Cerebral blood flow and metabolism during and after prolonged hypercapnia in newborn lambs.

OBJECTIVE: To study the effects of prolonged (6 hrs) hypercapnia on cerebral blood flow and cerebral metabolism in newborn lambs and to evaluate the effects on cerebral blood flow and cerebral metabolism on return to normocapnia after prolonged hypercapnia. DESIGN: Animal studies, using the newborn lamb, with comparison to control group. SUBJECTS: Newborn lambs of mixed breed, 1-7 days of age, were used for the study. Two groups of animals were studied: a hypercapnic group (n = 10) and a normocapnic control group (n = 5). SETTING: Work was conducted in the research laboratories at Children's National Medical Center, Washington, DC. INTERVENTIONS: Animals were anesthetized with pentobarbital, intubated, paralyzed, and mechanically ventilated. After baseline measurements were made, CO2 was blended into the ventilator gas until a PaCO2 of 75-80 torr (10-10.6 kPa) was obtained. Measurements were made 1 hr after the desired PaCO2 was achieved and after 6 hrs of hypercapnia. After 6 hrs of hypercapnia, the ventilator gas was returned to the baseline value, that is, normocapnia. Measurements were made 30, 60, and 90 mins after PaCO2 returned to baseline. MEASUREMENTS: Six measurements were made during the study. For each measurement, blood samples were drawn from the sagittal sinus and brachiocephalic artery catheters and were analyzed for pH, hemoglobin concentration, oxygen saturation, and blood gas values. Cerebral blood flow (CBF) was measured by using the radiolabeled microsphere technique. Cerebral oxygen consumption, fractional oxygen extraction, and oxygen transport values were calculated at each study period. MAIN RESULTS: Increasing PaCO2 from 37 +/- 3 torr to 78 +/- 6 torr (4.9 +/- 0.4 kPa to 10.3 +/- 0.8 kPa) for 1 hr increased CBF by 355%. After 6 hrs of PaCO2 at 78 +/- 3 torr (10.3 +/- 0.4 kPa), CBF remained 195% above baseline. At 30 mins of normocapnia, CBF had returned to baseline and remained at baseline until the conclusion of the study, a total of 90 mins of normocapnia. Cerebral oxygen consumption did not change during hypercapnia or with return to normocapnia. Oxygen transport increased 331% above baseline after 1 hr of hypercapnia and stayed 180% above baseline after 6 hrs of hypercapnia. Fractional oxygen extraction decreased by 55% at 1 hr of hypercapnia and stayed 39% below baseline at 6 hrs of hypercapnia. CONCLUSIONS: Healthy lambs seem to tolerate undergoing hypercapnia for 6 hrs with a return to normocapnia. The return to baseline of CBF and cerebral metabolism at normocapnia seen in our study with lambs may explain why prolonged hypercapnia appears to be well tolerated in mechanically ventilated patients. If these results can be extrapolated to human subjects, our study in lambs supports evidence that patients who have undergone permissive hypercapnia seem to be neurologically unaffected.

Effect of nitric oxide and high-frequency oscillatory ventilation in meconium aspiration syndrome.

OBJECTIVE: To test the hypothesis that inhaled nitric oxide, when combined with high-frequency oscillatory ventilation, is an effective therapeutic agent in meconium aspiration syndrome. DESIGN: Prospective, interventional study. SETTING: The animal research laboratory at The Children's National Medical Center. SUBJECTS: Five newborn piglets, 1-2 wks old, weighing 3.6 +/- 0.2 kg. INTERVENTION: Animals were anesthetized, paralyzed, intubated, and ventilated. Catheters were placed in the femoral vein and artery and the pulmonary artery. After 1 hr of recovery, 10 mL/kg of 20% meconium in normal saline solution was insufflated into the lungs. Animals were ventilated with a SensorMedics oscillator to maintain arterial blood gases in a normal range (pH, 7.35-7.45; Paco2, 40-45 mm Hg [5.3-6.0 kPa]; Pao2, 70-90 mm Hg [9.3-12.0 kPa]). Ventilator settings were increased as needed until maximum settings as follows: Fio2, 1.00; proximal oscillatory pressure amplitude, 36 cm H2O; mean airway pressure, 25 cm H2O; frequency, 10 Hz. After a short period of stabilization, inhaled nitric oxide was administered. Concentrations of 40, 20, and 10 ppm were given and measurements were taken after each exposure to inhaled nitric oxide and after its discontinuation. To assure that there was no additive effect of inhaled nitric oxide, each dose was given for 20 mins followed by a 15-min normalization period at 0 ppm. MEASUREMENTS AND MAIN RESULTS: Physiologic measurements, ventilatory settings, arterial blood gases, and methemoglobin were recorded at each study period. Measurements were taken after each exposure to inhaled nitric oxide and after its discontinuation. Arterial saturation and partial pressure of arterial oxygen (Pao2) were significantly lower after meconium aspiration when compared with baseline. Administration of inhaled nitric oxide improved oxygenation without a significant decrease in pulmonary artery pressure. CONCLUSION: In this model of meconium aspiration syndrome, short-term exposure to inhaled nitric oxide when combined with high-frequency oscillatory ventilation improved oxygenation secondary to better distribution of inhaled nitric oxide. The increase in oxygenation may be secondary to improved ventilation perfusion mismatch, as the primary etiology of hypoxia in this model may be a combination of parenchymal lung disease and pulmonary hypertension.

Use of nitric oxide in meconium aspiration syndrome: lack of response.

PURPOSE: To test the hypothesis that inhaled nitric oxide (INO) may not be an effective therapeutic agent in meconium aspiration syndrome (MAS). DESIGN: Prospective, interventional study. SETTING: The animal research laboratory at The Children's National Medical Center. SUBJECTS: Seven newborn pigs, 2-7 days old, weighing 2.8 +/- 0.17 kg were used for the study. MATERIALS AND METHODS: Animals were anaesthetized, paralysed, intubated and ventilated. Catheters were placed in the jugular vein, carotid artery, and pulmonary artery. After 1 h of recovery 10 ml/kg of 20% meconium in normal saline solution was insufflated into the lungs. Animals were ventilated to maintain ABGs in a normal range, i.e. pH = 7.35-7.45, PaCO2 = 40-45, and PaO2 = 70-90 torr. Ventilator settings were increased as needed until maximum settings of: FiO2 = 1.00, PIP = 40, IMV = 60. After 2 h of conventional ventilation or demonstration of significant lung disease by failure to maintain desired blood gases on maximum ventilator settings, INO was administered for 20 min in concentrations of 10, 20 and 40 ppm. To ensure that there was no additive effect of INO, a 15-min normalization period at 0 ppm was allowed between each dose of INO. Physiologic measurements, ventilatory settings, arterial blood gases, and methemoglobin were recorded at each study period. Measurements were taken after each exposure to INO and after its discontinuation. RESULTS: Arterial saturation (SaO2) and PaO2 were significantly lower ([81 +/- 18] and [54 +/- 14], respectively) and PAP was significantly higher [24 +/- 3] after MAS when compared with baseline. Administration of INO did not improve oxygenation nor decrease PAP at any of the study doses. CONCLUSION: In this model of MAS, short-term exposure to INO did not decrease PAP nor improve oxygenation. It may be postulated that poor distribution of INO caused by the obstructive nature of this disease may be responsible for the lack of response in this disease state, or that the primary etiology for hypoxia is parenchymal lung disease and not pulmonary hypertension.

Use of intratracheal pulmonary ventilation versus conventional ventilation in meconium aspiration syndrome in a newborn pig model.

OBJECTIVE: To determine whether intratracheal pulmonary ventilation (ITPV) allows for effective oxygenation and ventilation at lower mean airway pressures and peak inspiratory pressures than conventional ventilation in a piglet model of meconium aspiration syndrome. DESIGN: Prospective, interventional study. SETTING: The animal research laboratory at Children's National Medical Center, Washington, DC. SUBJECTS: Twenty newborn piglets, 2 to 7 days of age, weighing 1.8 to 2.8 kg. INTERVENTION: Animals were anesthetized, paralyzed, intubated, and ventilated. Femoral arterial and venous catheters were inserted; 5 mL/kg of 20% meconium in normal saline was instilled into the endotracheal tube. Animals were randomized to either ITPV or conventional ventilation, and settings were adjusted to maintain ideal blood gases, i.e., pH 7.35 to 7.45, PCO2 40 to 45 torr (5.3 to 6 kPa), PO2 80 to 100 torr (10.7 to 13.3 kPa), and SaO2 > or = 90%. Ventilatory settings were adjusted as needed to a maximum of: FIO2 1.0, peak inspiratory pressure 40 cm H2O, positive end-expiratory pressure 5 cm H2O, and respiratory rate 80 breaths/min. MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were taken every 30 mins for 4 hrs and ventilatory settings were adjusted to maintain optimal blood gases. Heart rate, mean arterial blood pressure, and arterial saturation were monitored continuously. The animals in the ITPV group had significantly lower peak inspiratory pressure at 1, 2, 3, and 4 hrs after meconium instillation (p < .018) and significantly lower mean airway pressure at 2, 3, and 4 hrs after meconium instillation (p < .03). The mean peak inspiratory pressure in the ITPV animals ranged from 17 +/- 2.7 cm H2O at baseline to 16.6 +/- 5.7 cm H2O at 4 hrs compared with 16.5 +/- 2.7 cm H2O at baseline to 31.8 +/- 9.1 cm H2O at 4 hrs in the conventionally ventilated animals (p < .04). The mean airway pressure ranged from 6.3 +/- 1.1 mm Hg at baseline to 6.8 +/- 2.5 mm Hg at 4 hrs in the ITPV group compared with 5.5 +/- 1.2 mm Hg at baseline to 10.7 +/- 3.4 mm Hg at 4 hrs in the conventional ventilation group (p < .03). The lungs of the ITPV animals were less hemorrhagic and had less pathologic evidence of injury than the lungs of the conventionally ventilated animals. CONCLUSIONS: These results indicate that ITPV can be used to effectively ventilate and oxygenate piglets with meconium aspiration syndrome at lower mean airway pressures and peak inspiratory pressures than conventional ventilation. This lower pressure causes less injury to the lungs of the animals.

Effect of nitric oxide in meconium aspiration syndrome after treatment with surfactant.

OBJECTIVE: To test the hypothesis that inhaled nitric oxide may be an effective therapeutic agent in meconium aspiration syndrome and may improve oxygenation after pretreatment with surfactant. DESIGN: Prospective, interventional study. SETTING: The animal research laboratory at The Children's National Medical Center. SUBJECTS: Eight newborn pigs, 1 to 2 wks of age, 4.1 +/- 0.4 kg, were used for the study. INTERVENTIONS: Animals were anesthetized, paralyzed, intubated, and mechanically ventilated. Catheters were placed in the femoral vein and artery, and in the pulmonary artery. After 1 hr of recovery, 10 mL/kg of 20% meconium in normal saline solution was insufflated into the lungs. Animals were ventilated to maintain arterial blood gases in a normal range (i.e., pH of 7.35 to 7.45, Paco2 of 40 to 45 torr [5.3 to 6.0 kPa], and Pao2 of 70 to 90 torr [9.3 to 12.0 kPa]). Ventilatory settings were increased, as needed, until the following maximum settings were reached: FIO2 of 1.0; peak inspiratory pressure of 40 cm H2O; and intermittent mandatory ventilation of 60 breaths/min. After 2 hrs of conventional ventilation or demonstration of clinically important lung disease by failure to maintain desired blood gases on the maximum ventilatory settings, 4 mL/kg of beractant was given intratracheally. After a short period of stabilization following surfactant therapy, inhaled nitric oxide was administered. Concentrations of 40, 20, and 10 parts per million were given. To assure that there was no additive effect of inhaled nitric oxide, each dose was given for 20 mins, followed by a 15-min normalization period at 0 parts per million. MEASUREMENTS AND MAIN RESULTS: Physiologic measurements, ventilatory settings, arterial blood gases, and methemoglobin were recorded at each study period. Measurements were taken after each exposure to inhaled nitric oxide and after its discontinuation. Arterial oxygen saturation and Pao2 were significantly lower after meconium aspiration when compared with baseline values. After treatment with surfactant, administration of inhaled nitric oxide improved oxygenation without a significant decrease in pulmonary arterial pressure. CONCLUSIONS: In this model of meconium aspiration syndrome, short-term exposure to inhaled nitric oxide after treatment with surfactant improved oxygenation secondary to better distribution of inhaled nitric oxide. The increase in oxygenation may be secondary to an improved ventilation/perfusion mismatch, since the primary etiology of hypoxia in this model may be a combination of parenchymal lung disease and pulmonary hypertension.

Improved oxygenation with reduced recirculation during venovenous extracorporeal membrane oxygenation: evaluation of a test catheter.

OBJECTIVE: To determine whether modifications of the original design of a double-lumen, venovenous, extracorporeal membrane oxygenation (ECMO) catheter would reduce recirculation and improve oxygenation during venovenous ECMO. DESIGN: Prospective, interventional study. SETTING: The animal research laboratory at The Children's National Medical Center. SUBJECTS: Six newborn lambs, 1 to 7 days old and weighing 4.7 +/- 0.9 kg. INTERVENTIONS: Animals were anesthetized, intubated and ventilated. The ductus arteriosus was ligated. Femoral artery and vein, cephalic jugular vein, and pulmonary artery catheters were placed. After systemic heparinization, the test catheter (with venous drainage holes moved away from the arterial return holes) was placed in the right internal jugular vein and advanced into the right atrium. The animal was placed on ECMO and stabilized, with the ventilator settings decreased to a peak inspiratory pressure of 15 cm H2O, peak positive end-expiratory pressure of 5 cm H2O, respiratory rate of 15 breaths/min, and an FIO2 of 0.21. ECMO flows were increased in 100-mL increments from 200 to 600 mL/min, with measurements taken 15 mins after each change. The test catheter was removed, the double-lumen, venovenous ECMO catheter was placed, and the studies were repeated. MEASUREMENTS AND MAIN RESULTS: Heart rate, mean arterial pressure, PaO2, jugular cerebral oxygen saturation, pulmonary artery oxygen saturation, mixed venous oxygen saturation, and postmembrane circuit pressures were measured at each study period. The test catheter improved oxygenation significantly, with higher systemic PaO2, higher pulmonary artery and cerebral oxygen saturations, and lower mixed venous oxygen saturations (indicating less recirculation). With the test catheter, PaO2 levels ranged from 62 +/- 6 torr (8.3 +/- 0.8 kPa) to 112 +/- 12 torr (14.9 +/- 1.6 kPa), compared with 46 +/- 4 torr (6.1 +/- 0.5 kPa) to 59 +/- 2 torr (7.9 +/- 0.3 kPa) for the double-lumen, venovenous ECMO catheter (p < or = .001). These findings indicate that at all flow rates studied, less recirculation occurred with the test catheter than with the double-lumen, venovenous ECMO catheter. CONCLUSIONS: These findings indicate that the redesign of the double-lumen, venovenous ECMO catheter, as outlined in this study, resulted in a significant reduction of recirculation, thereby resulting in a significant improvement in oxygenation while on venovenous ECMO. This newly designed catheter makes venovenous ECMO more effective, and represents a design that could be used for pediatric and/or adult ECMO.

In vitro evaluation of the Mera Silox-S 0.5 and 0.8 m 2 silicone hollow-fibre membrane oxygenator for use in neonatal ECMO.

The Mera Silox-S is a silicone hollow-fibre membrane oxygenator made up of thousands of fibres in a clear polycarbonate housing. Being a silicone membrane it does not have the plasma leakage problem associated with conventional microporous hollow fibres when used in a long-term application. This device (Mera Senko Medical Instrument Co., Japan) is made in three sizes: 0.3, 0.5 and 0.8 m 2. The performance of the 0.5 m 2 and 0.8 m 2 Silox-S membrane oxygenators was tested in vitro using filtered ovine blood and a customized test circuit designed to provide a continuous source of de-oxygenated, CO 2-laden blood, according to the AAMI standard for oxygenator performance. The 0.8 m 2 membrane provided excellent oxygenation, with a transfer rate of 13.0-43.5 ml/min for blood flows of 200-800 ml/min. CO 2 transfer over the same range of flows measured 32.3-40.8 ml/min. Flow rates of 100-500 ml/min for the 0.5 m 2 membrane provided an oxygen transfer of 6.8-28.3 ml/min and would probably not be suited for the existing neonatal ECMO population. A matter of concern with both oxygenators was an increased pressure drop for blood flow through the devices. The delta P for the 0.5 m 2 for flows of 100-500 ml/min ranged from 155 +/- 7 mmHg to 516 +/- 6 mmHg. For the 0.8 m 2, delta P was 194 +/- 39 mmHg to 492 +/- 53 mmHg for flows of 200-800 ml/min. Overall, favourable results support further long-term evaluation for potential use in neonatal ECMO.

Maximum blood flow rates for arterial cannulae used in neonatal ECMO.

The arterial cannulae used in neonatal ECMO cause hemolysis and red blood cell damage at elevated blood flows. Hemolysis in extracorporeal circuits has been found to occur with shear stress greater than 132 dynes/cm2, turbulence as measured by Reynold's number greater than 1,000, and velocity greater than 120 to 200 cm/sec. These parameters need to be considered when sizing the proper arterial cannula for a required flow rate. In-vitro measurements of the pressure drop across six arterial cannulae at varying flow rates were performed using human blood with a hematocrit of 43%. Shear stress, Reynold's number, velocity, and pressure drop were calculated for each catheter at flow rates from 50 to 1,000 cc/min. The maximum mean flow rate to maintain the shear stress, Reynold's number, velocity, and pressure drop within the accepted range, was determined for each cannula. Recommended maximum blood flow rates for each of the six cannulae are given. Internal diameter, length, and cannula geometry appear to be the factors most affecting the flow achievable without causing red blood cell damage and hemolysis. Ten French Biomedicus, 10 French Cook, and 10 French Elecath arterial cannulae appear best suited to deliver the range of blood flow rates used in neonatal ECMO.

Interaction of hemoglobin S with anionic polysaccharides.

Our previous studies on the mechanism by which citrate agar electrophoresis separates hemoglobins led to the conclusion that hemoglobins bind to at least some sulfated polysaccharides. In the present report, we describe our deduction at the location of the binding site on the hemoglobin molecule. This led to the prediction, on theoretical grounds, that the anionic polysaccharides should possess anti-gelling actions toward hemoglobins and might be useful drug models. We have shown that anionic polysaccharides including heparin, lambda-carrageenan, dermatan sulfate, fucoidan, and agaropectin have anti-gelling activity. Evidence indicates that heparin can be introduced into red cells by synthetic lipid vesicles (liposomes) and that, once introduced, acts to block sickling. Because of the high solubility and low toxicity of the polysaccharides, we propose that these compounds deserve further study as potential anti-sickling agents.