Plasma thromboxane and pulmonary artery pressure in neonates treated with extracorporeal membrane oxygenation.

To examine whether neonates with persistent pulmonary hypertension are subject to a thromboxane-mediated exacerbation of their pulmonary hypertension during extracorporeal membrane oxygenator therapy (a form of partial cardiopulmonary bypass), we performed serial measurements of plasma thromboxane B2 and pulmonary artery pressure before, during, and after extracorporeal membrane oxygenation. Pulmonary artery pressure was high before extracorporeal membrane oxygenation, did not increase after the start of this therapy, but began to decrease after 48 hours of extracorporeal membrane oxygenation. During the course of extracorporeal membrane oxygenation, mean pulmonary artery pressure decreased by 50% and mean plasma thromboxane B2 levels decreased by 70%. In addition, serial plasma thromboxane B2 levels were significantly correlated with pulmonary artery pressures in individual infants with a primary diagnosis of meconium aspiration (r = 0.965 to 0.723). We speculate that the decrease in pulmonary artery pressure and plasma thromboxane B2 levels over time may reflect resolution of acute lung injury and that thromboxane B2 may play a role in regulating pulmonary artery pressure in infants with meconium aspiration.

Plasma prostanoids in neonates with pulmonary hypertension treated with conventional therapy and with extracorporeal membrane oxygenation.

Thromboxane may be a mediator of pulmonary hypertension in the neonate. Acute thromboxane-mediated pulmonary hypertension has been described in sheep receiving extracorporeal membrane oxygenation, which raises concerns about a potential thromboxane-mediated exacerbation of pulmonary hypertension in human neonates with severe pulmonary hypertension who are treated with extracorporeal membrane oxygenation. We measured plasma levels of thromboxane, prostaglandin F2 alpha, and 6-keto-prostaglandin F1 alpha in infants with pulmonary hypertension, some of whom were treated medically and some of whom were treated with extracorporeal membrane oxygenation. Plasma levels of all three prostanoids were elevated in infants with pulmonary hypertension and decreased with time, whether the neonates were treated with extracorporeal membrane oxygenation or with medical management alone. In infants treated with extracorporeal membrane oxygenation, we collected samples simultaneously from preoxygenator sites, postoxygenator sites, and umbilical artery catheter. We could demonstrate no significant difference in plasma prostanoid levels across the oxygenator. In two patients, plasma thromboxane and prostaglandin F2 alpha levels measured shortly after a platelet transfusion were distinctly higher in the umbilical artery catheter than in venous samples.

Plasma prostanoids in neonatal extracorporeal membrane oxygenation. Influence of meconium aspiration.

Thromboxane B2 may be a mediator of neonatal persistent pulmonary hypertension. Elevated levels of plasma thromboxane and prostacyclin have been described previously in hypoxic newborn infants with neonatal pulmonary hypertension. We measured serial plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha (stable metabolite of prostacyclin) in 21 newborn infants with severe respiratory failure and pulmonary hypertension who required extracorporeal membrane oxygenation support. We sought to study (1) the evolution of plasma prostanoids in pulmonary hypertensive infants treated with extracorporeal membrane oxygenation and (2) whether different pulmonary hypertensive diagnostic subgroups have distinctive prostanoid profiles. Our data indicated that infants with meconium aspiration had significantly lower levels of plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha while receiving extracorporeal membrane oxygenation than did infants with persistent pulmonary hypertension but no meconium aspiration. Levels of all infants decreased progressively as extracorporeal membrane oxygenation support continued.

Extracorporeal membrane oxygenation for cardiac support in pediatric patients.

Extracorporeal membrane oxygenation (ECMO) has been used for pediatric cardiac support in settings of expected mortality due to severe myocardial dysfunction. We reviewed the records of 34 children (<18 years) placed on ECMO between March 1995 and May 1999. Demographic, cardiac, noncardiac, and outcome variables were recorded. Data were subjected to univariate analysis to define predictors of outcome. Eighteen patients were placed on ECMO after cardiac surgery (Group A); seven of 18 were weaned off ECMO, and four survived to discharge (22%). Thirteen patients were placed on ECMO as a bridge to cardiac transplantation (Group B), six of 13 received a heart transplant, one recovered spontaneously, and six survived to discharge (46%). Three patients were placed on ECMO for failed cardiac transplantation while awaiting a second transplant (Group C); one recovered graft function, two received a second heart transplant, and two of three survived (66%). The primary cause of death was multiorgan system failure (68%). Group A patients supported on ECMO for more than 6 days did not survive. Mediastinal bleeding complications and renal failure requiring dialysis were associated with nonsurvival. We conclude that ECMO as a bridge to cardiac transplant was more successful than ECMO support after cardiotomy. Mediastinal bleeding and renal failure were associated with poor outcome. Recovery of cardiac function occurred within the first week of ECMO support if at all. Longer support did not result in survival without transplantation.

Extracorporeal membrane oxygenation in neonatal respiratory failure. A brief overview.

Extracorporeal membrane oxygenation has been used for over 15 years to salvage neonates with severe respiratory failure. This article briefly reviews the indications, cannulation procedures, management on bypass, possible complications, and available neurodevelopmental follow-up data of the survivors.

Persistent pulmonary hypertension of the newborn. Managing the unmanageable?

Persistent pulmonary hypertension of the newborn is a complex syndrome with multiple causes, which retains a high morbidity and mortality. This article presents pathophysiologic and diagnostic foundations and then focuses the discussion on management issues.

The efficacy of extracorporeal life support in premature and low birth weight newborns.

Based on data obtained early in the development of neonatal extracorporeal life support (ECLS), contraindications to the use of ECLS have included low estimated gestational age (EGA) and low birth weight (BW). However, multiple improvements in the technical and management aspects of neonatal ECLS have been implemented since those early data were evaluated. The purpose of this study, therefore, is to assess in the "modern era" the efficacy of prolonged extracorporeal support in premature and low birth weight newborns. Examination of the Extracorporeal Life Support Organization (ELSO) Registry showed that between 1988 and 1991 ECLS was utilized in 158 premature (PREM, EGA < or = 34 weeks), 4,128 full-term (FT, EGA > or = 35 weeks), 26 low birth weight (LBW, BW < 2.0 kg), and 4,333 normal birth weight (NBW, BW > or = 2.0 kg) patients with respiratory failure. Data were evaluated for variables thought to be associated with a decrease in survival or an increase in the incidence of intracranial hemorrhage (ICH). A logistic regression model was developed to evaluate the ability of EGA and BW to predict survival. The incidence of survival (SURV) was decreased (63% v 84%) and ICH increased (37% v 14%) significantly in PREM when compared with FT newborns (P < .001). However, respectable survival rates in PREM patients with EGA > 32 weeks were documented. In addition, both survival and ICH in PREM patients have improved substantially when compared with past reports (Past: SURV = 25% and ICH = 100%; current: SURV = 63% and ICH = 37%; ICH P < .001; SURV P = .056). Survival was significantly decreased in LBW when compared to NBW neonates (65% v 83%, P < .05), but there was no significant difference in ICH.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of intratracheal pulmonary ventilation with hybrid intratracheal pulmonary ventilation in a rabbit model of acute respiratory distress syndrome by saline lavage.

We compared different hybrid mode ITPV (h-ITPV) flow rates, and h-ITPV with intratracheal pulmonary ventilation (ITPV) with respect to CO2 clearance and oxygenation. Surfactant deficiency was induced in six adult rabbits with saline lavage. The study consisted of three phases. Phase 0: Stabilization on conventional mechanical ventilation (CMV). Phase I: Bias flow initiated at same pressure and respiratory rate as Phase 0. Flow rates of 25%, 50%, 75% h-ITPV, and ITPV were initiated. Animals were transitioned from CMV to 25% h-ITPV proceeding sequentially to ITPV or vice versa. Phase II: Animals were returned to CMV. Statistical analysis included the two-way analysis of variance (ANOVA) and repeated measures ANOVA with Tuckey's test. No difference in PaCO2 was observed among all h-ITPV flow rates or between h-ITPV and ITPV. After bias flow was introduced (transition from Phase 0 to Phase I), PaCO2 decreased by 37%. PaCO2 increased by 119% during Phase II. Oxygenation improved in all animals, particularly in those transitioned to 25% h-ITPV and proceeding to ITPV. No difference in CO2 clearance between ITPV and h-ITPV was observed. Even at low bias flows, excellent CO2 clearance was achieved. Oxygenation was superior when animals were transitioned from CMV to h-ITPV. Hybrid-ITPV offers some advantages over ITPV and may represent a powerful tool in the management of acute respiratory distress syndrome (ARDS).

Predictors of neonatal mortality in 1,500-1,999 g premature infants with respiratory failure. Basis for ECMO Therapeutic Trial.

Despite the introduction of new ventilation techniques and surfactant therapy, some premature infants still experience severe respiratory failure and either die or survive with severe bronchopulmonary dysplasia. Extracorporeal membrane oxygenation is currently not offered for preterm infants with a birth weight less than 2,000 g, mainly because of the potential high risk for intracranial hemorrhage. The aim of this study was to determine risk predictors for mortality alone and for mortality or major lung morbidity in 1,500-1,999 g premature infants with respiratory failure. We reviewed the medical records of all preterm infants (n = 459) with respiratory failure and a birth weight of 1,500-1,999 g treated at five medical centers from 1989 to 1991. Of those infants, 23 (5%) had severe respiratory failure, defined as a requirement for ventilatory support with the fraction of inspired oxygen > or = 0.8 or peak inspiratory pressure > or = 30 cmH2O for > or = 3 hr in the 1st week of life. A mortality of > or = 75% was associated with a single arterial/alveolar oxygen ratio < or = 0.04; pulmonary air leak alone or pulmonary air leak with a mean airway pressure > or = 12 cmH2O; and arterial oxygen tension < or = 50 mmHg. These risk predictors may provide a basis for the selection of patients for future clinical trials of extracorporeal membrane oxygenation in this high-risk group of 1,500-1,999 g premature infants with severe respiratory failure.

Reduction of respiratory system resistance of rabbits with surfactant deficiency using a novel ultra thin walled endotracheal tube.

The ultra thin walled, two-stage endotracheal tube (UTW-TS-ETT) is very flexible, nonkinking, and has a widened extralaryngeal portion. The UTW-TS-ETT has a greater ID/OD (internal diameter/outer diameter) ratio than a comparable standard endotracheal tube (ST-ETT) because of its thinner wall: 0.2-0.25 mm in UTW-TS-ETT, compared to 0.55-0.8 mm in ST-ETT. The authors hypothesized that in an animal model of lung disease, significant reductions in respiratory system resistance (Rrs) of 30-40% would be achieved using the UTW-TS-ETT, compared to Rrs achieved with the comparable ST-ETT. This study compared the pulmonary mechanics of rabbits (N = 17, body weight 3.4-4.7 kg) before and after induction of surfactant deficiency, using either ST-ETT (OD 4.9 mm, ID 3.5 mm) or UTW-TS-ETT (OD 5.0 mm, ID 4.6 mm). Animals were sedated, paralyzed, and ventilated by an ETT placed through a tracheotomy incision. Surfactant deficiency was induced by lavaging the lungs with normal saline (10 ml/kg). Pulmonary mechanics were measured on identical ventilator settings for each ETT used at baseline and at 45 min after lavage. Compared to ST-ETT, UTW-TS-ETT reduced Rrs by 50.6 +/- 8.7% in normal lungs (significantly more than 40%; p < 0.01), and by 41.47 +/- 16.2% in surfactant deficient lungs (significantly more than 30%; p < 0.05). Tidal volume increased with UTW-TS-ETT in all animals but did not achieve statistical significance. The UTW-TS-ETT did not induce significant changes in respiratory system compliance, PaO2, PaCO2, or pH. It is concluded that UTW-TS-ETT significantly reduces Rrs in rabbits with either normal lungs or with surfactant deficient lungs. This novel ETT may be beneficial for ventilated patients with increased Rrs, by effecting a decrease in Rrs and thus reducing the work of breathing and improving ventilation efficiency.

Differential expression of cyclin D2 and cdc2 genes in proliferating and nonproliferating alveolar epithelial cells.

Alveolar epithelial cells (AEC) proliferate during embryonic and fetal life, while in the adult lung AEC form a highly differentiated population that does not usually divide. Herein, we tested the hypothesis that differential expression of specific cell cycle control genes may occur during AEC development and transformation. We compared normal rat AEC in primary culture with transformed AEC for the expression of D-type G1 cyclins and cyclin-dependent protein kinases (cdc2 and cdk2). Cyclin D1 mRNA and protein were expressed at comparable levels in both normal rat AEC and in transformed AEC. In contrast, high levels of cyclin D2 mRNA and protein expression were only observed in normal 19-day fetal rat AEC and in transformed mink Mv1Lu cells derived from fetal mink lung epithelium. Moreover, treatment either with antisense oligodeoxynucleotides directed against cyclin D2 mRNA or with genistein (a tyrosine kinase inhibitor) caused significant inhibition of [3H]thymidine incorporation into DNA as well as inhibition of cyclin D2 expression in normal 19-day fetal rat AEC. p34cdc2 (but not p33cdk2 or p34cdk4) was expressed at progressively decreasing levels with corresponding histone H1 kinase activities during rat AEC development (19-day fetal > 21-day fetal > 13-day postnatal > adult rat AEC). The levels of p34cdc2 histone H1 kinase activity were significantly up-regulated or amplified in adult rat type 2 AEC following hyperoxic injury and repair and in transformed AEC. Collectively, these data support an important functional role for cyclin D2 and cdc2 genes in determining the proliferative versus nonproliferative phenotype of AEC during lung development, injury and repair, and transformation.

Cell cycle-dependent expression of cyclin D1 and a 45 kD protein in human A549 lung carcinoma cells.

Cyclin D1, which is suggested to have a role in G1 control during the cell cycle, is genetically linked to BCL-1 and is widely overexpressed in parathyroid, breast, and squamous cancer cells. We postulated that cyclin D1 regulation may also be important in lung cancer. Therefore, we characterized the cell cycle-dependent expression of cyclin D1 at both mRNA and protein levels in synchronized human A549 lung carcinoma cells. Monospecific anti-cyclin D1 C-terminal peptide antibodies recognized both p36cyclinD1 and an as-yet uncharacterized 45 kD protein (p45). A549 cells were synchronized with well-studied drugs. Cyclin D1 mRNA expression remained relatively constant, with less than a twofold fluctuation during the cell cycle and with a minor peak at M phase. However, the p36cyclinD1 protein fluctuated during the A549 cell cycle and was expressed at very low levels in late G1 and at the G1/S boundary, but then increased in S phase and peaked at M phase. In contrast, p45 protein was expressed at relatively high levels in late G1 and reached maximal levels at the G1/S boundary, was expressed at decreased levels in S phase, and then had disappeared by M phase. Moreover, p45 was highly expressed only in transformed alveolar epithelial cells, but not in normal rat alveolar epithelial cells or fetal rat lung fibroblasts in primary cultures. In mink Mv1Lu cells, the expression of p45 was totally blocked by transforming growth factor-beta 1 treatment or contact inhibition. p45 protein was phosphorylated on serine, threonine, and tyrosine residues in A549 cells in culture. The phosphorylation of the p45 protein was cell cycle-regulated and reached its maximal levels at G2/M phase. The p45 protein had a different peptide map from p36cyclinD1 after cleavage with N-chlorosuccinimide. Immunoprecipitation studies showed that p45 was also anti-ubiquitin immunoreactive during the cell cycle. We conclude that p36cyclinD1 and the p45 protein are differentially regulated in a cell cycle-dependent manner in A549 cells. Although p45 is antigenically related to p36cyclinD1, it is probably not a closely cyclin-related protein. We speculate that p45 may be associated with malignant transformation and may play a distinct role from p36cyclinD1 in regulation of the cell cycle in A549 cells.

Variations in local PGE levels: a potential factor in therapeutic responsiveness?

It was hypothesized that it is the concentration of PGE in the plasma which actually reaches the ductus arteriosus which determines ductal response to PGE administration. Therefore, site specific PGE levels were studied in two infants with ductus dependent congenital heart lesions who were receiving PGE1 infusions. PGE levels were found to vary in a fashion related to the infusion site and the specific cardiac anatomy and hemodynamics of each patient. One of our patients, for instance, had a double outlet right ventricle with high pulmonary vascular resistance and right to left ductal shunting. This infant was given an intraarterial infusion of PGE. The plasma concentrations of PGE in the ductal blood of the infant were negligible. Assuming that ductal site specific PGE levels are critical in mediating the therapeutic response, hemodynamics and infusion site are factors that should be considered when initiating a PGE infusion, or in evaluating a therapeutic failure of PGE.

Endogenous dilator prostaglandins in congenital heart disease.

Maintaining patency of the ductus arteriosus pending surgical intervention can be critical to the survival of the neonate with ductal dependent congenital heart disease. Spontaneously delayed ductal closure has been observed clinically and experimentally in newborns with critical pulmonic stenosis. Infants with ductal dependent congenital heart lesions were therefore studied to ascertain whether there was an endogenous increase in dilator prostaglandins prolonging ductal patency. Six neonates with cyanotic lesions (group 1) and six with left ventricular obstructive lesions (group 2) were studied. Circulating PGE2 was not increased in either group. The levels of plasma 6 keto PGF1 alpha, a stable hydrolysis product of prostacyclin, were found to be elevated, but only in the cyanotic group (3143 +/- 1844 vs 404 +/- 250 pg/ml; p less than 0.05; normal less than 500 pg/ml). As expected, PaO2's were also different (36 +/- 15 vs 72 +/- 34 mmHg; p less than 0.05). It is speculated, therefore, that increased synthesis and/or release of prostacyclin, possibly mediated by the hypoxia of the cyanotic ductal dependent lesion, contributes to persistent patency of the ductus arteriosus.

Dynamics of TGF-beta 3 peptide activity during rat alveolar epithelial cell proliferative recovery from acute hyperoxia.

Hyperoxia causes a reproducible pattern of lung injury and recovery, characterized by proliferation of type II alveolar epithelial cells (AEC2) during the recovery phase. We measured TGF-beta peptide production by AEC2 and macrophages from lungs of adult male rats exposed to 100% oxygen for 48 h and then allowed to recover for up to 72 h in room air. TGF-beta peptide activity levels were measured using the PAI-1 promoter-luciferase mink lung epithelial cell assay and characterized with peptide specific inhibitory antibodies. Control AEC2 produced 997 +/- 54 pg active TGF-beta x 10(6) cells-1.24h-1 (mean +/- SD), of which > 70% was TGF-beta 3, while cultured macrophages produced 58 +/- 17 pg active TGF-beta x 10(6) macrophages-1.24 h-1, > 80% of which was TGF-beta 1. During hyperoxia and recovery, active TGF-beta 3 production by AEC2 decreased by 75%, with a nadir at 24 h recovery (P < 0.005). In contrast, TGF-beta peptide activity increased from undetectable levels in lung lavage from control rats to a peak of 1,470 +/- 743 pg/rat after 48 h oxygen exposure and 24 h recovery, while lavaged macrophage TGF-beta production in culture also increased threefold to a peak of 150 +/- 5 pg. 10(6) cells-1. 24 h-1 after 48 h oxygen exposure (P < 0.005). The nadir of active TGF-beta 3 production by AEC2 coincided with the peak of the AEC2 proliferative phase of repair as determined by BrdU incorporation and FACS analysis of freshly isolated AEC2. We conclude that active TGF-beta 3 production by AEC2 is dynamically downregulated during the proliferative phase of recovery from acute hyperoxic injury in rat. We speculate that decreased autocrine negative regulation of AEC2 proliferation by TGF-beta 3 may facilitate AEC2 proliferation during recovery from acute hyperoxic injury.

Telomerase in alveolar epithelial development and repair.

Telomerase expression and activity were examined in the developing lung and in the adult lung during repair after injury. Both whole lung tissue and primary cultures of type 2 alveolar epithelial cells (AEC2) isolated from fetal and adult rodents were analyzed for 1) telomerase expression by immunohistochemistry and 2) telomerase activity with a telomerase repeat amplification protocol. We found that telomerase was expressed in a temporally regulated manner in fetal lung through the late stages of gestation, with peak expression just before birth. Expression persisted for a brief period in neonates, then decreased to nearly undetectable levels by postnatal day 9. Telomerase expression and activity were reinduced in normally quiescent adult lung by in vivo treatment with hyperoxia. In populations of AEC2 isolated from both developing and repairing lungs, telomerase expression and activity showed a strong correlation with the proliferation marker proliferating cell nuclear antigen. It has been suggested that telomerase expression and activity are hallmarks of stem or progenitor cells. Our observations suggest that a telomerase-positive subpopulation is present within the general AEC2 population. Telomerase may act as a marker for the proliferative status of this subpopulation.

ECMO in premature infants. Review of factors associated with mortality.

During the first few years of clinical research on neonatal extracorporeal membrane oxygenation (ECMO), 16 premature infants of less than 35 weeks gestational age were treated by the authors (RHB), and only four (25%) survived. Intracranial hemorrhage was common, prompting the authors to recommend that ECMO not be used in premature infants with respiratory failure. Since diagnostic methods, indications, and techniques of extracorporeal support have improved considerably, the records of these previous cases were reviewed in detail to determine if there was reason to believe that results might be better in the modern era. Of the 16 patients, four had pre-ECMO conditions that would now be considered contraindications and five of the remaining patients had major technical complications that are now rare. Anticoagulation and fluid management of these patients also would be handled much differently. Based on this review and on current experience with extracorporeal support in near-term infants, it is reasonable to expect that survival of moribund premature infants might be 50% or greater with extracorporeal support. New phase I trials using improved indications and technology are suggested.

Phospholipid and surfactant protein A concentrations in tracheal aspirates from infants requiring extracorporeal membrane oxygenation.

To test the hypothesis that infants with severe respiratory failure and the need for extracorporeal membrane oxygenation (ECMO) are surfactant deficient, we measured the amount of surfactant phospholipids, disaturated phosphatidylcholine, surfactant protein A, and protein in tracheal aspirates from 22 infants, who received ECMO therapy for respiratory failure with meconium aspiration syndrome (n = 18) or pneumonia (n = 4). Tracheal suction material was obtained in a standardized way every 4 hours during the period of ECMO treatment and pooled for 24-hour periods. During ECMO, mean total phospholipid, disaturated phosphatidylcholine, and surfactant protein A values in tracheal aspirates increased and protein values decreased significantly, predominantly during the 72-hour period before infants were weaned from ECMO. Of the 22 infants, 14 had an increase in tracheal aspirate phospholipid values of more than 200% and were found to need a shorter period of ECMO support (p less than 0.005) and post-ECMO ventilatory support (p less than 0.025) than did the eight infants with stationary or only moderate increases in tracheal aspirate phospholipid values, three of whom had pneumonia. We conclude that infants with respiratory failure who require ECMO treatment often have surfactant deficiency. We speculate that surfactant treatment might decrease the need for or the duration of ECMO support.

Metoclopramide promotes enteral feeding in preterm infants with feeding intolerance.

We hypothesized that the feeding difficulties experienced by premature infants are related to immature peristaltic activity and that a bowel accelerant might promote feeding in prematures. We administered metoclopramide (Meto) to 14 infants admitted to the Intensive Care Nursery at The University of Chicago between January 1, 1984, and January 1, 1987. Each infant had failed enteral feeding on at least two separate occasions. At the time of initiation of Meto, the group of infants tolerated only 11.7 +/- (SEM) 3.6 cm3/kg/day enterally. Feeding tolerance improved steadily after Meto was initiated, and by 29 days the infants tolerated 134 +/- 12.6 cm3/kg/day enterally. The average slope of the post-Meto feeding regression lines was +4.21 +/- 0.94 cm3/kg/day/day, significantly greater than -0.67 +/- 0.59 cm3/kg/day/day pre-Meto. The percentage of feedings followed by significant gastric residual volumes was 33.1 +/- 4.6% pre-Meto, compared to 6.9 +/- 2.5% post-Meto. No child receiving Meto developed any extrapyramidal neurologic symptoms, worsening of hepatic function, or necrotizing enterocolitis. Meto may have a role in the treatment of premature infants with enteral feeding intolerance.

Comparison of intratracheal pulmonary ventilation and hybrid intratracheal pulmonary ventilation with conventional mechanical ventilation in a rabbit model of acute respiratory distress syndrome by saline lavage.

OBJECTIVES: To study changes in PaCO2 and PaO2 during intratracheal pulmonary ventilation (ITPV) and hybrid intratracheal pulmonary ventilation (h-ITPV) compared with conventional mechanical ventilation (CMV) in a rabbit model of respiratory failure, and to define the technique of h-ITPV that combines conventional mechanical ventilation and ITPV. DESIGN: Prospective, interventional study. SUBJECTS: Twelve adult New Zealand White rabbits. INTERVENTIONS: Surfactant deficiency was induced by saline lavage, and rabbits were randomized to either ITPV or h-ITPV. The study consisted of four phases: phase 0, CMV after saline lavage, ventilator rate 30 breaths/min; phase I, ITPV or h-ITPV initiated at the same pressure and rate as in phase 0; phase II, ITPV or 1.0 L/min h-ITPV bias flow, with peak inspiratory pressure (PIP) decreased and ventilator rate increased to achieve the lowest tidal volume while maintaining adequate gas exchange; and phase III, animals returned to CMV. MEASUREMENTS AND MAIN RESULTS: In phase I, no difference in PaCO2 was observed between ITPV, h-ITPV, or CMV. There was a decrease in PaO2 when switching from CMV to ITPV but not to h-ITPV. In phase II, it was possible to decrease PIP (average of 37% for ITPV and 36% for h-ITPV) and tidal volume (average of 64% for ITPV and 53% for h-ITPV) without compromising gas exchange (p < .05). Oxygenation tended to improve from phase 0 to the end of phase II. In phase III, PaCO2 increased (average of 71% for ITPV and 79% for h-ITPV) and pH decreased (p < .05). Normocapnia was achieved using significantly higher PIP and tidal volume, compared with phase 0 (p < .05). CONCLUSIONS: ITPV and h-ITPV can effectively ventilate and oxygenate rabbits with surfactant-deficient lungs at tidal volumes and therefore pressures lower than required with CMV. Maximum benefit appears to occur at high ventilator rates. These findings suggest that both modes of ventilation may represent powerful new tools in the management of patients with acute respiratory failure. (Crit Care Med 2000; 28:774-781)