Bi-level CPAP does not improve gas exchange when compared with conventional CPAP for the treatment of neonates recovering from respiratory distress syndrome.

AIM: We hypothesised that short-term application of bi-level nasal continuous positive airway pressure CPAP (SiPAP) compared with conventional nasal CPAP (nCPAP) at the same mean airway pressure in infants with persistent oxygen need recovering from respiratory distress syndrome would improve CO2 removal with no change in oxygen requirement. DESIGN: Non-blinded, randomised, observational four-period crossover study. SETTING/POPULATION: Level III NICU; low-birthweight infants requiring CPAP and oxygen while recovering from respiratory distress syndrome. METHODS: Infants requiring nasal CPAP for >24 h prior to study enrolment, and fraction of inspired oxygen requirement (FiO2) of 0.25-0.5, were randomised to either nCPAP or SiPAP. A crossover design with four 1 h treatment periods was used such that each infant received both treatments twice. Oxygen saturations (SaO2), transcutaneous CO2 (tcCO2) and vital signs were monitored continuously. Polysomnographic recordings were analysed for apnoea, bradycardia and oxygen desaturation. RESULTS: Twenty low-birthweight infants receiving 0.3±0.04% supplemental oxygen on CPAP of 6 cm H2O were studied at an average of 33 days of age (±23 days, SD). There were no differences in tcCO2 or other physiological parameters except mean blood pressure, which was lower during nCPAP (52.3±8.3 vs 54.4±9.1 mm Hg; ±SD; p<0.01). No differences in short or prolonged apnoea, bradycardia or significant desaturation events were observed. CONCLUSIONS: At similar mean airway pressures, SiPAP does not improve CO2 removal, oxygenation or other studied physiological parameters with the exception of mean blood pressure, which was not clinically significant. TRIAL REGISTRATION NUMBER: NCT01053455.

Aerosolized KL4 surfactant improves short-term survival and gas exchange in spontaneously breathing newborn pigs with hydrochloric acid-induced acute lung injury.

BACKGROUND: Surfactant therapy may be beneficial in acute lung injury (ALI). In spontaneously breathing newborn pigs with ALI supported with continuous positive airway pressure (CPAP), we evaluated the hypothesis that aerosolized KL4 surfactant (AERO KL4 S) would provide a similar therapeutic effect as intratracheal KL4 surfactant (ETT KL4 S) when compared to controls. METHODS: We randomized pigs with HCl-induced ALI to: (1) 175 mg/kg KL4 surfactant via endotracheal tube (ETT); (2) AERO KL4 S (22.5 mg/min phospholipid) for 60 min via continuous positive airway pressure (CPAP); or (3) sham procedure on CPAP. We obtained physiologic data and arterial blood gases throughout the 3-hr study. At study end, lungs were excised for analysis of interleukin-8 (IL-8), myeloperoxidase (MPO) levels and histomorphometric data. RESULTS: Pigs treated with ETT KL4 S and AERO KL4 S had improved survival and sustained pO2 compared to controls. The AERO KL4 S group had higher pH compared to controls. Lung IL-8 levels were lower in the AERO KL4 S group compared to controls. Histomorphometric analysis showed less hemorrhage in the ETT and AERO KL4 S groups compared to controls. The AERO KL4 S group had more open lung units per fixed-field than the ETT KL4 S or controls. CONCLUSIONS: AERO KL4 S produced similar improvements in survival, physiology, inflammatory markers, and morphology as ETT KL4 S in an ALI model.

Improved gas exchange and survival after KL-4 surfactant in newborn pigs with severe acute lung injury.

OBJECTIVE: To determine the effectiveness of artificial surfactant therapy using KL-4 surfactant in newborn pigs with hydrochloric acid (HCl)-induced acute lung injury (ALI). DESIGN: After induction of ALI via intratracheal HCl instillation, pigs were randomized to receive 5.8 ml/kg KL-4 surfactant or no surfactant prior to extubation to bubble CPAP. SETTING: Clinical laboratory. SUBJECTS: Spontaneously breathing newborn pigs (<1 week of age). INTERVENTIONS: Treatment with KL-4 surfactant on bubble CPAP with PEEP of 6 cmH(2)O for 3.5 hr after extubation compared with controls. MEASUREMENTS: Physiologic parameters and arterial blood gases were measured every 15 min. At the conclusion of the study, the lungs were excised for the analysis of histopathology and morphometric data. MAIN RESULTS: Pigs treated with KL-4 surfactant had arterial blood gases with less acidosis (P < 0.001), higher P(a)O(2) levels (P < 0.001), and lower P(a)CO(2) levels (P < 0.001). Pigs treated with KL-4 surfactant had improved survival compared with controls (6/12 KL-4, 2/12 control, P < 0.05). Postmortem morphometric data demonstrated that pigs treated with KL-4 surfactant had larger (P < 0.05) exchange units in the caudal-dorsal lung as compared to relatively atelectatic region in the control animals. CONCLUSIONS: In newborn pigs with severe HCl-induced ALI, treatment with KL-4 surfactant resulted in improved respiratory parameters, less dependent atelectasis, and improved short-term survival.

Laryngeal mask airway for surfactant administration in a newborn animal model.

Premature infants are subjected to adverse effects of intubation to benefit from surfactant. We hypothesized that administration of surfactant through a laryngeal mask airway (LMA) is as effective as administration through an endotracheal tube (ETT) and that time and physiologic changes during instrumentation will be less in the LMA group. This study is a randomized, controlled trial using newborn pigs. Lung injury was induced via surfactant washout. Animals were randomized into groups: 1) LMA placed, no surfactant administered (control; n = 8); 2) surfactant via an LMA (LMA group; n = 8); and 3) surfactant via an ETT (ETT group; n = 8). We demonstrated that partial pressure of oxygen in arterial blood (Pao2) levels of the LMA and ETT groups were not statistically different. Time for successful placement of LMA was 19 ± 1 s versus ETT 123 ± 35 s (mean ± SEM); number of attempts for successful LMA placement was 1.1 (1-2) versus ETT 1.9 (1-7) [mean (range)]. Administration of surfactant via an LMA compared with an ETT resulted in similar improvements in oxygenation. Placement of the device required less time and fewer attempts. These data suggest that further study in human neonates is justified. If proven effective, some infants with respiratory distress may be able to receive surfactant while avoiding intubation.

Observational study of humidified high-flow nasal cannula compared with nasal continuous positive airway pressure.

OBJECTIVES: To conduct an in vitro evaluation of a humidified high-flow nasal cannula (HFNC) system at different flows, cannula sizes, and air leaks and also an in vivo analysis of mean end-expiratory esophageal pressure (EEEP) from nasal continuous positive airway pressure at 6 cm H(2)O (NCPAP+6) versus HFNC. STUDY DESIGN: In the in vitro study, we measured HFNC system pressure and flow, with varying degrees of leak and with and without the use of a pressure-limiting valve. In the in vivo study, we measured EEEP in 15 newborns on NCPAP+6 and then on HFNC at 6 L/minute, with flow decreased by 1 L/minute every 30 minutes. Heart rate, respiratory rate, fraction of inspired oxygen, arterial oxygen saturation, respiratory distress syndrome score, and EEEP were recorded for each intervention. Data analysis was done using repeated-measures analysis of variance and linear regression. RESULTS: In the in vitro study, in the absence of leaks, the pressures were limited by the pressure-limiting valve only at flows > or = 2 L/minute. With leaks of 30% and 50%, delivered pressures were always < 3 cm H(2)O. In the in vivo study, respiratory rate increased from baseline (NCPAP+6) as flow decreased (P < .02). Intrapatient and interpatient coefficients of variation were always high. CONCLUSIONS: A pressure-limiting valve is necessary in a HFNC system. Although mean EEEP levels were similar in NCPAP+6 and HFNC, tachypnea developed as flow diminished. This system apparently cannot predict EEEP, because of interpatient and intrapatient variation.

Gas exchange and lung inflammation using nasal intermittent positive-pressure ventilation versus synchronized intermittent mandatory ventilation in piglets with saline lavage-induced lung injury: an observational study.

OBJECTIVE: Physiologic and pathologic comparison of two modes of assisted ventilation, nasal intermittent positive-pressure ventilation (NIPPV) and synchronized intermittent mandatory ventilation (SIMV), in spontaneously breathing term newborn piglets with saline lavage-induced lung injury. DESIGN: After inducing acute lung injury via repetitive saline lavage, piglets were randomized to NIPPV (n = 12) or SIMV (n = 11) and treated for 6 hrs. SETTING: Clinical laboratory. SUBJECTS: Spontaneously breathing term newborn piglets. INTERVENTIONS: Invasive (SIMV) or noninvasive (NIPPV) assisted ventilation for 6 hrs. MEASUREMENTS: Physiologic parameters and arterial blood gases were continuously monitored. At the conclusion of the study, lung tissue was obtained to analyze for evidence of inflammation, including myeloperoxidase, interleukin-8, and hydrogen peroxide levels, as well as for evidence of pathologic injury. MAIN RESULTS: Piglets treated with NIPPV demonstrated higher arterial blood gas pH (p < .001), lower PaCO2 (p < .05), and a lower set respiratory rate (p < .0001) as compared with the SIMV-treated piglets. The piglets in the SIMV group had higher PaO2/PaO2 ratio than those in the NIPPV group (p = .001). There was significantly more interstitial inflammation (p = .04) in the SIMV-treated piglets compared with the NIPPV-treated piglets. Total respiratory rate, heart rate, blood pressure, oxygen saturation, and biochemical markers of lung inflammation were not different between the groups. CONCLUSION: In surfactant-deficient term newborn piglets, NIPPV offers an effective and noninvasive ventilatory strategy with the potential for less pathologic lung inflammation.

Decreased lung injury after surfactant in piglets treated with continuous positive airway pressure or synchronized intermittent mandatory ventilation.

BACKGROUND: Treatment with surfactant (S) decreases lung injury in paralyzed, mechanically ventilated animals. The use of nasal continuous positive airway pressure (CPAP) as an alternative to mechanical ventilation may further improve acute pulmonary outcomes. OBJECTIVES: To evaluate the effect of surfactant (+S, -S) and synchronized intermittent mandatory ventilation (SIMV) on lung morphology and inflammatory markers in 24 spontaneously breathing piglets treated with CPAP or SIMV after saline lavage-induced lung injury. METHODS: After induction of lung injury, animals were randomized to CPAP-S, CPAP+S or SIMV+S and treated for 4 h. Physiologic parameters were continuously monitored. After treatment, animals were euthanized and lungs fixed. Bronchoalveolar lavage (BAL) samples were collected for neutrophil count and H(2)O(2). RESULTS: No physiologic differences were noted. BAL fluid from CPAP-S animals contained more neutrophils and more neutrophil H(2)O(2) than fluid from the SIMV+S or CPAP+S groups (p < 0.05 or greater). Pathologic injury scores were higher in dependent lung regions from CPAP groups (p < 0.05). Injury pattern scores showed greater dependent alveolar inflammation in all (p < 0.02), with more dependent atelectasis in the CPAP groups (p < 0.01). Morphometrics showed less total open alveolar air space in nondependent regions of the SIMV+S group compared to CPAP groups (p < 0.001). Dependent regions showed less total open alveolar air space compared to nondependent regions in the CPAP groups (p < 0.001). CONCLUSIONS: Animals treated with surfactant prior to CPAP or SIMV had less acute lung injury. SIMV+S animals had less open air space in nondependent regions. This suggests, during early ventilatory support, surfactant administration may modulate pulmonary inflammation. CPAP alone without surfactant may not provide optimal pulmonary protection. The addition of mechanical breaths may alter and add to injury.

Altered pathways for auditory discrimination and recognition memory in preterm infants.

Preterm infants are at increased risk for cognitive disorders, including impairments in recognition memory. This study evaluated the effects of extreme prematurity on the neural pathway for auditory recognition memory using event-related potentials (ERPs), a neurophysiological technique widely used in cognitive neuroscience. ERPs were recorded at term postmenstrual age in 35 preterm infants born at less than 32 weeks' gestation (22 males, 13 females; mean birthweight ([BW] 1154g, SD 374g) with normal brain ultrasounds, compared with 40 healthy, term newborns (1 to 3 days of age; 20 males, 20 females; BW 3672g, SD 420g). Because infants must be able to detect and discriminate sounds before recognizing them, two paradigms were used to assess these functions. The first evaluated the detection and discrimination of speech sounds. The second tested recognition of the mother's voice compared with a stranger's. Results showed significantly different patterns of speech sound discrimination in preterm infants compared with term infants. No evidence of maternal voice recognition was elicited from the preterm infants. No specific patterns of auditory detection or discrimination were associated with patterns of recognition memory, suggesting that the function of multiple neural pathways may have been altered in this group of preterm infants. These results provide a functional corroboration of magnetic resonance imaging studies showing effects of prematurity on early brain development, even among preterm infants with normal cranial ultrasonography.

Iron deficiency alters auditory recognition memory in newborn infants of diabetic mothers.

Infants of diabetic mothers (IDMs) are at risk for perinatal brain iron deficiency that may target the developing hippocampus. The objective of this study was to evaluate hippocampally based recognition memory and infant development in IDMs with suspected brain iron deficiency (BID; cord ferritin 34 microg/L) using event-related potentials (ERPs). ERPs assessed neonatal auditory cortical responses to sounds and auditory recognition memory in response to the mother's voice compared with a stranger's voice. Thirty-two newborn IDMs had cord serum ferritin concentrations and provided neonatal ERP data (n = 23) and/or blinded 1 y developmental assessments (n = 28). Auditory cortical responses to speech and nonspeech sounds were similar in the BID and BIS groups. In the maternal voice recognition paradigm, peak latencies were shorter in the BID group than in the BIS group. Infants in the BIS group displayed a significant negative slow wave for the strangers' voices compared with the mothers' voices, whereas the BID group did not. Higher cord ferritin concentrations were correlated with larger negative slow waves at the right temporal (T4) electrode site. At 1 y of age, motor development was slower in the BID group than in the BIS group. IDMs suspected to have BID demonstrated impaired neonatal auditory recognition memory and lower psychomotor developmental scores at 1 y of age than IDMs with BIS. These impairments map onto areas of the developing brain known to be vulnerable to iron deficiency.

Standardized lung recruitment during high frequency and conventional ventilation: similar pathophysiologic and inflammatory responses in an animal model of respiratory distress syndrome.

OBJECTIVE: To evaluate standardized lung recruitment strategy during both high frequency oscillation (HFO) and volume-targeted conventional ventilation (CV+V) in spontaneously breathing piglets with surfactant washout on pathophysiologic and inflammatory responses. DESIGN: Prospective animal study. SETTING: Research laboratory. SUBJECTS: Twenty-four newborn piglets. INTERVENTIONS: We compared pressure support and synchronized intermittent mandatory ventilation, both with targeted tidal volumes, (PSV+V, SIMV+V) to HFO. Animals underwent saline lavage to produce lung injury, received artificial surfactant and were randomized to one of the three treatment groups (each n=8). After injury and surfactant replacement, lung volumes were recruited in all groups using a standard protocol. Ventilation continued for 6 h. MEASUREMENTS AND MAIN RESULTS: Arterial and central venous pressures, heart rates, blood pressure and arterial blood gases were continuously monitored. At baseline, post lung injury and 6 h we collected serum and bronchoalveolar lavage samples for proinflammatory cytokines: IL 6, IL 8 and TNF-alpha, and performed static pressure-volume (P/V) curves. Lungs were fixed for morphometrics and histopathologic analysis. No physiologic differences were found. Analysis of P/V curves showed higher opening pressures after lung injury in the HFO group compared to the SIMV+V group ( p<0.05); no differences persisted after treatment. We saw no differences in change in proinflammatory cytokine levels. Histopathology and morphometrics were similar. Mean airway pressure (P(aw)) was highest in the HFO group compared to SIMV+V ( p<0.002). CONCLUSIONS: Using a standardized lung recruitment strategy in spontaneously breathing animals, CV+V produced equivalent pathophysiologic outcomes without an increase in proinflammatory cytokines when compared to HFO.