Artificial placenta: two days of total extrauterine support of the isolated premature lamb fetus.

A premature lamb fetus was totally sustained by extracorporeal perfusion with the use of a silicone-membrane blood oxygenator and parenteral nutritional support. The fetus remained in a metabolically stable state lasting several days.

Fresh platelet-rich plasma from a flow-through centrifuge for lamb heart perfusion at 13degrees C. Protective effect of added erythrocytes.

Isolated lamb hearts perfused at 13degrees C. with acellular perfusates developed progressive intersitital edema and a rise in vascular resistance. They did not exhbit any electrical or mechanical activity. In contrast, hearts perfused with whole fresh blood remained well preserved, had no edema or change in vascular resistance, and contracted vigorously while being perfused at 10degrees and 13degrees C. This study was designed to determine which particular component(s) of whole blood contributed to improved cardiac preservation. Isolated lamb hearts were perfused for 18 hours at 13degrees C. with plasma containing platelets and some or no red blood cells. Continuously fresh plasma was obtained from a donor animal by means of a flow-through centrifuge. Hearts perfused at 13degrees C. with fresh plasma of either low or high platelet count contracted during the initial 2 to 4 hours of the perfusion only and were as poorly preserved as hearts perfused with acellular microfiltered plasma. A hematocrit value of 2 to 5 per cent in the plasma perfusate resulted in the hearts being preserved almost as well as with fresh whole blood; they showed a forceful cardiac activity at 13degrees C., there was no edema, the vascular resistance was stable, and after rewarming they had good ventricular function. The improvement in cardiac preservation brought about by addition of a minimal amount of red blood cells suggests a specific effect of erythrocytes on the cardiac microcirculation.

Intratracheal pulmonary ventilation and continuous positive airway pressure in a sheep model of severe acute respiratory failure.

STUDY OBJECTIVES: Previously we have shown that optimal pulmonary gas exchange can be sustained at normal airway pressures in a model of severe acute respiratory failure (ARF), using intratracheal pulmonary ventilation (ITPV), with weaning to room air. In an identical model of ARF, we have now explored whether ITPV, combined with continuous positive airway pressure (CPAP), can sustain adequate ventilation, with weaning to room air. DESIGN: Randomized study in sheep. SETTING: Animal research laboratory at the National Institutes of Health. INTERVENTIONS: ARF was induced in 12 sheep, using mechanical ventilation at peak inspiratory pressure of 50 cm H2O, but excluding 5 to 8% of lungs. Sheep were then randomized into two groups: the CPAP-ITPV group (n=6), in which ITPV was combined with a novel CPAP system; and a control group (n=6) in which the same CPAP circuit was used, but without ITPV. MEASUREMENTS AND RESULTS: All sheep in the CPAP-ITPV group were weaned to room air in 38.7+/-14 h. PaO2/fraction of inspired oxygen (FIO2) progressively increased from 108.8+/-43 to 355.7+/-93.1; PaCO2 remained within normal range; respiratory rate (RR) ranged from 18 to 120 breaths/min, and tidal volume (VT) was as low as 1.1 mL/kg. All sheep in the control group (CPAP alone) developed severe respiratory acidosis and hypoxemia after 4.8+/-4 h. PaO2/FIO2 decreased from 126.6+/-58.2 to 107.2+/-52.5 mm Hg, with a final PaCO2 of 166.8+/-73.3 mm Hg. CONCLUSIONS: All sheep treated with CPAP-ITPV maintained good gas exchange without hypercapnia at high RR and at low VT, with weaning to room air. All control animals treated with CPAP alone developed severe hypercapnia, respiratory acidosis, and severe hypoxemia, and were killed.

Intratracheal pulmonary ventilation at low airway pressures in a ventilator-induced model of acute respiratory failure improves lung function and survival.

STUDY OBJECTIVE: The pulmonary parenchyma in patients with acute respiratory failure (ARF) is commonly not involved in a homogenous disease process. Conventional mechanical ventilation (MV) at elevated positive end-expiratory pressure (PEEP) and peak inspiratory pressure (PIP) aims at recruiting collapsed or nonventilated lung units. Invariably, those pressures are also transmitted to the healthiest regions, with possible extension of the disease process (barotrauma). During intratracheal pulmonary ventilation (ITPV), a continuous flow of fresh gas is delivered directly at the carina, bypassing the dead space proximal to the catheter tip. In healthy sheep, it allows lowering tidal volume (VT) to as low as 1.0 mL/kg, at respiratory rates (RR) up to 120 breaths/min, while maintaining normocapnia. In a model of ventilator-induced lung injury, we wished to explore whether ITPV, applied at low VT and low PEEP and tailored to ventilate the healthiest regions of the lungs, could provide adequate oxygenation and alveolar ventilation, without any attempt to recruit lungs. DESIGN: Randomized study in sheep. SETTING: Animal research laboratory. PARTICIPANTS: We induced ARF in 12 sheep following 1 to 2 days of MV at a PIP of 50 cm H2O, except that 5 to 8% of lungs were kept on apneic oxygenation of 5 cm H2O, sparing those regions from the injury process. INTERVENTIONS: Sheep were randomized to volume-controlled MV (control group) (n = 6) with VT of 8 to 12 mL/kg, PEEP of 5 to 10 cm H2O, or to ITPV (n = 6) at PEEP of 3 to 5 cm H2O, VT of 2.5 to 4 mL/kg, PIP of <20 cm H2O, at RRs sufficient to sustain normocapnia. MEASUREMENTS AND RESULTS: Hemodynamic status in the ITPV group progressively improved, and all six sheep were weaned to room air within 83+/-54 h. Sheep in the control group had progressively deteriorating conditions and all animals died after a mean of 50+/-39 h. Barotrauma and postmortem histopathologic changes were more pronounced in the control group. CONCLUSION: In this model of ventilator-induced lung injury, low PEEP-low VT ventilation with ITPV sustained normocapnia and prevented further lung injury, allowing weaning to room air ventilation.

Acute respiratory failure. Survival following ten days' support with a membrane lung.

An 11-year-old boy with acute lymphoblastic leukemia in remission developed a bilateral pneumonia which rapidly progressed to acute respiratory failure. During 9 days of intensive therapy the patient's respiratory status progressively deteriorated. When it became impossible to maintain the arterial oxygen tension (PAO2) above 40 mm.Hg by conventional means, extracorporeal blood-gas exchange with a membrane lung was begun. After 5 days of bypass the patient's respiratory function began to improve, and he was weaned from the membrane lung on the tenth day. Seven days later he was discharged from the hospital and is currently in excellemt health 23 months after bypass. This perfusion, the longest successful effort to provide respiratory assist with a membrane lung, attests to the efficacy of this therapeutic modality.

Long-term cardiopulmonary bypass by peripheral cannulation in a model of total heart failure. The decompression of the left heart through a percutaneous helical spring positioned within the lumen of the tricuspid and pulmonary artery valves.

We performed long-term closed-chest cardiopulmonary bypass in an animal model of total heart failure (induced ventricular fibrillation). The extracorporeal system included a venous reservoir, a roller pump, a membrane lung, and a blood pulsator system. We cannulated the right external jugular vein for venous drainage and the right subclavian artery for arterial return. To decompress the left heart we passed by percutaneous cannulation a special helical spring mounted on a Swan-Ganz catheter (Baxter Edwards Divisions, Irvine, Calif.) and positioned it to rest within the pulmonary artery and tricuspid valves, which rendered them partly incompetent. After induced ventricular fibrillation, blood flow was raised to keep the central venous pressure at baseline values. The lungs were ventilated with 5% carbon dioxide in room air. During bypass, mean pulmonary artery pressure was 10.0 +/- 1.7 mm Hg, mean wedge pressure 11.9 +/- 1.8 mm Hg, and mean blood pressure 95.2 +/- 5.6 mm Hg. After 2 days (four animals) and 3 days (two animals) the hearts were defibrillated. There was immediate ejection from both sides of the heart. All sheep were weaned from bypass within 29 +/- 11 minutes and their lungs were ventilated with room air within 42 +/- 34 minutes. At autopsy hearts and lungs grossly appeared normal. We conclude that the percutaneous helical spring resting within right heart valves provided excellent decompression throughout the study, with full recovery of heart and lung function on defibrillation.

An alternative to breathing.

If carbon dioxide is removed by an extracorporeal membrane lung ventilated with room air, the natural lung can be used for oxygen transport alone; we have demonstrated this in lambs by maintaining lungs "inflated" with 100 percent oxygen at constant pressure and removing all carbon dioxide through the membrane lung. This process is a variant of "apneic oxygenation" without its disadvantages, because the arterial pH, PCO2, and PO2 all remain normal. No nitrogen washout is needed. These studies were carried out in five lambs anesthetized and paralyzed for 24 hours. For carbon dioxide removal, blood from the subclavin artery was pumped through an extracorporeal membrane lung and was returned into the external jugular vein. For oxygen delivery, the lungs were inflated through a tracheostomy tube with 100 percent oxygen to a pressure of 5 cm. H2O. There was no significant change in arterial blood PO2 after perfusion had begun or at the end of the perfusion 24 hours later. The arterial PCO2 remained steady, and there was no change in acid-base balance. The functional residual capacity (FRC) and static lung compliance remained unchanged. The total dead space was 10 to 15 ml. All animals recovered and survived in good health. At equilibrium, alveolar nitrogen partial pressure was always equal to the partial pressure of nitrogen in the ventilating gas of the membrane lung and was the sole determining factor in controlling alveolar oxygen concentration. Direct measurement of pulmonary gas showed alveolar gas at the level of the carina.

Evaluation of a new thin-walled endotracheal tube for use in children.

Conventional endotracheal tubes have high intrinsic resistive properties due to their high outer-to-inner diameter ratio. This has significant disadvantages in the treatment of the small neonatal or pediatric patient as work of breathing increases with decreasing internal radius. Diagnostic and therapeutic procedures, including suctioning, may be very difficult in patients with small endotracheal tubes. We therefore measured airway resistance and pressure differential during simulated mechanical ventilation using proximal and distal endotracheal tube flow transducers. Conventional and new, ultrathin-walled endotracheal tubes reinforced with flat stainless steel or a novel, crush-proof nickel-titanium alloy were compared using fixed ventilator settings. Ventilation through the ultrathin-walled tubes resulted in a significantly reduced airway resistance (p < or = 0.01). These new ultrathin-walled endotracheal tubes showed flow characteristics typical of much larger conventional endotracheal tubes: the 3.2-mm internal diameter had an airway resistance (Raw) of 36, while a standard 2.5-mm internal diameter endotracheal tube had a Raw of 146. Both endotracheal tubes have identical external diameters of 3.6 mm. We conclude that ultrathin-walled endotracheal tubes could have a significant role in the treatment of the ventilated child by facilitating interactive ventilation and maintenance of airway patency and may make procedures such as fiberoptic endoscopy and intrapulmonary ventilation using reverse-thrust catheters possible in the small child.

Acute respiratory failure following pharmacologically induced hyperventilation: an experimental animal study.

The pulmonary effects of hyperventilation following infusion of sodium salicylate into the cisterna magna was studied in 16 spontaneously breathing adult sheep. We found a fall in PaO2, a decrease in the static compliance of the respiratory system, abnormal chest roentgenographic films, and grossly abnormal lungs following 3.5 to 13 h of hyperventilation. A control group of 15 sheep (10 sheep similarly injected with sodium salicylate, but then sedated and paralyzed and ventilated at normal tidal volume and respiratory rate on a mechanical ventilator, and 5 sheep infused with saline alone and breathing spontaneously) showed no pulmonary or arterial blood gas abnormalities. We conclude that prolonged hyperventilation under the conditions of this experiment precipitated events that resulted in acute lung injury.

Prevention of hyaline membrane disease in premature lambs by apneic oxygenation and extracorporeal carbon dioxide removal.

Hyaline membrane disease is found only in lungs where pulmonary ventilation has been established, i.e. after birth. We delivered eleven fetal lambs of a gestational age of 128-130 days but instead kept their lungs in total apnea and inflated to constant pressure, while removing all metabolically produced carbon dioxide with an extracorporeal membrane lung. Oxygen was provided by the membrane lung, and by apneic oxygenation through the natural lungs. Hence, arterial blood gases remained always normal, without any pulmonary ventilation. After 6-66 h the lungs had sufficiently cleared to allow normal mechanical pulmonary ventilation in 10 our of 11 lambs so treated. In a control group treated with mechanical ventilation alone, five of seven lambs died within the first 24 h of severe hyaline membrane disease.

The role of total static lung compliance in the management of severe ARDS unresponsive to conventional treatment.

A group of 36 patients with severe adult respiratory distress syndrome (ARDS) meeting previously established blood gas criteria (mortality rate 90%) became candidates for possible extracorporeal respiratory support [low frequency positive pressure ventilation with extracorporeal CO2 removal (LFPPV-ECCO2R)]. Before connecting the patients to bypass we first switched the patients from conventional mechanical ventilation with positive end expiratory pressure (PEEP) to pressure controlled inverted ratio ventilation (PC-IRV), and then when feasible, to spontaneous breathing with continuous positive airways pressure (CPAP). Forty eight hours after the patients had entered the treatment protocol, only 19 out of the 36 patients in fact required LFPPV-ECCO2R, while 5 were still on PC-IRV, and 12 were on CPAP. The overall mortality rate of the entire population was 23%. The only predictive value of success or failure of a particular treatment mode was total static lung compliance (TSLC). No patients with a TSLC lower than 25 ml (cm H2O)-1 tolerated either PC-IRV or CPAP, while all patients with a TSLC higher than 30 ml (cm H2O)-1 were successfully treated with CPAP. Borderline patients (TSLC between 25 and 30 ml (cm H2O)-1) had to be treated with PC-IRV for more than 48 h, or were then placed on LFPPV-ECCO2R if Paco2 rose prohibitively. We conclude that TSLC is a most useful measurement in deciding on the best management of patients with severe ARDS, unresponsive to conventional treatment.

Acute lung injury from mechanical ventilation at moderately high airway pressures.

We have explored adverse pulmonary effects of mechanical ventilation at a peak inspiratory pressure of 30 cmH2O in paralyzed and anesthetized healthy sheep. A control group of eight sheep (group A) was mechanically ventilated with 40% oxygen at a tidal volume of 10 ml/kg, a frequency of 15 breaths/min, a peak inspiratory pressure less than 18 cmH2O, and a positive end-expiratory pressure of 3-5 cmH2O. During the ensuing 48 h, there were no measurable deleterious changes in lung function or arterial blood gases. Another 19 sheep were ventilated with 40% oxygen at a peak inspiratory pressure of 30 cmH2O under a different set of conditions and were randomly assigned to two groups. In group B, the respiratory rate was kept near 4 breaths/min to keep arterial PCO2 in the normal range; in group C, the frequency was kept near 15 breaths/min by including a variable dead space in the ventilator circuit to keep arterial PCO2 near baseline values. There was a progressive deterioration in total static lung compliance, functional residual capacity, and arterial blood gases. After some hours, there were abnormal chest roentgenographic changes. At time of death we found severe pulmonary atelectasis, increased wet lung weight, and an increase in the minimum surface tension of saline lung lavage fluid.

A stopped-flow mixer device for a batch microcalorimeter application to NAD-NADase reaction.

A new molded polypropylene, diamond-like carbon (DLC)-coated mixing cell has been developed for use in the batch microcalorimeter. Reagent volume can be varied from 25 microliters to 100 microliters. A 10 microcalorie reaction heat can be measured to 5%. Repeat reactions can be done as often as every 10 min for a fast reaction. Reactions can be started within 1 h or less after loading. A pre-equilibrator and a temperature-controlled syringe drive unit permit solutions to be stored at 4 degrees C while being run at any temperature from -20 degrees C to 40 degrees C. The kinetics and enthalpy of reaction of NAD-NADase have been measured. delta H is about 21 kcal/mol endothermic.

Intratracheal pulmonary ventilation and congenital diaphragmatic hernia: a report of two cases.

Previous studies from our institution have shown that neonates with congenital diaphragmatic hernia (CDH), whose best postductal PaO2 (BPDPO2) was less than 100 mm Hg while on maximal conventional mechanical ventilation (CMV), had a mortality exceeding 90%. When combined with extracorporeal membrane oxygenation (ECMO), the mortality rose to 100% in those infants who developed hypercarbia following decannulation. Historically, those patients have required increasing ventilator support, leading to iatrogenic lung damage, and eventual death. Intratracheal pulmonary ventilation (ITPV) using the reverse thrust catheter (RTC) developed by Kolobow incorporates a continuous flow of humidified gas through a reverse Venturi catheter positioned at the distal end of the endotracheal tube. In animal studies, ITPV was shown to result in a reduced physiological dead-space (VD), to facilitate expiration, and to enhance CO2 elimination. In our current study, we have applied ITPV in two neonates with CDH who could not be weaned from ECMO because of uncontrollable hypercapnia, and who met above criteria for 100% mortality. In both cases, ITPV restored normal PaCO2 at low peak inspiratory pressure (PIP) with a substantial decrease in VD. We believe ITPV is suited to ventilating newborns with CDH in whom barotrauma is known to be common. Beyond its present use, ITPV may be useful to ventilate children with other forms of respiratory failure, and should be so considered along with other now available methods of mechanical pulmonary ventilation.

Cardiopulmonary bypass through peripheral cannulation with percutaneous decompression of the left heart in a model of severe myocardial failure.

Prolonged closed chest cardiopulmonary bypass for severe total biventricular myocardial dysfunction requires invasive decompression of the left heart. The authors have developed an elongated helical coil that is permanently attached to the distal 8-10 cm of a flow directed Swan-Ganz catheter. When properly positioned, the helical coil kept the pulmonary artery (PA) and the tricuspid valves open, and allowed closed chest retrograde decompression of the left heart. The authors have evaluated the merits of closed chest cardiopulmonary bypass with decompression of the left heart in this manner in four sheep subjected to 30 min of warm global myocardial ischemia, along with induced ventricular fibrillation. All sheep developed severe global myocardial failure, with no left ventricular (LV) ejection. The authors have shown that pulmonary blood flow during cardiopulmonary bypass was reversed from the left heart, across the lungs, and into the right heart. The wedge pressure never exceeded 12 mmHg at any time, attesting to good decompression during periods of total ventricular failure, during partial recovery with some LV ejection, and after good recovery of LV function, followed by weaning from bypass after 44, 67, and 78 h of such support. One sheep could not be weaned from bypass, even after 5 days of CPBP. Lung function in all sheep remained unimpaired throughout, and there was no wound bleeding. The authors conclude that in this model of total myocardial failure, and while on closed chest CPBP, at all times and with all degrees of myocardial dysfunction, excellent LV decompression with the helical coil catheter was attained.

Rescue from pediatric ECMO with prolonged hybrid intratracheal pulmonary ventilation. A technique for reducing dead space ventilation and preventing ventilator induced lung injury.

Hybrid intratracheal pulmonary ventilation (h-ITPV) is a continuous flow ventilatory technique that uses a "reverse thruster" catheter to redirect the flow of gas away from the carina. We report here the use of h-ITPV in a pediatric patient with acute sickle cell chest syndrome who required venoarterial ECMO support because of refractory hypoxemic respiratory failure. Her ECMO course was complicated by air leaks, coagulopathy, cardiac tamponade, and necrotizing tracheobronchitis. She could be weaned from ECMO only by maintaining high pressure conventional ventilatory support. To prevent ventilator induced barotrauma, we initiated h-ITPV and weaned her from ECMO bypass. After 12 days of h-ITPV, with tidal volumes of 2-3 ml/kg at carinal peak inspiratory pressures of 25-30 cm H2O, the air leaks ceased and h-ITPV was discontinued. Dead space ventilation fraction (VD/VT) as low as 0.29 was achieved with this technique. Post-h-ITPV bronchoscopy displayed a dramatic resolution of the necrotizing tracheobronchitis. The patient survived and was discharged from the hospital. We conclude that the use of hybrid ITPV may facilitate weaning from ECMO to low pressure conventional ventilation and prevent the development of pulmonary barotrauma.

The promise of the membrane artificial lung.

Membrane lungs are more physiologic than bubble or disc blood oxygenators. Membrane lungs are indispensable in long term perfusions. Recently, there has been a noticeable trend toward use of the membrane lung in open heart surgery. Improper use of the membrane lung lowers its optimum potential and may lead to disenchantment on the part of the user. It is important to recognize that for optimum performance of the membrane lung it is necessary to learn to correctly use the membrane lung.

Hemodynamic, mechanical and renal effects during "apneic oxygenation" with extracorporeal carbon dioxide removal, at different levels of intrapulmonary pressure in lambs.

It has been shown that apneic oxygenation can be safely performed for many days when metabolic carbon dioxide is removed by an extracorporeal membrane lung, and 100% oxygen is supplied directly into the trachea to keep the intrapulmonary pressure at 5 cm. H2O. The study was designed to find "best intrapulmonary pressure (IP)", analogous to "best PEEP" during continuous positive pressure ventilation. In the present study we have shown that when IP was progressively raised from 5cm H2O to 20 cm H2O the PaO2 rose significantly due to progressive decrease in QVA/Q. A linear positive correlation was found between CO and QVA/Q. There was a negative correlation between QVA/Q and FRC. Total static lung compliance and FRC increased significantly at 15--20 cm H2O IP. There was no significant change in urinary flow, urea and creatinine clearances. We conclude that in apneic oxygenation a more "optimal IP" is attained at an IP pressure of 20 cm H2O than at 5 cm H2O.

High density tissue culture on microporous membranes perfused by blood: report of a new bioartificial system.

A new tissue culture system has been developed to support high density cell growth using the sheep as the host. Cellular nutrition is provided by plasma solutes as they diffuse from arterial blood across microporous polycarbonate membranes into a device attached to an arteriovenous shunt. Culture chambers are constructed with transparent polycarbonate to allow photomicroscopy of the tissue in situ. System performance is demonstrated by the high density growth of fetal sheep thymus allografts and rat soft tissue sarcoma xenografts.

Massive pulmonary infarction during total cardiopulmonary bypass in unanesthetized spontaneously breathing lambs.

We provided total cardiopulmonary support for 1-18 hours in unanesthetized tethered lambs by peripheral vascular cannulation, using a roller pump and the spiral membrane lung. Respirations were allowed to remain spontaneous and unaided. A Swan-Ganz catheter was placed for retrograde pulmonary artery blood flow sampling. Within a few minutes following induced ventricular fibrillation the PCO2 of sampled blood flowing retrograde through the lungs fell below 10 mm Hg, the PO2 rose to near 150 mm Hg, the pH rose to above 7.8, and the glucose level fell to less than 20 mg %. All of these values later gradually shifted, approaching mixed venous blood values within minutes. After 1-18 hrs of perfusion the animals went into shock and were sacrificed. At autopsy, the lungs of animals breathing room air were beefy and hemorrhagic. In lambs that were "breathing" CO2 enriched air the retrograde pulmonary artery blood pH and PCO2 was usually maintained close to the mixed venous blood values. The observed pulmonary changes were considerably less abnormal, and the microscopic abnormalities were at times nonexistent. We believe the integrity of pulmonary blood flow is vital to the survival of the lungs as a functioning organ. Cessation of total forward pulmonary blood flow (unlike partial cardiopulmonary bypass), combined with spontaneous pulmonary ventilation, rapidly leads to massive, pulmonary infarctions, shock, and death.