Persistent pulmonary hypertension of the newborn. Rational therapy based on pathophysiology.

Persistent pulmonary hypertension of the newborn is a common disorder among near-term gestation newborns. Persistent pulmonary hypertension of the newborn is characterized by hypoxemia that is frequently refractory to conventional management. This article describes the pathophysiologic basis of the disorder and the current therapy that is based on this knowledge.

Effect of exogenous and endogenous nitric oxide on the airway and tissue components of lung resistance in the newborn piglet.

Despite widespread reports of the vasodilatory actions of nitric oxide (NO), little is known of the relaxant effect of NO on newborn airways or lung parenchymal structures. We studied the effects of inhaled NO at 20, 40, and 80 ppm on lung (Rl), tissue (Rti), and airway (R(aw)) resistance in 13 2-5-d-old anesthetized, ventilated, open-chested piglets. Rl was measured from transpulmonary pressure and air flow. Rti was measured by alveolar capsules, and R(aw) was calculated as the difference between Rl and Rti. Any given concentration of inhaled NO (20, 40, or 80 ppm) significantly decreased Rl (p < 0.001), Rti (p < 0.001), and R(aw) (p < 0.05). In addition, blockade of endogenous NO with 30 mg/kg N omega-nitro-L-arginine methyl ester (L-NAME) given i.v. in 12 piglets significantly increased Rti and Rl with variable changes in R(aw), and caused a decrease in dynamic compliance. Readministration of NO to eight piglets induced a significant decreased in Rl and Rti at 20 and 80 ppm, whereas R(aw) significantly decreased only at 80 ppm. Pulmonary arterial pressure decreased after exposure to inhaled NO and increased after L-NAME administration. Systemic arterial pressure was unaffected by inhaled NO but increased after L-NAME administration. Our results indicate that Rl, R(aw), and Rti are reduced by exogenous NO, suggesting NO-mediated airway smooth muscle relaxation throughout the newborn lung. In contrast, blockade of endogenous NO significantly increases only Rti, suggesting a physiologic role for endogenous NO in regulation of peripheral contractile elements. We speculate that NO-mediated modulation of resistance in pulmonary parenchyma may serve to regulate the balance of ventilation and perfusion and resultant gas exchange in the lungs during early postnatal development.

Severe respiratory failure in neonates: mortality and morbidity rates and neurodevelopmental outcomes.

OBJECTIVE: To compare the survival, neurodevelopmental, and health outcomes of children with severe respiratory illness treated with and without extracorporeal membrane oxygenation (ECMO). DESIGN: Prospective collection of clinical and demographic data of all neonates reaching illness severity criteria, with follow-up at 8 and 20 months of age. Patients were assigned to treatment by the attending physician. PATIENTS: Consecutive sample of 74 neonates during a 24-month period with an alveolar-to-arterial gradient exceeding 620 for 8 or more hours. RESULTS: Eighteen (69%) of 26 neonates treated with conventional therapy survived to 20 months, in comparison with 43 (90%) of 48 neonates treated with ECMO. The conventionally treated group had significantly more chronic lung disease, longer duration of oxygen therapy, more chronic reactive airway disease, and more rehospitalizations than those treated with ECMO. Hospital charges were similar in the two groups. Macrocephaly was noted in 24% of those treated with ECMO and in none of the conventional group. Of those completing evaluation, 4 (24%) of 17 conventionally treated survivors and 20 (26%) of 38 ECMO-treated survivors had neurodevelopmental impairment. CONCLUSION: Survivors of severe neonatal respiratory illness have significant pulmonary and neurodevelopmental impairment, regardless of the treatment used. Neonates treated with ECMO had neurodevelopmental outcomes similar to those of patients treated conventionally, but better pulmonary outcomes.

The natural history of direct hyperbilirubinemia associated with extracorporeal membrane oxygenation.

OBJECTIVE: To determine the incidence and natural history of direct hyperbilirubinemia in neonates treated with extracorporeal membrane oxygenation. DESIGN: A prospective series of patients. SETTING: A level 3 neonatal intensive care unit and center for extracorporeal membrane oxygenation in Ohio. PARTICIPANTS: Sixty-seven consecutive patients treated with extracorporeal membrane oxygenation in 33 months. INTERVENTION: None. MEASUREMENTS/RESULTS: Twenty-six (39%) developed direct hyperbilirubinemia. In 14 (54%), bilirubin levels were mildly elevated and occurred only during extracorporeal membrane oxygenation therapy. Levels were more severely elevated in the remaining 12 patients (46 +/- 10 mumol/L [2.7 +/- 0.6 mg/dL] vs 159 +/- 101 mumol/L [9.3 +/- 5.9 mg/dL], P less than .0001). Duration and severity of hyperbilirubinemia were correlated. Hyperbilirubinemia resolved in all patients by 9 weeks after extracorporeal membrane oxygenation therapy. No structural abnormalities or infectious agents were identified as causes. Aluminum levels were evaluated for 40 patients, were not in the toxic range, and did not correlate with hyperbilirubinemia. Multiple linear regression analysis suggested that hyperbilirubinemia in these cases resulted from interaction of injuries, with the primary contributor being hemolysis during extracorporeal membrane oxygenation. CONCLUSIONS: Direct hyperbilirubinemia occurs frequently in patients treated with extracorporeal membrane oxygenation and may be severe. However, direct hyperbilirubinemia typically resolves without short-term sequelae. Hemolysis may be an important contributing factor.

Carotid reconstruction in the neonate following ECMO.

Permanent ligation of the carotid artery remains a major objection to the use of extra corporeal membrane oxygenation (ECMO) in infants with severe cardiorespiratory disorders. Because reconstruction of the carotid artery is highly desirable, we began a study to evaluate the feasibility and risks of carotid artery repair following decannulation. All infants placed on ECMO from December 1988 to January 1990 were evaluated for carotid artery reconstruction. During this period 18 infants underwent carotid reconstruction and 8 infants were deemed unsuitable candidates. Patency of the right common carotid artery was demonstrated in 14 of the 18 infants with good bilateral anterior and middle cerebral artery flow. Seven infants have had MRA evaluation at 6 months and have demonstrated no significant change from their discharge study. These preliminary findings suggest that carotid reconstruction can be performed safely with no apparent morbidity in the majority of infants placed on ECMO, but long-term follow-up data concerning patency rate and neurological status must be obtained before this technique is applied to all infants with this problem.

Parenchymal and vascular magnetic resonance imaging of the brain after extracorporeal membrane oxygenation.

Three-dimensional (volume) magnetic resonance angiography is a new and noninvasive method for imaging the intracranial vasculature. The combination of magnetic resonance angiography and conventional magnetic resonance imaging was used to evaluate brain parenchyma and vessels in 30 survivors of extracorporeal membrane oxygenation. Magnetic resonance imaging findings were abnormal in 33% of the patients, with no increased frequency of right hemispheric lesions. Magnetic resonance angiography demonstrated good intracranial flow in all infants and demonstrable right internal carotid arterial flow in 35% of those patients with permanent carotid ligation. An abnormal magnetic resonance imaging study was found more often in infants with abnormal predischarge neurologic examination results. These techniques have several advantages over other neuroimaging modalities, including better definition of deep structures, myelin formation, and intracranial vasculature, the absence of bone artifact, and the elimination of catheter or contrast use.

Granulocyte transfusions in septic adult and newborn rats: distribution of granulocytes and effect on peripheral blood and bone marrow.

Granulocyte transfusions are increasingly being used as therapy for newborns with sepsis and neutropenia. We injected either group B Streptococcus or phosphate-buffered saline solution intraperitoneally into adult and newborn rats. Human granulocytes, labeled with chromium 51, were transfused seven hours later. When the newborn rats were killed 13 to 19 hours after injection, they had 10(2) to 10(6) cfu/gm Streptococcus organisms in both lung and brain. Only one third of the adult rats had 10(2) to 10(4) cfu/gm Streptococcus organisms in either lung or brain. A greater proportion of the transfused granulocytes was present in lung and brain tissue of newborn rats, compared with adult rats (p less than 0.05), irrespective of infection. Granulocyte transfusion did not change the peripheral blood leukocyte count in adult rats but increased the count in newborn rats (p less than 0.05). The immature myeloid pool in the bone marrow of adult rats increased significantly with either infection or transfusion (p less than 0.01). The immature pool in newborn rats increased significantly only with infection (p greater than 0.001), although the combination of infection and transfusion also had a significant effect on the pool (p less than 0.01). Infection and both infection and transfusion, but not transfusion alone, significantly affected the mature myeloid bone marrow pool in adult and newborn rats (p less than 0.001). The depletion of the mature myeloid elements of the bone marrow in response to infection was dramatic in neonatal rats, compared with that in adult rats. Both transfused granulocytes and hematogenously spread streptococci lodge in the brains and lungs of neonatal rats more effectively than in those of adult rats.

Extracorporeal membrane oxygenation in infants: angiographic and parenchymal evaluation of the brain with MR imaging.

The authors report their preliminary experience with intracranial three-dimensional Fourier transform magnetic resonance (MR) angiography and T2-weighted MR imaging of the brain parenchyma in 15 neonates less than 1 week old after extracorporeal membrane oxygenation (ECMO) with permanent ligation of the right common carotid artery and internal jugular vein, four 1-year-old infants after ECMO with carotid ligation, and four neonates less than 1 week old after ECMO with reanastomosis of the same artery. MR angiography was technically satisfactory in 20 of the 23 patients and documented patency of the right internal carotid artery proximal to the ophthalmic artery in nine of 16 patients with permanent carotid ligation and in all four patients with reanastomosis. This study suggests MR angiography is feasible in newborns and infants and that, in combination with parenchymal MR imaging, it provides a sensitive, noninvasive method to assess vessel patency and follow cerebrovascular and parenchymal changes in infants after ECMO.

Neonatal neutropenia. Clinical manifestations, cause, and outcome.

Neutropenia, defined as an absolute neutrophil count that falls below 2.0 x 10(9)/L, is being identified more frequently in the newborn intensive care unit and significantly influences clinical decisions regarding therapy. We prospectively identified 119 episodes of neutropenia in 87 infants (6% of admissions). Less than half of the episodes could be attributed to infections. The majority of noninfectious neutropenia episodes were related to specific perinatal events or were of unknown cause. Infants weighing less than 2500 g were more likely to have neutropenia than term infants (13% vs 3%, respectively) and less likely to have neutropenia related to bacterial infections. Short-term survival (89% vs 95%) and long-term survival (74% vs 77%) were not different in infants with infectious diseases compared with those with noninfectious diseases. Mortality was highly correlated with the need for assisted ventilation (20%) or with an absolute neutrophil count of 0.5 x 10(9)/L (24%). We conclude that the cause of neutropenia and the clinical condition must be carefully evaluated before instituting aggressive therapy for infection.

Buffy coat transfusions in neutropenic neonates with presumed sepsis: a prospective, randomized trial.

Neonatal sepsis, accompanied by neutropenia, is associated with a high mortality. To determine whether granulocyte transfusions improve the survival of critically ill neutropenic infants, we prospectively randomized 25 infants to transfusion and nontransfusion groups, matching for birth weight (less than or equal to 1,500 g or greater than 1,500 g). Infants with necrotizing enterocolitis were randomized separately. Neutropenia was established by two successive absolute neutrophil counts less than or equal to 1,500 cells prior to randomization. The transfusion (n = 12) and nontransfusion (n = 13) groups did not differ with respect to clinical or hematologic characteristics. In 23 of 25, bone marrow aspirations were performed to determine the percentage of neutrophil storage pool. Granulocyte transfusions of buffy coats from single units of whole blood (0.1 to 0.9 X 10(9) polymorphonuclear leukocytes per kilogram) were given daily until the absolute neutrophil count increased to more than 1,500/microL. Only five infants, mostly those with necrotizing enterocolitis, required more than one transfusion. A circulating immature to total neutrophil ratio (I:T) greater than or equal to 0.80 was not predictive of an infant with a neutrophil storage pool less than or equal to 7%, and neither an I:T less than 0.80 nor a neutrophil storage pool greater than 7% were predictive of survival. Granulocyte transfusions did not improve survival when either comparing the whole group, those 17 infants with cultures positive for bacteria or viruses, the 19 infants with a circulating I:T greater than or equal to 0.80, or the nine infants with a neutrophil storage pool less than or equal to 7%.(ABSTRACT TRUNCATED AT 250 WORDS)

Limitations of transcutaneous PO2 and PCO2 monitoring in infants with bronchopulmonary dysplasia.

Despite the well-documented correlation between transcutaneous and arterial PO2 and PCO2 in sick neonates, the effect of maturation on this relationship has not been well characterized. Eight premature infants with bronchopulmonary dysplasia (BPD) and indwelling arterial lines beyond the immediate neonatal period were studied. Transcutaneous PO2 always underestimated PaO2 beyond 10 weeks of postnatal life, such that transcutaneous PO2 - PaO2 was -16 +/- 5 torr (P less than .001). Corrected transcutaneous PCO2 simultaneously overestimated PaCO2 by 9 +/- 3 torr (P less than .001), although this occurred over a wider range of postnatal ages. Transcutaneous PO2 monitoring may be a useful tool for estimating PaO2 in this population, provided an appropriate correction is made beyond 10 weeks of age. It is suggested that caution be exercised when using transcutaneous PCO2 measurements to estimate absolute arterial values in older infants with bronchopulmonary dysplasia.