Characteristics of pulmonary hypertension in preterm neonates.

OBJECTIVE: Characteristics of preterm infants who develop pulmonary hypertension (PHT) and their response to inhaled nitric oxide (iNO) are not well described. Our objective was to identify risk factors for PHT in infants <37 weeks gestational age (GA) and to evaluate their response to iNO. STUDY DESIGN: A retrospective chart review was conducted in infants <37 weeks GA born from July/2000 to October/2005 who had an echocardiographic diagnosis of PHT in the first 4 weeks of life. A comparison non-PHT group was generated matched for GA and birth date. Data on prenatal and postnatal characteristics, response to iNO and mortality were collected. RESULTS: Low Apgar scores, preterm premature rupture of membranes, oligohydramnios, pulmonary hypoplasia and sepsis were independently predictive of PHT. Mortality was significantly higher in the PHT group (26.2% versus 4.1%; P<0.0001) compared to the control group. Low birth weight, severe intraventricular hemorrhage and male sex were significantly associated with death in infants with PHT. Thirty-seven percent (23/61) of infants with PHT were treated with inhaled NO. Infants < 29-week GA had poor response to iNO and the response to iNO increased with GA (P<0.02). CONCLUSIONS: Low Apgar scores, oligohydramnios and pulmonary hypoplasia are associated with the development of PHT in premature infants. The percentage of infants responding to iNO increases with advancing GA.

Laryngeal and diaphragmatic muscle activities after central nervous system lesions in cats.

AIM: To examine the central control and coordination of respiratory pump muscles and laryngeal valve muscles by systematic decerebration (DECER), cerebellectomy (CBELL), pontine respiratory group lesioning (PRG) and pontomedullary section (PMED). METHODS: Activities of posterior cricoarytenoid (PCA), thyroarytenoid (TA) and diaphragm (D) muscles and their responses to inspiratory (I) and expiratory (E) total occlusions were determined in 10 adult cats. RESULTS: INTACT anesthetized cats (n = 6) exhibited inspiratory PCA (PCA(I)) and D activities. Expiratory PCA (PCA(E)) was present but TA activity was absent. It was found that successive DECER, CBELL and PRG lesions attenuated PCA(E), the intact pattern being noted in 7/10, 4/10 and 0/6 cats, respectively. After PMED, variable PCA, TA and continuous D activities occurred only with blood gas abnormalities. Augmented PCA and D responses to I- and E-loads occurred after PRG lesions: the I-load PCA(I) and D responses resembled apneusis and the E-load PCA(E) and D responses resembled central apnea. CONCLUSION: The decreasing PCA(E) activity observed with successive DECER, CBELL and PRG lesions suggests that these areas influence laryngeal abductor control of glottic size. The synchronous activities after PMED transection suggest a role for more rostral structures in coordinating laryngeal and diaphragmatic muscle activities.

Endotracheal measurement of thyroarytenoid activity in newborn lambs.

Laryngeal control of expiratory airflow is a principal means by which the newborn establishes and maintains absolute lung volume. Specifically, retardation of expiratory airflow is effected by the major adductors of the larynx, the thyroarytenoid (TA) muscles. The long-term aim of this research is to determine if monitoring TA activity can be used to optimize absolute lung volume during artificial ventilation of the human baby. This initial study, performed in unanesthetized chronically instrumented newborn lambs, tests the hypothesis that the timings of the onsets, peaks and durations of TA activity recorded by the endotracheal electrode are equivalent to those measured by a surgically placed intramuscular electrode. Endotracheal measurement of TA activity is accurate and specific and can monitor changes in airway pressure and lung volume.

Nonimmune hydrops fetalis: fetal and neonatal outcome during 1983-1992.

Prognostic factors for survival of 62 fetuses and neonates with nonimmune hydrops fetalis (NIHF) were studied retrospectively. Twenty-eight infants survived >/=28 days which is 45% for all fetuses and newborns diagnosed with NIHF and 61% for liveborns with unresolved NIHF. Univariate analysis identified that mortality was associated with the presence of >/=2 serous cavity effusions and a need for chest compressions at birth. Multivariate logistic regression analysis confirmed that the presence of >/=2 serous cavity effusions was significantly associated with mortality from NIHF <28 days after birth [OR = 48.2 (CI 3.6, 662.9) (p < 0.004)]. We conclude that, compared to published cases from the 1970s and early 1980s, survival of liveborns with NIHF seems improved. The decrease in stillbirths is more notable. The severity of hydrops at birth is the key determinant for survival.

Nitric oxide inhalation in infants with respiratory distress syndrome.

OBJECTIVE: This study was designed to test the hypothesis that nitric oxide inhalation increases systemic arterial blood oxygen tension of prematurely delivered infants with respiratory distress syndrome. METHODS: Nitric oxide was administered to 23 preterm infants with a diagnosis of respiratory distress syndrome. The infants were randomly assigned to receive either 5 or 20 ppm of nitric oxide and were studied between 24 and 168 hours after delivery. The treatment period for each infant lasted 15 minutes and was preceded by and followed by a 15-minute control period. We evaluated all outcome variables by using two-way repeated measures analysis of variance; p values less than 0.01 were considered significant. RESULTS: Nitric oxide inhalation caused significant increases in the following: arterial blood oxygen tension, directly measured arterial oxyhemoglobin saturation, and transcutaneously measured arterial oxyhemoglobin saturation. No differences between the effects of the two nitric oxide concentrations were detected, nor were residual effects detected 15 minutes after either dose of nitric oxide was discontinued. CONCLUSIONS: Inhalation of both 5 and 20 ppm nitric oxide causes concentration-independent increases in the blood oxygen tensions of preterm infants with respiratory distress syndrome. We speculate that nitric oxide inhalation may be a useful adjunctive therapy for these patients.

Laryngeal and diaphragmatic activities with a single expiratory load in newborn lambs.

Expiratory resistive loads elicit compensatory reflexes in the neonate which regulate end-expiratory lung volume (EEV). This study investigated the coordination of laryngeal and diaphragmatic activities when awake neonatal lambs were exposed to a single breath expiratory resistive load. The lambs were chronically instrumented for recording trans-upper airway pressure and electromyographic signals from the posterior cricoarytenoid, thyroarytenoid, and diaphragm. The lambs breathed through a sealed face mask connected to a pneumotachograph and non-rebreathing valve with a loading manifold connected to the expiratory port. Single breath expiratory loads produced, decreased airflow; prolongations of PCA EMG activity and diaphragm EMG inhibition; decreased trans-upper airway resistance and increased EEV. In the post-load breath, inspiratory volume decreased, expired volume increased, and EEV returned towards control baseline. Thus, neonatal lambs compensate for a single breath expiratory load by dilating the larynx and prolonging expiratory time. In the post-load breath, integrated activities of laryngeal and diaphragmatic muscles, coupled with mechanical factors return EEV towards baseline.

Decreased imposed work with a new nasal continuous positive airway pressure device.

This model study compared the imposed work of two nasal continuous positive airway pressure (NCPAP) devices for very low birthweight (VLBW) babies: a new NCPAP device, designed by Moa et al., (Crit Care Med 16:1238, 1988), and a conventional NCPAP device. In addition, the variabilities in the pressures of a simulated airway were compared. A continuous flow (8 L/min) was used to generate CPAP. A Harvard ventilator was used to simulate breathing at a fixed volume (12.1 mL) and rate (45 breaths/min). The pressure drop across and the flow rate through each device were measured, thus allowing the determination of imposed work, i.e., the work of breathing done by the patient to overcome frictional losses due to the NCPAP device. In addition, the pressure fluctuations in the simulated airway were measured. The data presented are averages of 36 breaths using the new device and 34 breaths using the conventional device. The means of the imposed work in the new device and in the conventional device were 0.135 (95% CI +/- 0.004) mJ/breath and 0.510 (95% CI +/- 0.004) mJ/breath (P < 0.01) respectively. The coefficients of variation for pressure in the simulated airway were: new 6.8% and conventional 15.3%. We conclude that the imposed work of the new NCPAP device for the VLBW baby is approximately one-fourth of that of the conventional device. The airway pressure generated by the VLBW size of the new NCPAP device shows less variability during simulated breathing than that found with the conventional device. The findings support the clinical use of the new NCPAP device in the very low birthweight baby.

Contribution of vagal afferents to the volume-timing response to expiratory loads in neonatal lambs.

Expiratory loads elicit volume-dependent reflex increases in expiratory duration (TE) in adult animals. This reflex is mediated by pulmonary vagal afferents. It was hypothesized that this same reflex in newborn lambs is mediated by vagal afferents. Single-breath graded expiratory loads were presented to 4 day old, anesthetized neonatal lambs through a facemask (FM), via tracheostomy (TR) and after the cervical vagi were severed bilaterally in the TR animals (VAG). In FM and TR studies, expired volume (VE) decreased and TE increased with increasing load magnitude. There was no significant difference in the VE-TE curves for FM and TR. These results demonstrate that pulmonary vagal afferents are mediating the volume-related reflex modulation of TE during expiratory loading in the anesthetized neonatal lamb which is unaffected by bypass (TR) of upper airway afferents.

Respiratory disorders of the neonate.

This paper presents recently published literature linking current understanding of neonatal respiratory physiology and pathophysiology to current therapy. Respiratory development is a continuum. The persistence of a fetal breathing pattern into the neonatal period may explain idiopathic neonatal apnea and the pattern of breathing seen with asphyxial apnea. Discussion with the obstetrician will focus more on prenatal diagnosis and on ensuring that prenatal corticosteroids are given. The advent of inhaled nitric oxide therapy for persistent pulmonary hypertension of the newborn offers a viable method of avoiding extracorporeal membrane oxygenation. New insights into the management of respiratory distress syndrome are derived from studies of how lung mechanics are altered by surfactant therapy. Lung injury due to capillary stress is highlighted as is attention to the way in which artificial ventilation is performed. Finally, the development of optimal guidelines for care in respiratory distress syndrome must involve consideration of multiple, interacting factors and their impact on associated conditions, especially periventricular hemorrhage.

Respiratory muscle activities after birth in asphyxiated preterm lambs.

Laryngeal and pump muscle activities are important in the establishment and maintenance of functional residual capacity (FRC) after birth. The aim of this study was to determine the expiratory mechanisms by which laryngeal and diaphragmatic activities achieve the increments in FRC postnatally. Wire electrodes were placed in: the laryngeal abductor, a major laryngeal adductor, the inferior pharyngeal constrictor and the diaphragm of six fetal sheep. The lambs were delivered prematurely by cesarean section and a face mask with a pneumotachograph applied. A grunting respiratory pattern was characterized by severe expiratory airflow retardation, associated with laryngeal adductor activity. In grunting breaths, minimal volume loss at end-expiration and incremental increases in FRC occurred when the onset of diaphragmatic activity preceded the onset of laryngeal muscle activities associated with laryngeal opening. Thus the timing order of laryngeal and diaphragmatic muscle activities near end-expiration is a determinant of increments in FRC.

Multiresolution segmentation of respiratory electromyographic signals.

Analysis of respiratory electromyographic (EMG) signals in the study of respiratory control requires the detection of burst activity from background (signal segmentation), and focuses upon the determination of onset and cessation points of the burst activity (boundary estimation). This paper describes a new automated multiresolution technique for signal segmentation and boundary estimation. During signal segmentation, a new transitional segment is defined which contains the boundary between background and burst activity. Boundary estimation is then performed within this transitional segment. Boundary candidates are selected and a probability is attributed to each candidate, using an artificial neural network. The final boundary for a given transitional segment is the boundary estimate with the maximum a posteriori probability. This new method has proved accurate when compared to boundaries chosen by two investigators.

Vagally mediated volume-dependent modulation of inspiratory duration in the neonatal lamb.

Inspiratory mechanical loads elicit a reflex volume-timing response in human infants and experimental animals. In adult animals, this reflex has been shown to be mediated by vagal afferents. It was hypothesized that the volume-related regulation of inspiratory duration would also be vagally mediated in the newborn. Single-breath graded inspiratory loads were presented to 4-day-old anesthetized neonatal lambs breathing through a facemask, after tracheostomy, and after bilateral cervical vagotomy. Inspired volume decreased and inspiratory duration (TI) increased with increasing load magnitude. The increase in TI was greater with facemask loads than with loads presented after tracheostomy for equivalent changes in inspired volume. The volume-related prolongation of TI after tracheostomy was abolished after cervical bilateral vagotomy. The results demonstrate that the volume-timing reflex in neonatal lambs after tracheostomy is mediated by vagal afferents. However, in the intact lamb, there is also a significant contribution to this reflex by upper airway afferents.

Laryngeal and diaphragmatic muscle activities and airflow patterns after birth in premature lambs.

The nature and control of early neonatal respiratory patterns were determined in 10 premature, asphyxiated lambs. Severe retardation of early expiratory airflow (braking) characterized an initial pattern (A), but was absent in a final one (B). During a transition pattern (pattern T), pattern A and B airflow types occurred. Close temporal relationships between the airflow patterns and posterior cricoarytenoid (PCA), thyroarytenoid (TA), and diaphragm (D) integrated muscle activities were demonstrated quantitatively. Specifically, in pattern A, the duration of braked expiratory airflow was related to the durations of TA burst activity and the absence of PCA burst activity (r2 = 0.99). In pattern A, pH, but not arterial PCO2 or arterial PO2, differed from that in patterns T and B [7.01 +/- 0.14 (A), 7.11 +/- 0.12 (T), 7.19 +/- 0.08 (B) (P < 0.03)]. Within-breath airflow and respiratory muscle activity relationships and differences in neural and mechanical respiratory timing intervals between patterns suggested that neural feedback was important in the control of central pattern generation. Thus activities of PCA, TA, and D shape the early neonatal airflow patterns and are influenced mainly by neuromechanical, and not chemical, feedback.

Laryngeal and pump muscle activities during CO2 breathing in neonates.

Term human newborns were challenged with a 2-3% CO2 gas mixture during quiet sleep. A common ventilatory response, consisting of increased tidal volume with no change in respiratory frequency or timing, was observed in all eight subjects. Minute ventilation and mean inspiratory and expiratory flow rates were elevated in all eight subjects [38 +/- 8 (SE), 38 +/- 22, and 39 +/- 9%, respectively]. Diaphragm, intercostal, and posterior cricoarytenoid (PCA) muscle activities during inspiration were increased in four of eight, six of eight, and seven of eight subjects, respectively Changes in intercostal and PCA muscle activities correlated with changes in inspiratory flow rates (r = 0.77 and 0.66, respectively). Diaphragmatic braking of expiratory airflow varied between subjects during room air breathing and did not change in six subjects with CO2 breathing. The remaining two subjects increased postinspiratory inspiratory diaphragmatic activity. Baseline expiratory PCA activity was augmented with CO2 breathing in six of eight subjects and correlated with increases in mean expiratory airflow (r = 0.76). The newborn infant is capable of using a variety of breathing strategies to augment tidal volume and minute ventilation, and control of the upper airway appears to be critical in modulating airflow during CO2 breathing.

Local cerebral glucose utilization in normoxemic and hypoxemic newborn lambs.

To determine if hypoxemia altered local cerebral glucose utilization (LCGU) in newborn lambs, and where these alterations occurred, we measured LCGU using the 2-[14C]deoxyglucose [( 14C]DG) autoradiographic technique in lambs made hypoxemic by gradual reduction in inspired oxygen concentration. In 5 normoxemic control lambs, aged 3 days. LCGU of the cerebral cortex and white matter was higher than published values of LCGU in similar structures in near term normal fetuses and 2-4 times higher than reported values in normoxemic puppies. LCGU was highest in vestibular nuclei and auditory structures, followed by cerebellar nuclei, cerebral subcortical structures, and white matter. In 6 hypoxemic newborn lambs (paO2 14-18 torr) consistent increases in LCGU were noted only in the corona radiata compared to the values obtained in the normoxemic control lambs (36.5 +/- 8.1 vs. 23.9 +/- 1.7 mumol/100 per min, mean +/- S.D., P less than 0.02). This increase in LCGU in white matter was clearly noted in autoradiographs in which thin dark central regions within white matter often reached high into the gyri. In the hypoxic group. LCGU of the corona radiata superseded the value in many gray matter structures. In addition, patchy increases of [14C]DG utilization were present in the cerebral cortex of two hypoxemic lambs. Acute hypoxemia increases glucose utilization of the corona radiata to values equivalent to many gray matter structures, and leads to heterogeneous glucose metabolism in the cerebral cortex, but does not alter LCGU in other gray matter structures of newborn sheep.

Local cerebral blood flow is increased in rapid-eye-movement sleep in fetal sheep.

Behavioral state-induced changes in fetal cerebral blood flow were continuously monitored with a simple thermal dilution method. Thermojunctions were heated 1.5 degrees C above reference thermojunctions implanted contralaterally in various cerebral cortical and subcortical structures of four near-term fetal sheep. Temperature difference in rapid-eye-movement sleep was lower than in non-rapid-eye-movement sleep (p = 0.014), reflecting convective heat loss from increased blood flow. Temperature difference also varied significantly with the locus of placement in the brain (p = 0.003), reflecting, in part, regional differences in cerebral blood flow. The thermocouple method gives qualitative, continuous information on local cerebral blood flow that could be useful in monitoring the vascular response to changing functional activity during prenatal brain development.

Maturational and anesthetic effects on apneic thresholds in lambs.

Periods of apnea are relatively common in newborns but rare in older infants. Postnatal changes in the response of the central neural respiratory circuits to afferent inputs may have a role in the age-related incidence of apnea. Therefore we determined the central neural apneic threshold to CO2 and superior laryngeal nerve (SLN) stimulation in halothane-anesthetized newborn (4- to 7-day-old) and older (45- to 56-day-old) lambs. The animals were vagotomized, paralyzed, and mechanically ventilated with hyperoxic gas. Phrenic nerve activity served as a monitor of central respiratory output. The CO2 and SLN apneic thresholds were defined as the arterial PCO2 when phrenic activity began after hyperventilation, and the quantity of current applied to the SLN that abolished phrenic activity, respectively. At equivalent concentrations of halothane, newborn lambs had higher CO2 apneic thresholds (P less than 0.05) and lower SLN apneic thresholds (P less than 0.05) than did older lambs. Increasing concentrations of halothane decreased (P less than 0.05) the SLN apneic threshold and increased (P less than 0.05) the CO2 apneic threshold. Equal incremental changes in halothane concentration induced similar changes in the apneic thresholds of both ages of lambs. The data suggest that with maturation, the central neural respiratory circuits become more responsive to CO2 and less responsive to SLN afferents. Halothane alters central neural responsiveness to these inputs in both ages similarly.

Effect of high-intensity sound on local cerebral glucose utilization in fetal sheep.

The effects of external noise on fetal sheep cerebral glucose utilization were determined with the [14C]deoxyglucose method. Seventeen animals were prepared at 130 days gestation with catheters and electrodes for assessing fetal behavioral state. Five to 7 days later, 7 animals were studied under normal laboratory sound conditions (65-70 dB), 5 animals were exposed to 105-120 dB broadband noise levels produced by two earphones applied to the abdomen of the ewe, and 5 fetuses were stimulated with an electronic artificial larynx (EAL), positioned on the abdomen directly over the fetal head. There were no significant differences between local cerebral glucose utilization in controls and earphone ewes, and no obvious alteration in behavioral states. However, there were marked, significant differences in glucose utilization along the central auditory pathway during EAL stimulation. These autoradiographs revealed isofrequency-like bands in medial geniculate body and irregular darkening of cortex of the temporal lobe. Total time spent in clearly defined high and low voltage electrocortical activity did not change during EAL stimulation.