Inhaled nitric oxide inhibits the release of matrix metalloproteinase-2, but not platelet activation, during extracorporeal membrane oxygenation in adult rabbits.

BACKGROUND/PURPOSE: In neonates receiving extracorporeal membrane oxygenation (ECMO), platelet activation and dysfunction occur with the release of matrix metalloproteinase (MMP)-2, which stimulates platelet aggregation. Because inhaled nitric oxide (NO) reduces pulmonary hypertension and inhibits platelet aggregation, the authors examined the effects of inhaled NO on platelet activation induced by ECMO. METHODS: Ten adult white New Zealand rabbits were instrumented for ECMO and assigned randomly to receive either inhaled NO at 40 ppm or 30% oxygen for 1 hour before ECMO and continued for 4 hours after starting ECMO. Platelet counts, collagen-induced platelet aggregation ex vivo, plasma MMP-2, and MMP-9 activities were measured. RESULTS: (1) ECMO caused thrombocytopenia, decreased platelet aggregation, and increased plasma MMP-2 and MMP-9 activities in controls. (2) Inhaled NO inhibited platelet aggregation before ECMO but did not affect the ECMO-induced thrombocytopenia and platelet activation. (3) Inhaled NO significantly abolished the ECMO-induced increase in plasma MMP-2 but not MMP-9 activities. CONCLUSIONS: Although inhaled NO did not inhibit the platelet activation during ECMO in adult rabbits, it attenuated the increase in plasma MMP-2 activity that may be important for neonates treated with ECMO.

Isolated mental developmental delay in very low birth weight infants: association with prolonged doxapram therapy for apnea.

OBJECTIVE: We investigated factors associated with isolated mental delay in infants weighing < 1250 g at birth. STUDY DESIGN: With a case-control design, matching variables for 40 cases included gestation, birth weight, sex, grade of intraventricular hemorrhage, and socioeconomic status. Case subjects had a mental developmental index < 70, and controls had a mental developmental index > or = 85, according to the Bayley Scales of Infant Development II at 18 months' corrected age. RESULTS: There were no differences between the case and control subjects for neonatal complications and antenatal or postnatal steroid use. There was a marked difference in the cumulative dosage and duration of doxapram therapy used for apnea of prematurity (total dose 2233 +/- 1927 mg vs 615 +/- 767 mg, P < .001; duration 45.2 +/- 32.5 days vs 19.4 +/- 23.4 days, P < .001 for case subjects and control subjects, respectively). Multivariate analysis did not identify additive predictive variables. CONCLUSION: Isolated mental delay in infants weighing < 1250 g at birth was associated with the total dosage and duration of doxapram therapy for severe apnea. Although this may be a marker for cerebral dysfunction manifesting as apnea of prematurity, possible adverse effects of doxapram or its preservative, benzyl alcohol, on the developing brain deserve further study.

The mechanisms of platelet dysfunction during extracorporeal membrane oxygenation in critically ill neonates.

OBJECTIVE: Although bleeding associated with thrombocytopenia often complicates extracorporeal membrane oxygenation (ECMO), the mechanisms of platelet dysfunction during ECMO remain poorly understood. We investigated the role of matrix metalloproteinase (MMP)-2, which recently has been shown to mediate a novel pathway of platelet aggregation, in the platelet dysfunction induced by ECMO. DESIGN: Prospective longitudinal case study. SETTING: Level III neonatal intensive care unit. PATIENTS: Ten neonates treated with ECMO. INTERVENTION: ECMO procedure. MEASUREMENTS: Platelet counts and collagen-induced platelet aggregation ex vivo; plasma markers of platelet (soluble P-selectin) and endothelial (soluble E-selectin and total nitrite/nitrate) activation; plasma MMP-2 and MMP-9 activities; and concentrations of tissue inhibitors of MMPs. MAIN RESULTS: During ECMO, time-dependent platelet activation, as evidenced by thrombocytopenia, decreased platelet aggregation, and increased plasma soluble P-selectin concentrations were found in the absence of endothelial activation, as shown by normal plasma concentrations of soluble E-selectin and nitric oxide metabolites (nitrite/nitrate). There was a time-dependent increase in plasma MMP-2 but not MMP-9 activity; tissue inhibitors of MMPs were not detected. Plasma soluble P-selectin concentrations significantly correlated with simultaneous plasma MMP-2 (r2 = .37, p < .0001) but not with MMP-9 activities. Platelet dysfunction persisted despite repeated platelet transfusions to maintain platelet counts >100 x 10(9)/L. CONCLUSIONS: ECMO resulted in the activation of platelets but not endothelial cells. During ECMO, platelet dysfunction persisted despite platelet transfusions. MMP-2 may play a role in the development of platelet dysfunction caused by ECMO.

The hemodynamic effects of inhaled nitric oxide and endogenous nitric oxide synthesis blockade in newborn piglets during infusion of heat-killed group B streptococci.

OBJECTIVE: To determine the effects of therapy with inhaled nitric oxide (NO) gas and partial or complete blockade of endogenous NO synthesis with N(omega)nitro-L-arginine (L-NA) on the hemodynamic responses to group B streptococci infusion in newborn piglets. DESIGN: Randomized, acute intervention study. SETTING: Animal research laboratory. SUBJECTS: Twenty-five anesthetized piglets younger than 3 days of age divided into five groups. INTERVENTIONS: Heat-killed group B streptococci (GBS) were infused systemically until a 50% increase in pulmonary artery pressure (PAP) was obtained, and the infusion was continued for another 2 hrs. The five groups were designed as follows: group 1, sepsis control: continuous GBS infusion, with two brief trials (10 mins) of inhaled NO given after the initial development of pulmonary hypertension and again 2 hrs later; group 2, continuous inhaled NO: NO was given at 40 ppm for 2 hrs during GBS infusion; group 3, high-dose L-NA pretreatment: 10 mg/kg L-NA bolus followed by 1 mg/kg/min before, and continuing throughout, GBS infusion; group 4, high-dose L-NA: same dose as in group 3, but given after the start of the GBS infusion with continuous inhaled NO at 40 ppm; and group 5, low-dose L-NA: 3 mg/kg bolus given after start of GBS infusion with continuous inhaled NO at 40 ppm. MEASUREMENTS AND MAIN RESULTS: The sepsis controls, group 1, had an increase in PAP, which took 15-45 mins to develop, from a mean of 3.4 (SD 0.7) to 5.9 (1.9) kPa (p < .05), at which time the cardiac index had decreased from 169 (28) to 146 (46) mL/kg/min (p < .05). Brief inhaled NO during the early phase decreased PAP to normal. Two hours later, PAP had increased to 6.1 (0.2) kPa and cardiac index had decreased to 88 (31) mL/kg/min. Inhaled NO after 2 hrs decreased PAP to 3.2 (0.5) kPa and increased cardiac index to 106 (44) ml/kg/min (p < .05). Continuous inhaled NO (group 2) ameliorated the deterioration in cardiac index, which at 2 hrs was 140 (30) mL/kg/min (significantly greater than in the sepsis controls) (p < .05). The L-NA-pretreated animals (group 3) had a greater increase in PAP and pulmonary vascular resistance index when GBS infusion was started. PAP increased from 3.0 (0.7) to 7.3 (1.5) kPa within 15 mins, and cardiac index simultaneously decreased to 68 (20) mL/kg/min. Cardiac index subsequently rapidly deteriorated to 48 (21) mL/kg/min, and only one of five animals survived for 2 hrs. Group 4 animals also developed a rapid deterioration in cardiac output, and only two of five survived for 2 hrs. Group 5 animals had results indistinguishable from group 2 animals. CONCLUSION: Pulmonary hypertension and shock resulting from GBS infusion in newborn piglets are much worse if endogenous NO production is completely inhibited. Continuous inhaled NO with or without low-dose L-NA inhibits the decrease in cardiac output.

Partial liquid ventilation with and without inhaled nitric oxide in a newborn piglet model of meconium aspiration.

The object of this study was to determine the effects of partial liquid ventilation (PLV) with and without inhaled nitric oxide (NO) over a 4-h period on lung mechanics, gas exchange, and hemodynamics in an animal model of meconium aspiration syndrome (MAS). Twenty-four fentanyl-anesthetized piglets were instrumented and administered a slurry of human meconium to create a model with hypoxia, hypercarbia, acidosis, and pulmonary hypertension. They were then randomly assigned to conventional ventilation, conventional ventilation plus inhaled NO at 40 ppm, PLV using perfluorodecalin, or PLV plus inhaled NO. The perfluorocarbon was added until a meniscus was visible in the endotracheal tube during expiration. Hemodynamics, lung mechanics, and gas exchange were monitored for 4 h, and then the animals were killed. The conventionally ventilated animals continued to deteriorate, and three of the six died prior to 4 h. All the animals in the remaining groups survived. Oxygenation improved significantly immediately with the start of inhaled NO (from 43.8 SD 10.3 to 62.6 SD 11.7 mm Hg after 30 min) and stayed elevated compared with the control group for the remainder of the study (62.4 SD 21.8 mm Hg at 4 h compared with 44.9 SD 1.6 mm Hg for the control group, p < 0.05). Oxygenation improved more slowly in the PLV alone group, being slightly less than control at 30 min (p = NS) but increasing to 104 SD 34.9 after 4 h (p < 0.01 compared with the control group), at which time it was also greater than inhaled NO alone (p < 0.05). The combined group had an acute increase in oxygenation indistinguishable from the NO alone group and maintained this until the end of the study. Lung compliance was unaffected in the inhaled NO group. In both the liquid ventilation groups the lung compliance improved with the instillation of perfluorodecalin (from 0.46 SD 0.18 to 0.62 SD 0.09 ml/cm H(2)O/kg in the PLV alone group at 1 h, p < 0.05 compared with the control group) and remained stable for the remainder of the study. Cardiac output and pulmonary vascular resistance were not significantly affected by any of the treatments. It was concluded that in this animal model of MAS, inhaled NO led to an acute improvement in gas exchange and prolonged survival compared with conventional therapy. PLV improved lung mechanics, which was maintained over the course of the study. The combination of PLV and inhaled NO produced both effects, acutely improving both gas exchange and lung mechanics. Combined therapy with PLV and inhaled NO may have benefits in the MAS.

The Edmonton experience with venovenous extracorporeal membrane oxygenation.

BACKGROUND/PURPOSE: Despite the proven effectiveness of venovenous extracorporeal membrane oxygenation (VV ECMO) in the treatment of neonates with severe respiratory failure, this technique is not widely used. The purpose of this study was to assess the authors' policy of preferred use of VV ECMO with a cephalad catheter and to compare the results with those of the Extracorporeal Life Support Organization (ELSO) Registry. METHODS: Charts of neonatal ECMO candidates were reviewed retrospectively. Data were collected for gestational age, birth weight, and diagnosis. Severity of illness was assessed by oxygenation index, lactate levels, and inotropic requirements before cannulation. Patients were divided into three groups: venovenous (VV), venoarterial (VA), and VV to VA ECMO. A cephalad catheter was inserted in the distal part of the jugular vein. RESULTS: Sixty-five neonates were supported with ECMO. Cannulation with a double lumen venovenous (VVDL) catheter was attempted in 63 neonates and successfully accomplished in 57. A survival rate of 86% was observed in neonates initially placed on VV ECMO. Five neonates initially placed on VV ECMO underwent conversion to VA ECMO. CONCLUSIONS: This study showed that the authors' preferred policy of VV ECMO did not result in an increase in mortality rate based on a comparison with ELSO data. VV ECMO with a cephalad catheter provides adequate support for unstable neonates with respiratory failure.

Congenital diaphragmatic hernia: developing a protocolized approach.

BACKGROUND/PURPOSE: The purpose of this study was to evaluate the evolving outcome of newborns who have congenital diaphragmatic hernia (CDH) using a protocolized approach to management, which includes extracorporeal membrane oxygenation (ECMO) and to present the details of such a management protocol. METHODS: A retrospective chart review was conducted of the neonatal outcome of near-term (>34 weeks' gestation) newborns with CDH all referred to the Royal Alexandra Hospital either before or after delivery. A protocol was developed that included antenatal assessment, the use of antenatal steroids, planned delivery, use of prophylactic surfactant, pressure limited gentle ventilation, permissive hypercarbia and hypoxia, and venovenous ECMO, if indicated. RESULTS: Sixty-five infants with CDH were treated from February 1989 through August 1996. Twenty-three infants were inborn, 20 of whom were antenatal referrals. Overall, 51 of the 65 infants survived (78%). Thirteen of the 23 inborn infants survived with conservative management, and 10 required ECMO, of whom, eight were long-term survivors. Thirty-eight infants required ECMO, and 26 survived (68%), whereas there were only two deaths among the 27 conservatively treated infants. Eighteen of 20 inborn infants with an antenatal diagnosis survived, compared with 13 of 21 (62%) outborn infants. An antenatal diagnosis before 25 weeks' gestation was associated with a 60% survival rate. Sixty-three percent of infants whose best postductal PaO2 value before ECMO was less than 100 torr survived, and 7 of 11 infants with a best postductal PaO2 value of less than 50 torr before ECMO survived (64%). The average age at surgery progressively increased over time both for infants who did not require ECMO (1.3 days to 5.8 days; P = .01) and for infants who received ECMO (1.9 days to 8.2 days; P = .016). CONCLUSIONS: The use of a protocolized management for infants with CDH has been associated with improving outcome in a population at high risk. The components (either separately or combined) of these protocolized approaches need to be tested in prospective trials to determine their true benefit. In addition, there is a need to evaluate prospectively the outcomes of infants with CDH born in ECMO centers compared with those infants born in other tertiary care neonatal units to determine the most appropriate management of the fetus with CDH.

Inhaled nitric oxide improves oxygenation in piglets with meconium aspiration.

We hypothesized that nitric oxide (NO) inhalation in a model of meconium aspiration in newborn piglets would decrease pulmonary vascular resistance. Seven neonatal piglets were obtained at less than 48 hr of age and instrumented under fentanyl anesthesia. Inhaled NO (40 parts per million) was administered during normoxia and again after hypoxia was induced by reducing FiO2 to 0.13. During normoxia NO inhalation caused a fall in pulmonary artery pressure from a mean of 3.15 (SD 0.8) kPa to 2.84 (SD 0.7) kPa (P < 0.01). Hypoxia (mean arterial O2 saturation 35%) increased PA pressures to a mean of 5.4 (SD 1.6) kPa and NO administration during hypoxia decreased PA pressures to 3.6 (SD 1.2) kPa (P < 0.001). In order to determine the effects of NO in a model of meconium aspiration, 6 to 7 mL/kg of 20% human meconium in normal saline was instilled into the trachea. This procedure induced hypoxemia (mean SaO2 43.4%, SD 19), respiratory acidosis, (mean PaCO2 12.1 kPa, SD 0.5; mean pH 7.04, SD 0.03), and pulmonary arterial hypertension (mean pulmonary artery pressure 6.0 kPa, SD 1.3) despite ventilation with 90% oxygen. Inhaled NO was then administered in concentrations of 5, 10, 20, 30, 40, 60, and 80 parts per million in random order according to a Latin square design.(ABSTRACT TRUNCATED AT 250 WORDS)

Province-based study of neurologic disability of children weighing 500 through 1249 grams at birth in relation to neonatal cerebral ultrasound findings.

BACKGROUND: Adverse neurodevelopmental outcome in premature infants is more common in the presence of certain ultrasonographically detectable intracranial lesions. Present nomenclature and classifications of parenchymal changes in preterm infants of varying gestations have led to some confusion. Descriptive definitions may be clinically useful. Regionalized perinatal and neonatal care enables population-based studies of these lesions and subsequent outcomes. METHODS: Two- to 3-year outcomes of neonates weighing 500 through 1249 g born in Alberta to Alberta residents during 1987 through 1990 were reviewed in relation to neonatal cerebral ultrasound lesions. Odds ratios and confidence limits for disability were calculated. RESULTS: Of 960 live births in this weight group, 669 (70%) survived to 1 year adjusted age; 646 (96.6%) were assessed at follow-up, and 80 (12.4%) of these were disabled: cerebral palsy, 8.7%; vision loss, 2.9%; hearing loss, 1.3%; epilepsy, 0.6%; mental retardation, 4.8%; more than one disability per child, 3.6%; and projected dependent disability, 1.4%. Lesions considered to be predictive of disability on ultrasound (excluding germinal layer hemorrhage) were found in 79 (11.8%), parenchymal lesions in 63 (9.4%) of 1-year survivors: intraventricular hemorrhage (IVH) (n = 59), persistent or transient cerebral ventriculomegaly (n = 50), persistent or transient intraparenchymal periventricular echodensity (n = 29), and cystic periventricular leukomalacia (n = 7). All lesions except isolated IVH were associated with adverse outcome; 37% of disabled children, 61% of multiply disabled children, and all children projected to become dependently disabled had parenchymal lesions with or without IVH. Triple lesions of IVH, cerebral ventriculomegaly, and intraparenchymal periventricular echodensity gave an odds ratio for disability of 50. Transient lesions had significant risk. CONCLUSIONS: This province-based study provides a descriptive scheme of serial neonatal cerebral ultrasound lesions and outcome considered useful for clinicians caring for newborns of lowest gestational ages. The overall incidence of parenchymal lesions was lower than frequently reported. Combinations of lesions were linked to increased incidence, complexity, and severity of childhood disability.

Congenital diaphragmatic hernia: associated malformations--cystic adenomatoid malformation, extralobular sequestration, and laryngotracheoesophageal cleft: two case reports.

Two infants with unusual bronchopulmonary malformations associated with congenital diaphragmatic hernia (CDH) are presented. One infant had extralobular sequestration and cystic adenomatoid malformation of the lower lobe, in addition to a left-sided CDH. The second infant had a laryngotracheoesophageal cleft extending to the carina (type III) in addition to a left-sided CDH. These associated malformations can have major implications in terms of diagnosis, resuscitation, and surgical management of infants with CDH.

Inhaled nitric oxide for premature infants after prolonged rupture of the membranes.

We evaluated the use of inhaled nitric oxide in eight premature infants (520 to 1440 gm, 24 to 31 weeks of gestation) who failed to respond to conventional management and who had prolonged rupture of the membranes and oligohydramnios. All infants had a significant improvement in oxygenation and a fall in mean airway pressure with inhaled nitric oxide. Further studies are required to determine the safety and efficacy of this form of therapy.

Clinical monitoring of inhaled nitric oxide: comparison of chemiluminescent and electrochemical sensors.

In view of the rapidly increasing use of inhaled nitric oxide for infants with potentially reversible pulmonary hypertension, the ability to accurately measure nitric oxide and its by-products is an increasingly important safety issue. The authors evaluated the abilities of two chemiluminescent analyzers and two electrochemical sensors to detect known concentrations of nitric oxide (NO) and nitrogen dioxide (NO2). A calibrated mass spectrometer was utilized to determine the reference levels of NO2. Mass flowmeters calibrated with bubble flowmeters and an audited cylinder of NO were utilized to determine the levels of NO. In a test laboratory environment, all sensors yielded reasonably accurate measurements of NO. It was observed, however, that the amounts of NO recorded by the candidate analyzers in an 82% oxygen environment were slightly low compared with reference methods. The chemiluminescent analyzers consistently underread the true amounts of NO2 in a high-oxygen environment, producing negative concentrations on one instrument. Some monitors that are being clinically utilized to measure NO were designed for industrial and environmental applications in which the ambient oxygen concentrations are less than 21%. In the presence of higher oxygen concentrations, such analyzers can significantly underread the amounts of NO2 that are present, possibly because of reaction quenching or other effects. Measurements of NO and its by-products should be performed using analyzers that have been appropriately tested and calibrated with known concentrations of NO and NO2 prior to their clinical application.

Successful outcome in a case of cystic adenomatoid malformation of the lung complicated by fetal hydrops, using extracorporeal membrane oxygenation.

Severe fetal hydrops associated with cystic adenomatoid malformation of the lung inexplicably resolved spontaneously at 33-34 weeks' gestation. Following postnatal resection of the lesion which was of the macrocystic variety, the infant's respiratory status deteriorated, requiring 1 week of complicated support with extracorporeal membrane oxygenation. The baby survived and was discharged.

Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: dose response.

To determine the role of inhaled nitric oxide (NO) in a population of critically ill hypoxic near-term infants and to determine the dose response to inhaled NO, we examined a consecutive group of 23 infants referred for neonatal extracorporeal membrane oxygenation (ECMO) who had an oxygen index of 20 or greater after treatment with bovine surfactant. Inhaled NO was administered in concentrations from 5 to 80 ppm in random order to 23 infants. Overall, 13 infants had a significant response (an improvement in arterial oxygen pressure > 10 mm Hg or arterial oxygen saturation > 10%) to the first administration of inhaled NO, and one infant had a late response. There was no significant difference in the response to inhaled NO as measured by changes in arterial oxygen pressure or in the alveolar-arterial difference in partial pressure of oxygen, for any of the doses from 5 to 80 ppm. Thirteen infants had echocardiographic evidence of persisted pulmonary hypertension; 11 of these infants responded, compared with 3 responders among the 10 infants without persistent pulmonary hypertension of the newborn (p < 0.01). Overall, 11 infants required ECMO; there were two deaths in this group. Seven infants had congenital diaphragmatic hernia; five of those had a response to NO inhalation and four required ECMO. Our study demonstrates that there is no significant difference in response between low and high doses of inhaled NO and that this treatment may prevent the need for ECMO in some infants referred for this therapy, especially in infants with pulmonary hypertension. Prospective, controlled, randomized, and blinded trials of low doses of inhaled NO are needed to determine the clinical role of this potentially useful therapy.