Khodayar Rais-Bahrami

Follow-up study of adolescents exposed to di(2-ethylhexyl) phthalate (DEHP) as neonates on extracorporeal membrane oxygenation (ECMO) support.

Di(2-ethylhexyl) phthalate (DEHP) is used to make polyvinyl chloride (PVC) plastic tubing soft and flexible. Animal data show that adverse effects of DEHP exposure may include reduced fertility, reduced sperm production in males, and ovarian dysfunction in females. Known treatments that involve high DEHP exposures are blood exchange transfusions, extracorporeal membrane oxygenation (ECMO), and cardiovascular surgery. Although potential exposure to DEHP in ECMO patients is significant, the exposure has not been associated with short-term toxicity. To evaluate long-term toxicity, we undertook a study of neonatal ECMO survivors to assess their onset of puberty and sexual maturity. We evaluated 13 male and 6 female subjects at 14–16 years of age who had undergone ECMO as neonates. All subjects had a complete physical examination including measurements for height, weight, head circumference, and pubertal assessment by Tanner staging. The testicular volume and the phallic length were measured in male participants. Laboratory tests included thyroid, liver, and renal function as well as measurements of luteinizing hormone, follicle-stimulating hormone, testosterone for males, and estradiol for females. Except for one patient with Marfan syndrome, the rest had normal growth percentile for age and sex. All had normal values for thyroid, liver, and renal functions. Sexual hormones were appropriate for the stage of pubertal maturity. Our results indicate that adolescents exposed to significant quantities of DEHP as neonates showed no significant adverse effects on their physical growth and pubertal maturity. Thyroid, liver, renal, and male and female gonadal functions tested were within normal range for age and sex distribution.

Validation of a noninvasive neonatal optical cerebral oximeter in veno-venous ECMO patients with a cephalad catheter

Introduction:Cerebral Oximetry is an optical technique that allows for noninvasive and continuous monitoring of brain oxygenation by determining tissue oxygen saturation (SctO2). In conjunction with pulse oximetry, cerebral oximetry offers a promising method to estimate cerebral venous oxygen saturation (SvO2).Objective:The aim of this study was to validate the cerebral oximetry measurements with the cerebral oxygen saturation measured from blood drawn in neonates on veno-venous ECMO with existing cephalad catheter with a prototype neonatal cerebral oximeter developed by CAS Medical Systems (Branford, CT, USA).Study design:After obtaining informed consent, neonates undergoing VV-ECMO with cephalad catheterization were monitored by the CAS cerebral oximeter. Cephalad blood samples were periodically obtained to validate the monitors accuracy.Results:Seventeen neonates were studied with 1718 h of cerebral oximetry data collected. Compared to the reference values, the bias±precision for cerebral oximetry SctO2 was 0.4±5.1% and derived SvO2 was 0.6±7.3%Conclusion:We recommend the use of this noninvasive method as an alternative to blood draws for cerebral venous saturation measurements in neonates requiring extracorporeal life support.

Validation of the cas neonatal NIRS system by monitoring VV-ecmo patients : Preliminary results

The CAS neonatal NIRS system determines absolute regional brain tissue oxygen saturation (SnO2) and brain true venous oxygen saturation (SnvO2) non-invasively. Since NIRS-interrogated tissue contains both arterial and venous blood from arterioles, venules, and capillaries, SnO2 is a mixed oxygen saturation parameter, having values between arterial oxygen saturation (SaO2) and cerebral venous oxygen saturation (SvO2). To determine a reference for SnO2, the relative contribution of SvO2 to SaO2 drawn from a brain venous site vs. systemic SaO2 is approximately 70:30 (SvO2:SaO2). If the relationship of the relative average contribution of SvO2 and SaO2 is known and does not change to a large degree, then NIRS true venous oxygen saturation, SnvO2, can be determined non-invasively using SnO2 along with SaO2 from a pulse oximeter.

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

ObjectiveTo 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. DesignAnimal studies, using the newborn lamb, with comparison to control group. SubjectsNewborn 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). SettingWork was conducted in the research laboratories at Children’s National Medical Center, Washington, DC. InterventionsAnimals 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. MeasurementsSix 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 ResultsIncreasing 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. ConclusionsHealthy 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 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 Childrens 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 ECMO: comparison of two catheters

Objectives: To determine whether the new double-lumen catheter made by OriGen Biomedical (Austin, TX) for venovenous (VV) extracorporeal membrane oxygenation (ECMO) would reduce recirculation and improve oxygenation during VV ECMO when compared with the Kendall double-lumen catheter (Kendall Healthcare Products, Mansfield, MA). Design: Prospective intervention study. Setting: The animal research laboratory at Children’s National Medical Center, Washington, DC. Subjects: Nine newborn lambs one to seven days old and weighing 4.4± 0.8 kg. Intervention: Animals were anesthetized, intubated, and ventilated. The ductus arteriosus was ligated. Femoral arterial and venous, cephalic jugular vein, and pulmonary artery catheters were placed. After systemic heparinization, the catheter to be tested, an OriGen catheter, 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 15-20 cmH2O, peak end-expira-tory pressure of 5 cmH2O, rate of 15-25 breaths/min, and a fractional inspired oxygen concentration of 0.21-0.30. ECMO flows were increased in 100-ml increments from 200 to 600 ml/min with measurements taken 15 min after each change. The OriGen catheter was removed, the Kendall catheter was placed, and the studies were repeated. Measurements and Main Results: Heart rate, mean blood pressure, paO2, jugular cerebral oxygen saturation, pulmonary artery oxygen saturation, pump venous oxygen saturation, and postmembrane circuit pressures were measured at each study period. The OriGen catheter improved oxygenation, with higher systemic paO2, higher pulmonary artery and cerebral oxygen saturations, and lower pump venous oxygen saturations (indicating less recirculation). With the OriGen catheter, paO2 levels ranged from 69± 18 mmHg [9.2± 2.4 kPa] to 114 ± 45 mmHg [15.2± 6.0 kPa], compared range from 61± 15 mmHg [8.1± 2.0 kPa] to 87± 34 mmHg [11.5± 4.5 kPa] for the Kendall catheter. These findings indicate that, at all flow rates studied, less recirculation occurred with the OriGen catheter than with the Kendall catheter. The postmembrane pressures were significantly lower for the OriGen catheter at any given flow (from 30 ± 5 to 122 ± 18 mmHg) when compared with the Kendall catheter (from 77± 16 to 330 ± 78 mmHg). Conclusions: These findings indicate that the OriGen catheter resulted in a reduction of recirculation, thereby resulting in an improvement in oxygenation while on VV ECMO. The lower postmembrane pressure potentially could reduce the risk of ECMO circuit complications such as tubing rupture, bleeding complications, as well as hemolysis. This new catheter makes VV ECMO more effective and represents a design that could be used for neonatal and/or pediatric ECMO.

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 Childrens 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.

Altered cerebrovascular responses after exposure to venoarterial extracorporeal membrane oxygenation: role of the nitric oxide pathway.

Background: Previous studies in our laboratory on newborn lambs have shown cerebral autoregulation impairment after exposure to venoarterial extracorporeal membrane oxygenation (VA ECMO), with additional studies showing an altered cerebrovascular response to NG-nitro-l-arginine methyl ester in lamb cerebral vessels in this same model. Objective: To further study the mechanisms involved in altered cerebrovascular responses in vessels exposed to VA ECMO. Design: Prospective study. Setting: Research Animal Facility at Children’s National Medical Center, Washington, DC. Subject: Newborn lambs, 1–7 days of age, 4.76 ± 0.8 kg (n = 10). Methods: Animals randomly assigned two groups, control and VA ECMO, were anesthetized, ventilated, heparinized, and kept in a normal physiologic condition. Control animals were continued on ventilatory support, whereas animals in the VA ECMO groups were placed on VA ECMO, with bypass flows maintained between 120 and 200 mL·kg−1·min−1 for 2.5 hrs. Isolated third-order branches of the middle cerebral arteries were studied for myotonic reactivity to increasing intraluminal pressure changes, response to acetylcholine, an endothelium-dependent vasodilator, 3-morpholinyl-sydnoneimine chloride, an endothelium-independent vasodilator, and serotonin, a direct vascular vasoconstrictor. Arterial caliber was monitored using video microscopy. Results: Myogenic constriction response was significantly decreased in the VA ECMO group compared with the control group (p = .03). Intraluminal acetylcholine caused concentration-dependent arterial dilation in the control group, whereas it resulted in vasoconstriction in the VA ECMO group (p = .008). There were no significant differences in dilation responses to 3-morpholinyl-sydnoneimine chloride and contractile responses to serotonin among the groups. Conclusion: Cerebral arteries exposed to VA ECMO had impaired myogenic responses combined with altered endothelial function. The endothelial alteration seems to be mediated through the nitric oxide pathway, with recovery noted after addition of a nitric oxide donor. It can be postulated that these changes may reflect the mechanisms for the impairment of cerebral autoregulation previously reported in this lamb model.

Venoarterial versus venovenous ECMO for neonatal respiratory failure.

Extracorporeal membrane oxygenation (ECMO) continues to be an important rescue therapy for newborns with a variety of causes of cardio-respiratory failure unresponsive to high-frequency ventilation, surfactant replacement, and inhaled nitric oxide. There are approximately 800 neonatal respiratory ECMO cases reported annually to the Extracorporeal Life Support Organization; venoarterial ECMO has been used in approximately 72% with a cumulative survival of 71% and venovenous has been used in 28% with a survival of 84%. Congenital diaphragmatic hernia is now the most common indication for ECMO. This article reviews the development of the two types of extracorporeal support, venoarterial and venovenous ECMO, and discusses the advantages of each method, the current selection criteria, the procedure, and the clinical management of neonates on ECMO.

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 Childrens 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.