Elaine Barefield

Inhaled nitric oxide in term infants with hypoxemic respiratory failure

OBJECTIVE To determine whether inhaled nitric oxide (NO) administered during conventional mechanical ventilation could produce improvements in oxygenation and reduce the incidence of meeting extracorporeal membrane oxygenation (ECMO) criteria in infants with hypoxemia. DESIGN Prospective, randomized, controlled trial. Enrolled infants were assigned to conventional treatment with or without adjunctive inhaled NO. Control infants meeting failure criteria (partial pressure of arterial oxygen (PaO2)<80 mm Hg (10.7 kPa)) were allowed to cross over. Caregivers were not masked to group assignment. SETTING Neonatal intensive care units at the University of Alabama Hospital and the Childrens Hospital of Alabama, October 1993 to May 1994. PATIENTS Newborn infants, both term and near-term, with PaO2 less than 100 mm Hg (13.3 kPa) who were receiving mechanical ventilation with 100% oxygen. Exclusion criteria included major congenital anomalies, diaphragmatic hernia, profound asphyxia, and significant bleeding. INTERVENTIONS Inhaled NO was initiated in the NO group at a dose of 20 to 40 ppm and advanced stepwise to 80 ppm if PaO2 remained less than 100 mm Hg (13.3 kPa). OUTCOME MEASURES Primary outcome variables were treatment failure and meeting of ECMO criteria before crossover. Improvement in oxygenation and ultimate use of ECMO or high-frequency oscillatory ventilation were secondary outcome variables. RESULTS Seventeen neonates with hypoxemia were enrolled; 16 had echocardiographic evidence of pulmonary hypertension, and eight had extrapulmonary shunting. At 1 hour of treatment, two infants in the NO group responded with increases in PaO2 of more than 100 mm Hg (13.3 kPa); after crossover, two had increases in PaO2 of more than 10 mm Hg (1.3 kPa) and one control infant had an increase in PaO2 of more than 10 mm Hg (1.3 kPa). All control infants met failure criteria and crossed over to receive NO; two had increases in PaO2 of more than 10 mm Hg (1.3 kPa) with NO treatment. Despite initial responses, all subjects in both groups eventually met failure criteria. There were no differences between groups in primary outcome variables. CONCLUSIONS Although inhaled NO produced a transient improvement in oxygenation in some infants, it did not reduce the incidence of meeting ECMO criteria in this population.

The role of nitric oxide in the treatment of neonatal pulmonary hypertension.

Nitric oxide production appears to be decreased in infants with persistent pulmonary hypertension (PPHN). Inhaled nitric oxide may improve oxygenation by two mechanisms: increased pulmonary blood flow and improved ventilation-perfusion matching. Nitric oxide inhalation has been tested in newborns with PPHN, congenital heart diseases, and bronchopulmonary dysplasia. We present a review of the articles concerning inhaled nitric oxide for infants with PPHN. Overall, 59% of the neonates had an initial improvement in oxygenation in response to nitric oxide inhalation. A sustained response was observed in 60% of the infants. Patients with extrapulmonary shunting, clear chest radiographs, and adequate lung volume seem to have a better response, whereas patients with congenital diaphragmatic hernia, severe sepsis, and alveolar capillary dysplasia are more likely to fail. To define the benefit-risk ratio, six prospective randomized trials are currently in progress.

Thromboxane and pulmonary morphometry in the development of the pulmonary hypertensive response to group B streptococcus.

ObjectiveTo clarify the mechanism of the development of a severe pulmonary hypertensive response to group B streptococcus. DesignProspective, randomized controlled trial. SubjectsTwelve chronically instrumented and six age-matched uninstrumented newborn piglets. InterventionsSix animals received eight injections of group B streptococcus over an 11-day period (control group). Six additional animals (pretreatment group) were given 3 mg/kg of dazmegrel, a thromboxane synthase blocking agent, before each dose of group B streptococcus to prevent the pulmonary hypertensive response and to control for any secondary arterial remodeling. Measurements and Main ResultsHemody-namic measurements, pulmonary arterial morphometry, and thromboxane concentrations were examined in the instrumented animals. Lungs from the uninstrumented piglets were examined to determine morphometric norms for this population. The animals given only group B streptococcus developed a significant pulmonary hypertensive response after five daily doses (+6.8 ± 2.0 [SEM] mm Hg, p < .05) which became pronounced after eight doses (+13.2 ± 1.0 mm Hg). Pulmonary hypertension was not observed in the pretreatment group when dazmegrel was given; however, on the final day in this group, dazmegrel was withheld before group B streptococcus dosing and a significant pulmonary hypertensive response was observed (+20 ± 1.6 mm Hg). The medial thickness of pulmonary arteries was not different between the two groups nor when compared with that of six normal, uninstrumented animals. Plasma thromboxane B2 concentrations were determined from blood samples taken before and after group B streptococcus infusion at the first, seventh and eighth (final) dosing. Thromboxane concentrations increased significantly on days 7 and 8 in the control group (578 ± 312 to 752 ± 372 pg/mL, 638 ± 201 to 1462 ± 295 pg/mL, respectively) and on day 8 in the pretreatment group (545 ± 160 to 705 ± 187 pg/ mL). ConclusionsWe conclude that the development of potentiated pulmonary hypertension is not due to pulmonary arterial remodeling, but is associated with increased thromboxane production. (Crit Care Med 1994; 22:506–514)

NUMBER OF TRANSFUSIONS (TX) BY GESTATIONAL AGE (GA) AND LENGTH OF STAY (LOS).1700

To reduce blood product Tx and donor exposures, a number of methods have been proposed, including rhEpo, reduced sampling, sterile docking devices, and dedicated units. To assess the impact of different methods, the frequency of blood product Tx must be predicted for a given GA. Data were prospectively collected on PRBC, plasma (FFP) and platelet Tx, GA and LOS for 6248 infants admitted to UAB Hospitals newborn ICU 1989-1995. The mean Tx per baby and number of Tx per 100 days of stay were calculated. The relationship of PRBC Tx to GA and LOS was significant (p< 0.0001, mult. logistic regression). PRBC Tx/baby peaked at 24 wks and showed a nadir at 33wks(Table). Platelet Tx/baby and Tx/100 days were not significantly related to GA (0.07 ± 0.01, 0.7 ± 0.1 respectively). FFP Tx were related to GA (p <0.01) with Tx/100days peaking at 24 and 38wks (3.7 ± 1.9, 2.8 ± 1.6) with a nadir at 34wks(0.2 ± 0.1). Together with data on timing of Tx, these data should facilitate choosing which infants would benefit and the most effective method(s) of reducing donor exposure for a given GA so that appropriate strategies may be initiated at admission.

1150 EFFECTS OF INHIBITORS AND ANTIBODY ON THE PULMONARY HYPERTENSIVE EFFECTS OF BOLUS GRP B STREP IN CONSCIOUS PIGS

We have shown that heat-killed Group B Streptococci (GBS) cause dose-related pulmonary artery hypertension in chronically instrumented piglets. These responses are similar to those seen with gram negative bacterial endotoxins. Prostanoids and endorphins have been implicated as mediators of these responses. We tested the effect of a cycloxygenase inhibitor, indomethacin; a thromboxane synthesis inhibitor, dazmegrel (UK-38,185); a leukotreine synthesis inhibitor, BW 540C; and an endorphin antagonist, naloxone on the response to a bolus of 5 × 107 heat-killed GBS Type III (M 732) /kg. We also tested the effect of pre-incubating the GBS with high-titer, type-specific rabbit antibody.Neither leukotriene nor endorphin blockade affected the response. In contrast, both cyolooxygenase and specific thromboxane synthesis inhibition markedly blunted the GBS-induced pulmonary hypertension. This suggests that thromboxane A2 mediates this response. Antibody coated organisms increased the response, suggesting antibody participation in this reaction. Further work will increase our understanding of the response to sepsis.

1151 TIME-RELATED POTENTIATION OF THE PULMONARY HYPERTENSIVE RESPONSE TO BOLUS GROUP B STREPTOCOCCI IN CONSCIOUS PIGS

Infusions of Group B Streptococci; (GBS) cause pulmonary hypertension in acutely instrumented lambs. We developed a chronic piglet model to further study this response. We placed a pulmonary artery electromagnetic flow transducer plus pulmonary, aortic, left atrial and central venous catheters. After > 4 days recovery, animals were given 1×108 heat killed GBS type III (strain M732)/kg as a rapid bolus each weekday for 10 days. The table shows the mean ± SD change in mean pulmonary artery pressure (Ppa) for each day.The average increase in Ppa on days 8, 9 and 10 was 230% greater than on days 1, 2 and 3. Other variables changed little, if any, and returned to baseline within 1-2 minutes while pulmonary pressure was elevated for 6 ± 1.5 minutes on days 8, 9, and 10. These data document a previously unreported time-related potentiation in the pulmonary hypertensive response to bolus GBS in conscious piglets. Investigations into the mechanism(s) underlying this response are under way. Further work with this model may improve our understanding of the host response to infectious challenge.