Chronic radiographic lung changes in children with vertically transmitted HIV-1 infection.

OBJECTIVE: We prospectively studied children with and without maternally transmitted HIV-1 infection born to mothers infected with HIV-1 to determine the incidence of chronic radiographic lung changes (CRC) and to correlate these changes with clinical assessments. SUBJECTS AND METHODS: Between 1990 and 1997, we scored 3050 chest radiographs using a standardized form. Group I children (n = 201) were HIV-1-infected at enrollment. Group II children (n = 512) were enrolled prenatally or before 28 days postpartum and subsequently subdivided into group IIa (n = 86), children identified as HIV-1-infected; and group IIb (n = 426), those who were HIV-1-uninfected. CRC were defined as parenchymal consolidations or nodular disease lasting 3 months or more or increased bronchovascular markings or reticular densities lasting 6 months or more. Morbidity was assessed by CD4 counts, viral load, the presence of low oxygen saturation, wheezing, tachypnea, crackles, and clubbing. RESULTS: The cumulative incidence of chronic radiographic lung changes in HIV-1-infected children was 32.8% by 4 years old, with increased bronchovascular markings or reticular densities being most common. Chronic changes were associated with lower CD4 cell counts and higher viral loads. Resolution of these chronic changes was associated with decreasing CD4 cell counts but not with lower rates of clinical findings, viral load, or difference in survival. CONCLUSION: With increased survival, CRC are becoming more common. The resolution of these changes may indicate immunologic deterioration rather than clinical improvement.

Thoracoabdominal compression and respiratory system compliance in HIV-infected infants.

The thoracoabdominal compression technique (TAC) is used to measure expiratory flow in infants. We investigated whether TAC caused a change in total thoracic compliance (Crs), resistance (Rrs), and respiratory system time constant (Trs). We studied 41 infants (mean age, 12.4 mo; SD, 7.5) from five centers studying longitudinal lung and cardiovascular function of infants from HIV-infected mothers. We measured Crs, Rrs, and Trs before and after TAC. Changes in Crs, Rrs, and Trs after TAC were not dependent on the length of time since TAC. Crs and Trs were reduced after TAC, p = 0.013 and p = 0.003, respectively, whereas Rrs did not change. When compared with uninfected infants, HIV-infected infants had a larger post-pre TAC percent decline in Crs (p = 0.003) and a post-pre TAC rise in mean Rrs (p = 0.03). These differences remained significant after adjusting for sex and age. When performing infant pulmonary function testing, TAC itself produces a temporary decrease in Crs and Trs that is more significant in infants at risk for abnormal lung volume or compliance. Therefore, the sequence of performing the infant lung function parameters should be the same each time the testing is repeated with TAC as the last parameter tested at each testing session.

Neurodevelopmental outcome at 3.5 years of age in children treated with extracorporeal life support: relationship to primary diagnosis.

OBJECTIVE: Recent studies suggest that for neonates treated with extracorporeal membrane oxygenation (ECMO), children with congenital diaphragmatic hernia (CDH) have poorer neurodevelopmental outcome than children with other diagnoses. We therefore analyzed the neurodevelopmental outcome at 3(1/2) years of age in 130 neonatal ECMO survivors with 6 different primary diagnoses. STUDY DESIGN: Children were assessed with the McCarthy Scales of Children's Abilities, Peabody Picture Vocabulary Test, Vineland Adaptive Behavior Scales, and a neurologic/physical examination; 12 factors related to infant characteristics and ECMO/hospital course including primary diagnosis were identified as independent variables. Dependent variables included test scores and 2 outcome categories: functional status (normal, risk, abnormal) and major neurologic sequelae (presence or absence). Statistical tools included chi-squared analysis, t test, analysis of variance, and discriminant and regression analysis. RESULTS: No significant differences were found between diagnostic groups in functional status or neurologic sequelae. Hospital days was the only variable consistently expressed in all analyses as having significant influence on the outcome measures. This was not a factor of the longer hospital days experienced by children with CDH. CONCLUSION: Neurodevelopmental outcome in neonatal ECMO is multifactorial. Although hospital days has the greatest association with outcome at age 3(1/2) years, these days likely reflect degree of illness and various complications that are independent of diagnostic group. Further study is required to determine which factors influencing the length of hospital stay may be the best predictor of long-term outcome.

Measurement of lung volumes and pulmonary mechanics during weaning of newborn infants with intractable respiratory failure from extracorporeal membrane oxygenation.

Newborn infants with intractable respiratory failure who require extracorporeal membrane oxygenation (ECMO) experience diffuse pulmonary atelectasis shortly after initiation of ECMO. Atelectasis is likely due to the primary lung injury and the reduction of applied inspiratory ventilator pressure when the respirator settings are changed to the "rest settings." These pathophysiologic changes result in a decrease in lung compliance and lung volumes. We hypothesized that improving lung functions observed during ECMO and indicated by an increase in lung volumes will predict successful weaning from ECMO. Sixteen infants (mean +/- SEM: gestational age, 40.3 +/- 0.3 weeks; birth weight, 3.5 +/- 0.1 kg) with meconium aspiration syndrome (n = 13), sepsis (n = 2), and persistent pulmonary hypertension (n = 1) were studied. We measured passive respiratory system mechanics and lung volumes initially during full ECMO support (115 +/- 18 h on ECMO, Study I), and then within 24 h prior to weaning from ECMO (Study II). Respiratory system compliance (Crs), respiratory system resistance (Rrs), functional residual capacity (FRC), and tidal volume (VT) were measured. Prior to Study I lung volumes were too small to be detected. Crs increased between Study I and Study II (0.41 +/- 0.05 to 0.63 +/- 0.05 mL/cmH2O/kg, P < 0.05), and VT increased between Study I and Study II (5.6 +/- 0.6 to 10.4 +/- 0.8 mL/kg, P = 0.0005). FRC increased from 3.6 +/- 1.0 to 7.9 +/- 0.9 mL/kg (P = 0.0001). There was no change in Rrs (88 +/- 8 to 89 +/- 6 cm H2O/L/s, P = 0.9). The combination of Crs > 0.5 mL/cmH2O/kg and FRC > 5 mL/kg was a better predictor (P = 0.0002) of readiness to wean from ECMO than either Crs (> 0.5 mL/cmH2O/kg, P = 0.057) or FRC (> 5 mL/kg, P = 0.007) alone. The combination of FRC and Crs had a sensitivity of 73.3% and specificity of 100% for successful decannulation. We conclude that repeated measurements of FRC and Crs can assess lung recovery and may assist in establishing criteria for successful weaning from ECMO.

Pulmonary sequelae at six months following extracorporeal membrane oxygenation.

Mechanical assisted ventilation for neonatal respiratory failure is associated with residual lung disease. Because ECMO rests the lungs, it has been suggested that ECMO will prevent chronic lung disease in survivors. To determine whether or not ECMO survivors have evidence of pulmonary sequelae, we studied 19 infants who were treated with ECMO for neonatal respiratory failure. Ten infants still required supplemental oxygen or pulmonary medications or both to treat clinical lung disease during the first six months of life. Thoracic gas volume was normal. Pulmonary mechanics in ECMO survivors were compared with those of 13 preterm infants with BPD at similar age. We conclude that a significant proportion of ECMO survivors have residual abnormalities in pulmonary mechanics at 6 months of age. We speculate that neonatal lung injury due to meconium aspiration and other causes is a more important determinant of abnormal pulmonary sequelae than the method of treatment.

Serial measurement of pulmonary mechanics assists in weaning from extracorporeal membrane oxygenation in neonates with respiratory failure.

Extracorporeal membrane oxygenation (ECMO) is a highly invasive therapy for intractable neonatal respiratory failure, and serious complications may occur with increasing duration of bypass. Weaning from bypass is empirical at present. Thus, there is a need to accurately predict when infants can be successfully decannulated. We hypothesized that pulmonary mechanics would reflect lung recovery and, therefore, predict successful weaning from ECMO. We measured pulmonary mechanics daily in 22 neonates, at gestational age of 37.8 +/- 0.6 weeks (SE) requiring ECMO for severe respiratory failure (oxygen index 66 +/- 6). Pulmonary resistance (Rpul), dynamic compliance (Cdyn), and tidal volume (VT) were measured. Rpul did not predict lung recovery. Cdyn within 24 hours of starting ECMO was 0.3 +/- 0.04 ml/cm H2O. Cdyn within 24 hours of weaning from ECMO was 1.2 +/- 0.09 ml/cm H2O (p less than 0.001). All 22 infants had Cdyn greater than 0.6 ml/cm H2O at the time of decannulation, but four infants (20 percent) with Cdyn less than 0.6 ml/cm H2O could not be weaned from ECMO within 20 hours (p less than 0.01). Thus, a minimum Cdyn of 0.6 ml/cm H2O is associated with successful weaning from ECMO. Cdyn of 0.8 ml/cm H2O provided better overall discrimination between those who could be successfully weaned from ECMO. We conclude that serial measurement of dynamic pulmonary compliance predicts successful weaning from ECMO.

Digital clubbing and pulmonary function abnormalities in children with lung disease.

Digital clubbing and pulmonary function tests were measured in children, adolescents, and adults with chronic lung diseases to determine pulmonary function correlates with a quantitative measure of clubbing. The group had a mean age of 13.8 +/- 6.0 (SD) years, mean PaO2 of 81 +/- 21 mm Hg, and mean FEV1 of 60% +/- 26% predicted. Digital clubbing was diagnosed in 43 cases when the distal phalangeal depth to interphalangeal depth (DPD/IPD) ratio, measured on a finger cast, was greater than or equal to 1 (greater than 3 SD above mean from 85 controls; no history of pulmonary disease; mean age, 14.8 +/- 7.6). The PaO2 of patients with digital clubbing was 69.4 +/- 2.1 (SEM) mm Hg compared with 88.3 +/- 1.3 mm Hg in those without digital clubbing (P less than 0.0001). Digital clubbing was present in 39 of the 84 (46%) hypoxic patients (PaO2 less than or equal to 88) but only four of the 78 (5%) normoxic patients (P less than 0.0001). The DPD/IPD ratio was negatively correlated with PaO2 in subjects with cystic fibrosis and interstitial fibrosis. Weak negative correlations were seen for all other subjects except asthmatics. Overall, the DPD/IPD ratio was significantly correlated with PaO2 (r = -0.53; P less than 0.0001). The DPD/IPD ratio was correlated with other lung function abnormalities (increased RV, decreased FEV1, and FEF25%-75%) only for the subjects with cystic fibrosis. We conclude that digital clubbing is associated with hypoxemia and airway obstruction. The relation is seen most clearly in subjects with cystic fibrosis, possibly reflecting the prolonged duration of hypoxemia. Digital clubbing is rarely seen in normoxic subjects.

Capillary plasma ammonia concentration in neonates receiving total parenteral nutrition. Comparison with arterial and venous concentrations.

Plasma ammonia concentration in neonates has routinely been determined using arterial or venous blood. Expected plasma ammonia values in capillary blood obtained by heelstick have not been determined. We compared ammonia levels in 20 sets of plasma from simultaneously drawn arterial, venous, and capillary blood in a group of neonates receiving total parenteral nutrition. Mean ammonia concentrations in venous (107 +/- 44) and capillary blood (112 +/- 33) were 45% and 51% higher, respectively, than corresponding arterial (74 +/- 22) values (P less than .001). Ammonia levels in blood obtained by venipuncture (Ven), however, did not correlate consistently with arterial (Art) values (r = .43; Art = 51 + 0.21 Ven; P greater than .05). In contrast, ammonia levels in capillary blood (Cap) correlated well with arterial values (r = .86; Art = 10.3 + 0.6Cap; P less than .001). Ammonia levels in neonates may be reliably interpreted using the latter regression equation when blood for analysis is obtained by a properly performed heelstick, allowing the preservation of arteries and veins, and sparing the infant from repetitive needle punctures. Ammonia levels in blood obtained by venipuncture do not adequately correlate with arterial values and therefore may be therapeutically misleading.

Long-term pulmonary sequelae of meconium aspiration syndrome.

To determine the incidence of long-term sequelae after meconium aspiration syndrome (MAS), we studied 11 children who had MAS at age 8.2 +/- 0.2 years (mean +/- SD) and nine healthy control subjects with pulmonary function and exercise stress tests. The MAS children had evidence of mild airway obstruction, hyperinflation, and increased closing volumes in comparison with control values. During graded exercise stress tests on a treadmill, MAS children achieved normal maximal oxygen consumption and anaerobic threshold without a significant fall in arterial oxygen saturation or increase in CO2 tension. Exercise-induced bronchospasm occurred in four (36%) MAS subjects but in none of the control subjects. We conclude that children surviving MAS have long-term pulmonary sequelae, including airway obstruction, hyperinflation, elevated closing volumes, and airway hyperreactivity; yet they achieve normal aerobic capacity. These findings are similar, although less severe, than those after prematurity and bronchopulmonary dysplasia.

Childhood sequelae of infant lung disease: exercise and pulmonary function abnormalities after bronchopulmonary dysplasia.

To determine the long-term pulmonary sequelae and effect on exercise tolerance of bronchopulmonary dysplasia (BPD), we studied 10 children at a mean age of 10.4 years, who had been born prematurely, survived respiratory distress syndrome, and subsequently developed BPD, and compared them with eight age-matched normal children born at term. Pulmonary function tests and graded exercise stress tests were performed. Residual volume, the ratio between residual volume and total lung capacity, vital capacity, forced expiratory volume in 1 second, forced expiratory flow between 25% and 75% of vital capacity, and maximal expiratory flows at 80%, 70%, and 60% of total lung capacity were all abnormal (P less than 0.02) in the children with BPD, compared with control values. Pre-exercise transcutaneous CO2 tension was higher (P less than 0.05) in the BPD group than in the control group. At maximal workload, tcPCO2 remained high in patients with BPD compared with control values (P less than 0.05). Arterial oxygen saturation at maximal workload fell below pre-exercise levels in the BPD group (P less than 0.05) but not in control children. There were no differences in maximal oxygen consumption between the BPD group and control children. Exercise-induced bronchospasm occurred in 50% of the BPD group, but not in the control group. We conclude that long-term survivors of BPD have evidence of airway obstruction, hyperinflation, and airway hyperreactivity, compared with a control group. Aerobic fitness was not significantly different in the BPD and control groups, but was achieved in the BPD group at the expense of a fall in SaO2 and a rise in tcPCO2.

Unexpected hearing loss in high-risk infants.

Eleven high-risk infants who had normal auditory brainstem responses at the time of discharge from the neonatal intensive care unit were found on follow-up between 13 and 48 months later to have significant sensorineural hearing loss. All 11 infants were the products of high-risk pregnancies and deliveries. Birth weights ranged from 890 to 3,700 g, but seven had birth weights of more than 1,500 g. Gestational ages ranged from 28 to 42 weeks. The length of hospitalization ranged from 45 to 167 days. All of the infants had respiratory distress, requiring prolonged mechanical ventilation with resultant chronic lung disease. All of the infants had received pancuronium, morphine, ampicillin, and gentamicin, and ten had also received furosemide and chlorothiazide. Other frequent clinical complications included abnormal CNS findings during the neonatal intensive care unit stay (ten infants), acidosis (pH less than 7.25) on the initial blood gas test (eight infants), and persistent fetal circulation in all seven infants with birth weights greater than 1,500 g. Developmentally, eight of nine children tested between 12 and 36 months of age were normal in all respects other than the hearing loss and the related language impairment. We conclude that infants who have been very ill in the newborn period, including term infants, may remain at risk for development of significant sensorineural hearing loss even though they have passed an initial auditory brainstem responses screening test in the newborn period.

Hypoxic and hypercapneic arousal responses and prediction of subsequent apnea in apnea of infancy.

Hypoxic and hypercapneic arousal responses from quiet sleep were tested in 56 infants with apnea of infancy (one or more episodes of cyanosis, limpness, and apnea requiring vigorous stimulation or resuscitation with no treatable cause; age 6.8 +/- 1.1 [SEM] months). Responses were compared with those of nine control infants ranging from 1 to 25 months of age. To assess hypercapneic arousal, the inspired PCO2 was rapidly increased during quiet sleep to 60 mm Hg or until arousal (restlessness, agitation, eye opening) occurred. All control infants and those with apnea of infancy aroused to hypercapnea, but control infants aroused at a lower inspired PCO2 (inspired PCO2 40.1 +/- 2.6 mm Hg) than those with apnea of infancy (inspired PCO2 46.9 +/- 1.5 mm Hg, P less than .05). To assess hypoxic arousal, the inspired PO2 was rapidly decreased during quiet sleep to 80 mm Hg or until arousal occurred. All control infants aroused to hypoxia (inspired PO2 78.3 +/- 2.1 mm Hg). However, only 38% of those with apnea of infancy aroused (inspired PO2 78.1 +/- 0.8 mm Hg), indicating an abnormality in recognition of hypoxia, or central brainstem response to hypoxia. During the 10.4 +/- 1.2 months of follow-up, there was a high incidence of subsequent apneas (greater than 20 seconds) during sleep at home in 50 apneic infants. Infants with abnormal hypoxic arousal responses had more severe subsequent apneas than those with normal hypoxic arousal responses (P less than .05).

Effect of oral diuretics on pulmonary mechanics in infants with chronic bronchopulmonary dysplasia: results of a double-blind crossover sequential trial.

In a randomized double-blind crossover trial with sequential analysis, the effects of oral diuretics were compared with the effects of placebo on pulmonary mechanics in ten infants with bronchopulmonary dysplasia (BPD). Pulmonary mechanics were measured before and at the end of a week of treatment with oral diuretics (chlorothiazide, 20 mg/kg/dose and spironolactone, 1.5 mg/kg/dose) given twice daily, or placebo. Mean airway resistance decreased 35.3 cm H2O/L/s, mean specific airway conductance increased 0.095 1/L/s/cm H2O, and mean dynamic pulmonary compliance increased 1.74 mL/cm H2O during treatment with diuretics (all P less than .001), but not during treatment with placebo. The infants' rate of weight gain decreased on the first three days of diuretic treatment, but was thereafter comparable with weight gain during treatment with placebo. Fluid intake was similar in infants receiving diuretics and placebo. But, infants receiving diuretics not only had significantly increased urine output, osmolal clearance, and potassium and phosphorus excretion, but these infants also retained less fluid, and, in addition, excreted less calcium than infants receiving placebo. It is concluded that oral diuretics improve lung function in infants with chronic bronchopulmonary dysplasia; however, potassium and phosphorus depletion are potential complications of treatment.

Effect of isoproterenol inhalation on airway resistance in chronic bronchopulmonary dysplasia.

The effects of isoproterenol inhalation on pulmonary mechanics in ten infants with bronchopulmonary dysplasia (BPD), aged 41 +/- 1 (SE) weeks postconception, with gestational age at birth 30 +/- 1 weeks, and birth weight 1,590 +/- 200 g were studied. The infants had: (1) hyaline membrane disease requiring mechanical ventilation in the first five days of life, (2) mechanical ventilation and/or FIo2 greater than 30% for at least 30 days, and (3) stage III or IV radiographic changes. Thoracic gas volume, airway resistance, and specific airway conductance were measured in an infant body pressure plethysmograph during quiet breathing. Dynamic pulmonary compliance was measured using an esophageal balloon. These infants with BPD had greater airway resistance, lower specific airway conductance, and lower dynamic pulmonary compliance than 16 normal control infants (age 40 +/- 1 weeks postconception). In the infants with BPD, measurements were obtained before and 1/2, 1, 2, and 6 hours after the administration of isoproterenol aerosol 0.1% inhalation or saline aerosol placebo, five breaths by slow inflation of the lungs with an anesthesia bag. Within 30 minutes after isoproterenol inhalation, airway resistance decreased 28% +/- 5% and specific airway conductance increased 53% +/- 15%. Thoracic gas volume and dynamic pulmonary compliance did not change. There were no changes following administration of the placebo. Isoproterenol inhalation is associated with rapid short-term improvement in airway resistance and specific airway conductance in infants with BPD.

Furosemide acutely decreases airways resistance in chronic bronchopulmonary dysplasia.

We studied the effects of furosemide on pulmonary mechanics in 10 infants with bronchopulmonary dysplasia aged 41 +/- 1 (SE) weeks post-conception, gestational age at birth 30 +/- 1 wk, birth weight 1370 +/- 200 gm. Thoracic gas volume, airways resistance, and specific airway conductance were measured in an infant body pressure plethysmograph during quiet breathing. Dynamic pulmonary compliance was measured using an esophageal balloon. Infants with BPD had greater Raw, lower SGaw, and lower Cdyn than did 16 normal control infants. Within one hour after administration of furosemide 1 mg/kg IV to infants with BPD, Raw fell 36 +/- 13%, SGaw increased 84 +/- 22%, and Cdyn increased 54 +/- 13%; TGV did not change. Diuretic treatment of BPD in infants is associated with rapid, short-term improvement in Raw and Cdyn.

Developmental pattern of maximal transdiaphragmatic pressure in infants during crying.

Diaphragm strength was measured as maximal transdiaphragmatic pressure (Pdi) during airway occlusion in 38 infants aged 11.6 +/- 0.5 (S.E.) months postconception (mpc), range 8-21 mpc. All infants were asymptomatic at the time of study and required no mechanical ventilatory assistance. Ten infants had previous surgical correction of abdominal wall defects (gastroschisis/omphalocele); 10 infants had previous surgical correction of congenital diaphragmatic hernia; and 18 infants had no thoracic or abdominal surgery. The mean maximal Pdi for all infants was 72 +/- 3 cmH2O. There were no significant differences between the three groups. All infants with a maximal Pdi of less than 60 cmH2O were aged less than 10 mpc. After 13 mpc there was no significant increase in maximal Pdi. Between the ages 8-13 mpc there was a significant positive correlation between maximal Pdi and age postconception (r = 0.87, P less than 0.0005), reflecting a developmental pattern of increasing maximal transdiaphragmatic pressure in infants during crying.

Management of hydrocephalus secondary to intraventricular hemorrhage in the preterm infant with a subcutaneous ventricular catheter reservoir.

To control hydrocephalus resulting from massive intraventricular hemorrhage in premature neonates with respiratory distress syndrome, we inserted a specially designed low profile subcutaneous ventricular catheter reservoir (reservoir) by the 12th day of life (average; range, 3 to 30 days) in 20 neonates whose mean birth weight was 1110 +/- 270 g (28.7 +/- 1.6 weeks of gestation). The reservoir was repeatedly aspirated over 10 to 48 days. No cerebrospinal fluid infection, reservoir obstruction, or breakdown of the skin overlying the reservoir occurred. Serial computed tomographic scans documented control of the hydrocephalus and an increase in the thickness of the cortical mantle of the survivors. No mortality was associated with placement of the reservoir or its subsequent conversion, if necessary, to a ventriculoperitoneal shunt. However, only 7 of the 20 infants survived. On follow-up 3 to 5 years later, 2 of the 7 have normal intellectual and motor development. Two infants are normal intellectually, but have a motor deficit. The remaining 3 patients have both significant intellectual and motor developmental delay. The use of the reservoir is offered as a safe and effective alternative to repeated ventricular punctures, external ventricular drainage, or initial shunting. Aggressive management of hydrocephalus secondary to intraventricular hemorrhage may improve neurological function in some surviving neonates.