes, at 80 days gestation (term 140 to 145 days). MEASUREMENTS AND MAIN RESULTS The congenital diaphragmatic hernia lamb model was created in 16 animals. Twelve animals survived to be studied. All animals were mechanically ventilated for 4 hrs with a time-cycled, pressure-limited ventilator. Perfluorocarbon-associated gas exchange was started after 15 mins of ventilation (n = 6). Blood gases were analyzed at 30 mins and then hourly. The perfluorocarbon-associated gas exchange animals had dynamic compliance and tidal volumes measured. After 1 hr, inhaled nitric oxide (80 parts per million) was delivered to the perfluorocarbon-associated gas exchange animals for 10 mins. All blood gas parameters, including pH (6.72 +/- 0.06 vs. 7.14 +/- 0.07), PCO2 (186 +/- 12 vs. 70.5 +/- 16.7 torr [24.8 +/- 1.6 vs. 9.5 +/- 2.1 kPa]), and PO2 (48 +/- 17 vs. 156 +/- 48 torr [6.4 +/- 2.3 vs. 20.8 +/- 6.4 kPa]) were significantly improved in the perfluorocarbon-associated gas exchange-treated group at 4 hrs (p < .005). Dynamic compliance (0.13 +/- 0.02 vs. 0.32 +/- 0.06 mL/cm H2O/kg) and tidal volume (3.5 +/- 0.35 vs. 7.22 +/- 0.61 mL/kg) were also significantly (p < .001) increased in the perfluorocarbon-associated gas exchange group. In the perfluorocarbon-associated gas exchange animals, nitric oxide caused a significant (p < .05) increase in oxygenation and a reduction in pulmonary hypertension. This effect was reversed by stopping the inhaled nitric oxide. CONCLUSIONS Perfluorocarbon-associated gas exchange significantly improved gas exchange, dynamic compliance, and tidal volumes. Furthermore, inhaled nitric oxide can be effectively delivered during perfluorocarbon-associated gas exchange to reduce pulmonary hypertension and enhance oxygenation.