A novel in-line high frequency interrupter for use with bubble CPAP: A feasibility study in a premature lamb model.

BACKGROUND: Recent in vitro testing of high frequency (HF) oscillation applied to bubble continuous positive airway pressure (BCPAP) using a novel flow interrupter device (HFI) demonstrated significantly improved CO2 washout while not altering delivered mean airway pressure (MAP) in a premature infant lung model. This study's aim was to evaluate the safety and efficacy of the HFI paired with BCPAP in an animal model of prematurity prior to clinical testing. DESIGN/METHODS: Twelve fetal lambs, 131-135 days gestation, weight 3.51±0.42 kg, were delivered by Cesarean section. The lambs were supported by mechanical ventilation and weaned to spontaneous breathing with BCPAP at 6 cmH2O. A combined CO2/airflow sensor measured end-tidal (EtCO2) and tidal volume (VT). Blood gases, heart rate (HR), arterial pressure (Part), minute ventilation (MV), MAP, ventilatory efficiency index (VEI), thoracoabdominal phase angle and labored breathing index (LBI) were recorded over a 10-minute baseline period followed by four randomized 10-minute intervals with HFI set to either 8, 10, 12 or 15 Hz. RESULTS: EtCO2 decreased from baseline by 11.1±2.2SE%, 16.6±4.3SE%, 13.5±4.9SE%, and 19.5±4.5SE% at 8, 10, 12, and 15 Hz respectively (p < 0.001). Blood gases, SpO2, HR, Part, MAP, VT, MV, esophageal pressure, phase angle, and LBI underwent no significant change with HF. Respiratory rate decreased, and VEI increased, by 14.9±4.5SD% (p = 0.037) and 83±22SD% (p < 0.011) respectively, averaged over all frequencies. CONCLUSIONS: We demonstrated the safety and efficacy of a novel BCPAP flow interrupter device. HF applied to the respiratory system resulted in significantly improved CO2 clearance and ventilation efficiency with no deleterious physiological effects in a pre-term lamb model.

Caffeine decreases intermittent hypoxia in preterm infants nearing term-equivalent age.

OBJECTIVE: To determine whether intermittent hypoxia (IH) persisting after 36 weeks postmenstrual age (PMA) can be attenuated using caffeine doses sufficient to maintain caffeine concentrations >20 µg ml-1. STUDY DESIGN: Twenty-seven infants born <32 weeks were started on caffeine citrate at 10 mg kg-1 day-1 when clinical caffeine was discontinued. At 36 weeks PMA, the dose was increased to 14 or 20 mg kg-1 day-1 divided twice a day (BID) to compensate for progressively increasing caffeine metabolism. Caffeine concentrations were measured weekly. The extent of IH derived from continuous pulse oximetry was compared to data from 53 control infants. RESULT: The mean (s.d.) gestational age of enrolled infants was 27.9±2 weeks. Median caffeine levels were >20 µg ml-1 on study caffeine doses. IH was significantly attenuated through 38 weeks PMA compared with the control group. CONCLUSION: Caffeine doses of 14 to 20 mg kg-1 day-1 were sufficient to maintain caffeine concentrations >20 µg ml-1 and reduce IH in preterm infants at 36 to 38 weeks PMA.

Neonatal early-onset sepsis evaluations among well-appearing infants: projected impact of changes in CDC GBS guidelines.

OBJECTIVE: To determine (a) the proportion of asymptomatic infants born at ≥35 weeks gestation evaluated for early-onset sepsis (EOS) and exposed to postnatal antibiotics; (b) reasons for and outcomes of the evaluations, and (c) anticipated changes when applying the Centers for Disease Control and Prevention (CDC) 2010 guidelines to this study population. STUDY DESIGN: Retrospective cohort study of infants born at ≥35 weeks gestation in 2008-2009 in a large maternity center. RESULT: Out of the 7226 infants that met the study criteria: 1062 (14.7%) were evaluated for EOS and half of those evaluated, received empiric antibiotics. 70.4% of evaluations were performed owing to maternal intrapartum fever, but 23% were prompted by inadequate Group B Streptococcus (GBS) prophylaxis alone. Three cases of blood culture-proven infection were identified. CONCLUSION: Improved approaches are needed to identify asymptomatic infants who are at risk for EOS to decrease unnecessary evaluations and antibiotic exposure. Transition to the 2010 CDC GBS guidelines may eliminate a quarter of EOS evaluations among these infants.

Pilot trial of late booster doses of surfactant for ventilated premature infants.

OBJECTIVE: Many premature infants at risk for bronchopulmonary dysplasia experience episodes of surfactant dysfunction with reduced surfactant protein B (SP-B). In this study, we investigated the safety and responses to booster doses of surfactant. STUDY DESIGN: A total of 87 infants, 500 to 1250 g birth weight, who were ventilated at 7 to 10 days received 2 or 3 doses of Infasurf (Calfactant, Forest Pharmaceuticals, St Louis, MO, USA) within a 1-week period. RESULT: For 184 doses, occurrence rates of transient bradycardia (13) and plugged endotracheal tube (5) were low, and no other adverse effects were noted. Treatment transiently improved the respiratory severity score (FiO(2) × mean airway pressure), SP-B content (+75%) and surface properties of isolated surfactant. Levels of eight proinflammatory cytokines in tracheal aspirate were interrelated and unchanged from baseline after surfactant treatment. CONCLUSION: Booster doses of surfactant for premature infants with lung disease are safe and transiently improve respiratory status as well as composition and function of endogenous surfactant.

The effect of inhaled nitric oxide on pulmonary function in preterm infants.

OBJECTIVE: Bronchopulmonary dysplasia (BPD) in preterm infants is associated with impaired alveolar growth, inflammation and airway hyperreactivity. In animal models of BPD, inhaled nitric oxide (NO) improves alveolar growth and inhibits airway smooth muscle proliferation. This study was designed to assess the effect of inhaled NO on resistance and compliance in ventilated preterm infants with evolving BPD. STUDY DESIGN: Expiratory resistance and compliance of the respiratory system were measured in 71 ventilated preterm infants, < or = 32 weeks gestation, randomized to NO (n=34) versus placebo (n=37) for > or = 24 days at 7 to 21 days of life. RESULT: At baseline expiratory resistance (231+/-71 versus 215+/-76 cm H(2)O l(-1) s(-1)) and compliance (0.49+/-0.14 versus 0.53+/-0.13 ml cm H(2)O(-1) kg(-1)) were comparable between placebo and NO groups, respectively. There was no effect of NO on expiratory resistance or compliance at 1 h, 1 week or 2 weeks of study gas administration. CONCLUSION: NO had no short- or medium-term effect on expiratory resistance or compliance in ventilated preterm infants.

Unstudied infants: outcomes of moderately premature infants in the neonatal intensive care unit.

BACKGROUND: Newborns of 30-34 weeks gestation comprise 3.9% of all live births in the United States and 32% of all premature infants. They have been studied much less than very low birthweight infants. OBJECTIVE: To measure in-hospital outcomes and readmission within three months of discharge of moderately premature infants. DESIGN: Prospective cohort study including retrospective chart review and telephone interviews after discharge. SETTING: Ten birth hospitals in California and Massachusetts. PATIENTS: Surviving moderately premature infants born between October 2001 and February 2003. MAIN OUTCOME MEASURES: (a) Occurrence of assisted ventilation during the hospital stay after birth; (b) adverse in-hospital outcomes-for example, necrotising enterocolitis; (c) readmission within three months of discharge. RESULTS: With the use of prospective cluster sampling, 850 eligible infants and their families were identified, randomly selected, and enrolled. A total of 677 families completed a telephone interview three months after hospital discharge. During the birth stay, these babies experienced substantial morbidity: 45.7% experienced assisted ventilation, and 3.2% still required supplemental oxygen at 36 weeks. Readmission within three months occurred in 11.2% of the cohort and was higher among male infants and those with chronic lung disease. CONCLUSIONS: Moderately premature infants experience significant morbidity, as evidenced by high rates of assisted ventilation, use of oxygen at 36 weeks, and readmission. Such morbidity deserves more research.

No increase in rates of early-onset neonatal sepsis by non-group B Streptococcus or ampicillin-resistant organisms.

OBJECTIVE: We assessed the impact of a risk-based approach to group B Streptococcus (GBS) prophylaxis on the rates of early-onset neonatal sepsis (EONS). STUDY DESIGN: A retrospective cohort study of neonates born at a tertiary-care hospital from 1990 to 1996 was performed. Cases of EONS were identified among neonates born in a period without GBS prophylaxis (1990-1992) and compared with those born in a period with GBS prophylaxis (1993-1996). The antibiotic susceptibility data on each organism isolated in the blood culture were obtained. RESULTS: In the period without prophylaxis, 99 cases of EONS were identified among 25,934 neonates for a rate of 3.8 per 1000 births. In the period with prophylaxis, 90 cases of EONS occurred among 34,262 neonates for a rate of 2.6 per 1000. The rate of GBS-EONS significantly decreased between the 2 periods (from 1.9 to 1.1, P =.01). There was a trend toward a decrease in the rate of EONS caused by non-GBS gram-positive organisms (from 1.2 to 0.7, P =.06). There was no significant increase in the rate of EONS caused by gram-negative or ampicillin-resistant organisms. CONCLUSIONS: A risk-based approach to GBS prophylaxis reduced the incidence of GBS-EONS at a tertiary-care hospital. This decrease was not accompanied by an increase in the incidence of EONS by non-GBS or ampicillin-resistant organisms.

Inter-neonatal intensive care unit variation in discharge timing: influence of apnea and feeding management.

BACKGROUND: Premature infants need to attain both medical stability and maturational milestones (specifically, independent thermoregulation, resolution of apnea of prematurity, and the ability to feed by mouth) before safe discharge to home. Current practice also requires premature infants to be observed in hospital before discharge for several days (margin of safety) after physiologic maturity is recognized. OBJECTIVE: To compare postmenstrual age (PMA) at discharge in a homogeneous population of premature infants cared for in different neonatal intensive care units (NICUs) and to assess the impact on hospital stay of the recognition and recording of physiologic maturity and the required margin of safety. METHODS: We studied premature infants delivered at 30 to 34 6/7 weeks gestational age (GA), free of significant medical or surgical complications. Medical records of 30 eligible infants consecutively discharged from the hospital before July 1997 from each of 15 NICUs in Massachusetts (9 level 2 and 6 level 3) were reviewed. RESULTS: A total of 435 infants were included in the study sample. Mean (+/- standard deviation) GA and birth weight of the study population were 33.2 +/- 1.2 weeks and 2024 +/- 389 g, respectively. Infants were discharged at a similar PMA regardless of GA at birth. Considerable variation in the PMA at discharge between hospital sites was observed (range, 35.2 +/- 0.5 weeks to 36.5 +/- 1.2 weeks). Despite the homogeneous study population, hospitals in which infants had the latest PMA at discharge also recorded mature cardiorespiratory and feeding behavior at an older age. Longer duration of pulse oximetry use was associated with later resolution of apnea. Differences in the duration of the margin of safety between sites did not contribute to variation in hospital stay. CONCLUSION: NICUs vary widely in length of hospital stay for healthy premature infants. We speculate that this variation results in part from differences in monitoring for and documentation of apnea of prematurity and feeding behavior.

Intrapartum fever and unexplained seizures in term infants.

OBJECTIVE: Early-onset neonatal seizures are a strong predictor of later morbidity and mortality in term infants. Although an association of noninfectious intrapartum fever with neonatal seizures in term infants has been reported, it was based on only a small number of neonates with seizures. We therefore conducted a case control study to investigate this association further. METHODS: All term infants with neonatal seizures born at Brigham and Women's Hospital between 1989 and 1996 were identified. For this study, cases consisted of all term neonates with a confirmed diagnosis of seizure born after a trial of labor for whom no proximal cause of seizure could be identified. Infants with sepsis or meningitis were excluded. Four controls matched by parity and date of birth were identified for each case. The rate of intrapartum maternal temperature >100.4 degrees F was compared for case infants and controls. Potential confounding was controlled in logistic regression analysis. RESULTS: Cases comprised 38 term infants with unexplained seizures after a trial of labor. We identified 152 controls. Infants with seizures were more likely to be born to mothers who were febrile during labor (31.6% vs 9.2%). In almost all cases, the fever developed during labor (94.7% cases, 97.4% controls). At admission, mothers of infants with seizures were not significantly more likely to have factors associated with concern about infection such as a white blood cell count >15 000/mm(3) (28. 9% vs 19.1%) and premature rupture of the membranes (15.8% vs 17.8%). In a logistic regression analysis controlling for confounding factors, intrapartum fever was associated with a 3.4-fold increase in the risk of unexplained neonatal seizures (odds ratio = 3.4, 95% confidence interval = 1.03-10.9). CONCLUSION: Our data indicate that intrapartum fever, even when unlikely to be caused by infection, is associated with a fourfold increase in the risk of unexplained, early-onset seizures in term infants.

Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants.

OBJECTIVES: Premature infants experience brain injury, ie, germinal matrix-intraventricular hemorrhage (GMH-IVH) and periventricular leukomalacia (PVL), in considerable part because of disturbances in cerebral blood flow (CBF). Because such infants are susceptible to major fluctuations in mean arterial blood pressure (MAP), impaired cerebrovascular autoregulation would increase the likelihood for the changes in CBF that could result in GMH-IVH and PVL. The objectives of this study were to determine whether a state of impaired cerebrovascular autoregulation could be identified reliably and conveniently at the bedside, the frequency of any such impairment, and the relation of the impairment to the subsequent occurrence of severe GMH-IVH and PVL. PATIENTS AND METHODS: To monitor the cerebral circulation continuously and noninvasively, we used near-infrared spectroscopy (NIRS) to determine quantitative changes in cerebral concentrations of oxygenated hemoglobin (HbO(2)) and deoxygenated hemoglobin (Hb) from the first hours of life. Our previous experimental study showed a strong correlation between a measure of cerebral intravascular oxygenation (HbD), ie, HbD = HbO(2) - Hb, determined by NIRS, and volemic CBF, determined by radioactive microspheres. We studied 32 very low birth weight premature infants (gestational age: 23-31 weeks; birth weight: 605-1870 g) requiring mechanical ventilation, supplemental oxygen, and invasive blood pressure monitoring by NIRS from 1 to 3 days of age. MAP measured by arterial catheter pressure transducer and arterial oxygen saturation measured by pulse oximetry were recorded simultaneously. The relationship of MAP to HbD was quantitated by coherence analysis. RESULTS: Concordant changes (coherence scores >. 5) in HbD and MAP, consistent with impaired cerebrovascular autoregulation, were observed in 17 of the 32 infants (53%). Eight of the 17 infants (47%) developed severe GMH-IVH or PVL or both. Of the 15 infants with apparently intact autoregulation, ie, coherence scores <.5, only 2 (13%) developed severe ultrasonographic lesions. Thus, for the entire study population of 32 infants, 8 of the 10 with severe lesions exhibited coherence scores >.5. CONCLUSIONS: We conclude that NIRS can be used in a noninvasive manner at the bedside to identify premature infants with impaired cerebrovascular autoregulation, that this impairment is relatively common in such infants, and that the presence of this impairment is associated with a high likelihood of occurrence of severe GMH-IVH/PVL.

Enhancement of neonatal innate defense: effects of adding an N-terminal recombinant fragment of bactericidal/permeability-increasing protein on growth and tumor necrosis factor-inducing activity of gram-negative bacteria tested in neonatal cord blood ex vivo.

Innate defense against microbial infection requires the action of neutrophils, which have cytoplasmic granules replete with antibiotic proteins and peptides. Bactericidal/permeability-increasing protein (BPI) is found in the primary granules of adult neutrophils, has a high affinity for lipopolysaccharides (or "endotoxins"), and exerts selective cytotoxic, antiendotoxic, and opsonic activity against gram-negative bacteria. We have previously reported that neutrophils derived from newborn cord blood are deficient in BPI (O. Levy et al., Pediatrics 104:1327-1333, 1999). The relative deficiency in BPI of newborns raised the possibility that supplementing the levels of BPI in plasma might enhance newborn antibacterial defense. Here we determined the effects of addition of recombinant 21-kDa N-terminal BPI fragment (rBPI(21)) on the growth and tumor necrosis factor (TNF)-inducing activity of representative gram-negative clinical isolates. Bacteria were tested in citrated newborn cord blood or adult peripheral blood. Bacterial viability was assessed by plating assay, and TNF-alpha release was measured by enzyme-linked immunosorbent assay. Whereas adult blood limited the growth of all isolates except Klebsiella pneumoniae, cord blood also allowed logarithmic growth of Escherichia coli K1/r and Citrobacter koseri. Bacteria varied in their susceptibility to rBPI(21)'s bactericidal action: E. coli K1/r was relatively susceptible (50% inhibitory concentration [IC(50)], approximately 10 nM), C. koseri was intermediate (IC(50), approximately 1,000 nM), Klebsiella pneumoniae was resistant (IC(50), approximately 10,000 nM), and Enterobacter cloacae and Serratia marcescens were highly resistant (IC(50), >10,000 nM). All isolates were potent inducers of TNF-alpha activity in both adult and newborn cord blood. In contrast to its variable antibacterial activity, rBPI(21) consistently inhibited the TNF-inducing activity of all strains tested (IC(50), 1 to 1,000 nM). The antibacterial effects of rBPI(21) were additive with those of a combination of conventional antibiotics typically used to treat bacteremic newborns (ampicillin and gentamicin). Whereas ampicillin and gentamicin demonstrated little inhibition of bacterially induced TNF release, addition of rBPI(21) either alone or together with ampicillin and gentamicin profoundly inhibited release of this cytokine. Thus, supplementing newborn cord blood with rBPI(21) potently inhibited the TNF-inducing activity of a variety of gram-negative bacterial clinical pathogens and, in some cases, enhanced bactericidal activity. These results suggest that administration of rBPI(21) may be of clinical benefit to neonates suffering from gram-negative bacterial infection and/or endotoxemia.

Impaired innate immunity in the newborn: newborn neutrophils are deficient in bactericidal/permeability-increasing protein.

OBJECTIVE: The mechanisms by which newborns are at increased risk for invasive bacterial infections have been incompletely defined. A central element of innate immunity to bacterial infection is the neutrophil-a cell that contains cytoplasmic granules replete with antibiotic proteins and peptides. The activity of adult neutrophils against gram-negative bacteria is believed to depend to a significant degree on the presence in neutrophil primary (azurophilic) granules of the 55-kDa bactericidal/permeability-increasing protein (BPI), which binds with high affinity to bacterial lipopolysaccharides and kills gram-negative bacteria. In light of the importance of BPI to antibacterial host defense and to investigate possible factors underlying the risk of neonatal bacterial infections, we determined the relative content of BPI in the neutrophils of adults and newborns. DESIGN: The cellular content of BPI was determined by Western blotting of neutrophils derived from full-term newborn cord blood (n = 21; mean gestational age: 38.6 weeks) and from adult peripheral blood (n = 22; mean age: 29 years). Extracellular levels of BPI in adult and newborn plasma were assessed by enzyme-linked immunosorbent assay. Neutrophil content of other azurophil granule markers also was assessed: myeloperoxidase by Western blotting and defensin peptides by acid-urea polyacrylamide gel electrophoresis and Coomassie staining. Acid extracts of newborn and adult neutrophils were analyzed for antibacterial activity against serum-resistant encapsulated isolate Escherichia coli K1/r. RESULTS: The neutrophils of newborns contain at least threefold to fourfold less BPI per cell than adult neutrophils (67 +/- 13 ng per 10(6) cells vs 234 +/- 27 ng per 10(6) cells). The relative BPI-deficiency of newborn neutrophils apparently was not attributable to perinatal stress-related degranulation of intracellular BPI stores because: 1) newborn and adult neutrophils contained nearly identical amounts of 2 microbicidal constituents derived from the same primary (azurophil) granule compartment as BPI (the enzyme myeloperoxidase as well as defensin peptides), and 2) levels of extracellular BPI in newborn plasma, measured by enzyme-linked immunosorbent assay, represent only approximately 2% of cellular BPI content. As predicted by their lower BPI content, newborn neutrophil acid extracts demonstrated significantly lower antibacterial activity against E coli K1/r than did adult neutrophil acid extracts. CONCLUSION: These data suggest that the neutrophils of newborns are selectively deficient in BPI, a central effector of antibacterial activity against gram-negative bacteria. BPI deficiency correlates with decreased antibacterial activity of newborn neutrophil extracts against serum-resistant E coli and could contribute to the increased incidence of gram-negative sepsis among newborns relative to healthy adults.neonatal sepsis, gram-negative bacteria, endotoxin, neutrophil, polymorphonuclear leukocyte, innate immunity, bactericidal/permeability-increasing protein, defensin, myeloperoxidase.

Apnea frequently persists beyond term gestation in infants delivered at 24 to 28 weeks.

BACKGROUND: Apnea of prematurity remains among the most commonly diagnosed conditions in the Newborn Intensive Care Unit and may prolong hospital stays in some infants. Because survival of extremely premature infants has improved markedly, the natural history of apnea in this population needs to be reassessed. OBJECTIVE: To document the natural history of recurrent apnea and/or bradycardia events in infants delivered at 24 to 28 weeks' gestation. METHODS: Medical records of all infants delivered at 24 to 28 weeks' gestation admitted to the Brigham and Women's Hospital Newborn Intensive Care Unit between January 1989 and March 1994 were reviewed to document the clinical course of apnea of prematurity. Subjects were included in the study sample if they were discharged home from the Brigham and Women's Hospital or after transfer to an affiliated hospital. Recordings of apnea and/or bradycardia events were based on nursing observations of monitor alarms and assessment of the infant's condition. RESULTS: Of 457 eligible infants, 226 were included in the study sample and stratified by gestational age at birth assigned by the attending neonatologist. The time to resolution of recurrent apnea/bradycardia events was longer with lower gestational age at birth. Apnea/bradycardia events were frequently observed beyond 36 weeks' postconceptional age in all gestational age groups. The incidence of apnea persisting beyond 38 weeks postconceptional age was significantly higher in the 24- to 27-week infants combined compared with the 28-week infants. CONCLUSIONS: Apnea of prematurity frequently persists beyond term gestation in infants delivered at 24 to 28 weeks' gestational age. These persistent apnea and/or bradycardia events may contribute to prolonged hospitalization. Programs to promote earlier discharge of premature infants should take into account the variability in resolution of apnea and specifically address management of persistent apnea.

Perinatally transmitted neonatal bacterial infections.

Perinatally acquired bacterial infections remain a major contributor to morbidity and mortality in newborn infants, especially those delivered prematurely. Our understanding of the epidemiology, bacteriology, and pathogenesis of these infections has allowed development of better treatment and prevention strategies. Just as the bacteriology of perinatally acquired bacterial infections has changed over the past few decades, however, it is likely to continue to evolve. Whether widespread use of intrapartum antibiotics will alter the bacteriology and antibiotic resistance patterns seen in early-onset neonatal bacterial infections requires ongoing surveillance.

Hypercapnia increases expiratory braking in preterm infants.

In contrast to adults, newborn infants breathe from an elevated end-expiratory lung volume, determined by the interaction of airflow retardation (braking) by the diaphragm and larynx, and expiratory duration. To determine the effect of hypercapnia on this strategy, we examined changes in respiratory muscle activity and the ventilatory response to CO2 breathing in eight premature infants 33-34 wk gestational age in the first 3 postnatal days. We recorded tidal volume, airflow, and electromyograms (EMG) of the laryngeal abductor [posterior cricoarytenoid (PCA)], which abducts the vocal cords, and diaphragm during behaviorally determined quiet sleep in room air and during steady-state inhalation of 2% CO2 in air. As expected, tidal volume increased (P < 0.0005) without a change in inspiratory duration with hypercapnia. Unexpectedly, in all subjects, expiratory duration was longer during CO2 inhalation (P < 0.001), accompanied by marked changes in expiratory flow patterns consistent with increased expiratory braking. Diaphragm post-inspiratory EMG activity increased with hypercapnia (P < 0.005) with no change in baseline diaphragm or PCA EMG activity. Peak inspiratory EMG activity of the diaphragm and PCA increased with CO2 (10 and 37%, respectively; P < 0.05). We conclude that the mechanisms used to elevate end-expiratory lung volume are enhanced during hypercapnia in premature infants. This breathing strategy may be important in maintaining gas exchange in infants with lung disease.

Developmental changes in sequential activation of laryngeal abductor muscle and diaphragm in infants.

In animals and human adults, upper airway muscle activity usually precedes inspiratory diaphragm activity. We examined the interaction of the posterior cricoarytenoid muscle (PCA), which abducts the larynx, and the diaphragm (DIA) in the control of airflow in newborn infants to assess the effect of maturation on respiratory muscle sequence. We recorded tidal volume, airflow, and DIA and PCA electromyograms (EMG) in 12 full-term, 14 premature, and 10 premature infants with apnea treated with aminophylline. In most breaths, onset of PCA EMG activity preceded onset of DIA EMG activity (lead breaths). In all subjects, we also observed breaths (range 6-61%) in which PCA EMG onset followed DIA EMG onset (lag breaths). DIA neural inspiratory duration and the neuromechanical delay between DIA EMG onset and inspiratory flow were longer in lag than in lead breaths (P < 0.05 and P < 0.01, respectively). The frequency of lag breaths was greater in the premature infants [33 +/- 4% (SE)] than in either the full-term infants (21 +/- 3%, P < 0.03) or the premature infants with apnea treated with aminophylline (16 +/- 2%, P < 0.01). We conclude that the expected sequence of onset of PCA and DIA EMG activity is frequently disrupted in newborn infants. Both maturation and respiratory stimulation with aminophylline improve the coordination of the PCA and DIA.