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.

Pulmonary mechanics measurements by respiratory inductive plethysmography and esophageal manometry: Methodology for infants on non-invasive respiratory support.

BACKGROUND: Infants are commonly supported with non-invasive ventilation (NIV) such as nasal CPAP and high flow nasal cannula (HFNC). These modes utilize a nasal/oral interface precluding use of a traditional airway flow sensor, such as a pneumotachometer (PNT), needed for pulmonary mechanics (PM) measurements. Respiratory Inductive Plethysmography (RIP), when properly calibrated, records tidal volume non-invasively from chest wall movements. Our aim was to integrate RIP into an existing neonatal pulmonary function testing system to measure PM in infants on NIV and to compare measurements of dynamic lung compliance (CL) and resistance (RL) using RIP with those obtained using a PNT. DESIGN/METHODS: RIP ribcage (RC) and abdominal (ABD) signals were recorded simultaneously with the flow signal from a PNT; transpulmonary pressure was estimated using an esophageal catheter. Two calibration algorithms were applied to obtain RC and ABD scaling factors. RESULTS: Forty PM measurements were performed on 25 infants (GA 31.5±2.9 weeks; birth weight 1598±510 g; median age 7 days). Correlation coefficients for RIP- vs. PNT-based PM were r2 = 0.987 for CL and r2 = 0.997 for RL. From Bland-Altman analysis, the mean bias (±95% CI) between RIP and PNT methods was -0.004±0.021 ml/cmH2O/kg for CL and 0.7±2.9 cmH2O/(L/sec) for RL. The upper, lower limits of agreement (±95% CI) were 0.128±0.037, -0.135±0.037 ml/cmH2O/kg for CL and 18.6±5.1, -17.2±5.1 cmH2O/(L/sec) for RL. CONCLUSION: Properly calibrated RIP may be a useful tool with sufficient diagnostic accuracy for PM measurements without need for a nasal/oral airflow sensor in infants receiving NIV.

Nanosystems for skin hydration: a comparative study.

The present investigation describes a comparative study for the design of innovative topical formulation for skin hydration. In particular, different colloidal forms based on lipidic components have been produced and characterized. Morphology and dimensional distribution have been investigated by means of electron microscopy and photon correlation spectroscopy. Nanoparticulate systems characterized by different morphology and dimensions depending on production procedures have been obtained, namely cubosomes, nanovesicles, solid lipid nanoparticles and liposomes. Hydration power has been studied by means of a corneometer, measuring the skin electrical capacitance before and after the application of opportunely viscosized nanoparticulate systems. It has been demonstrated that nanovesicle gel displayed a pronounced hydration power with respect to the other nanostructured forms, its hydration effect on skin was 3.5-fold higher, with respect to the untreated area, after 5 min from the application and 1.5-fold higher after 2 h.

Evaluation of bedside pulmonary function in the neonate: From the past to the future.

Pulmonary function testing and monitoring plays an important role in the respiratory management of neonates. A noninvasive and complete bedside evaluation of the respiratory status is especially useful in critically ill neonates to assess disease severity and resolution and the response to pharmacological interventions as well as to guide mechanical respiratory support. Besides traditional tools to assess pulmonary gas exchage such as arterial or transcutaenous blood gas analysis, pulse oximetry, and capnography, additional valuable information about global lung function is provided through measurement of pulmonary mechanics and volumes. This has now been aided by commercially available computerized pulmonary function testing systems, respiratory monitors, and modern ventilators with integrated pulmonary function readouts. In an attempt to apply easy-to-use pulmonary function testing methods which do not interfere with the infant́s airflow, other tools have been developed such as respiratory inductance plethysmography, and more recently, electromagnetic and optoelectronic plethysmography, electrical impedance tomography, and electrical impedance segmentography. These alternative technologies allow not only global, but also regional and dynamic evaluations of lung ventilation. Although these methods have proven their usefulness for research applications, they are not yet broadly used in a routine clinical setting. This review will give a historical and clinical overview of different bedside methods to assess and monitor pulmonary function and evaluate the potential clinical usefulness of such methods with an outlook into future directions in neonatal respiratory diagnostics.

Continuous skeletal muscle paralysis: effect on neonatal pulmonary mechanics.

Pancuronium bromide (Pavulon) is used to induce skeletal muscle paralysis in preterm infants, presumably for effective ventilatory support during acute respiratory failure. Twelve infants with respiratory failure were evaluated for sequential changes in pulmonary mechanics during continuous pancuronium administration (0.1 mg/kg every two to three hours) for more than 48 hours. The study weight of the neonates ranged from 980 to 2,950 g, and the postconceptional age ranged from 27 to 41 weeks. Pulmonary compliance, resistance, and resistive work of breathing were determined, using least mean square analysis technique, daily for three days and after discontinuation of pancuronium (even though there was no clinical improvement in ventilatory management). The dynamic pulmonary compliance decreased from 0.38 +/- 0.05 to 0.30 +/- 0.04 mL/cm H2O/kg (mean +/- SE) (P less than .05) and the total pulmonary resistance increased 51% from 115.6 +/- 21.3 to 174.9 +/- 27.3 cm H2O/L/s (P less than .005) during prolonged skeletal muscle paralysis. Upon discontinuation of pancuronium, the dynamic pulmonary compliance increased 43% to 0.43 +/- 0.4 mL/cm H2O/kg (P less than .05) and the total pulmonary resistance decreased by 41% (P less than .005). These data question the advisability of prolonged skeletal muscle paralysis in neonates and suggest the need for further detailed evaluation of the effects of prolonged paralysis on neonatal pulmonary mechanics.

Evaluation of pulmonary functions during pressure-limited manual ventilation in preterm neonates.

Manual ventilation (MAV) or handbagging is a frequent and often life-saving procedure for neonates; however, few studies allow for an objective evaluation of techniques or possible risks. We compared parameters of ventilation and pulmonary mechanics obtained during routine pressure-limited MAV to those obtained during spontaneous breathing (SPB) in the same infant at approximately the same time. We selected 20 preterm neonates in the recovery phase of respiratory distress syndrome who received periodic MAV and were capable of optimum spontaneous minute ventilation (> 300 mL/kg/min). During MAV compared to SPB we measured higher tidal volume (8.1 +/- 0.5 SE vs. 5.4 +/- 0.4 SE mL/kg, P < 0.001), lower total pulmonary compliance (0.65 +/- 0.05 vs. 1.16 +/- 0.11 SE mL/cmH2O, P < 0.001), end-inspiratory compliance, higher pulmonary resistance (121 +/- 11 vs. 61 +/- 7 SE cmH2O/L/s, P < 0.001) and higher peak inspiratory airflow (2.8 +/- 0.2 vs. 1.6 +/- 0.1 L/s, P < 0.001). Inspiratory time (Ti) was consistently longer during MAV (0.49 +/- 0.02 vs. 0.36 +/- 0.02 SE, P < 0.001) such that during MAV the difference between actual Ti and minimal effective Ti (fivefold inspiratory time constant) was larger (0.29 +/- 0.03 vs. 0.13 +/- 0.03 s, P < 0.05). Our study suggests that operator-dependent ventilatory variables such as tidal volume, inspiratory time, frequency, and airflow need to be further evaluated in order to develop standardized guidelines for the safe administration of MAV. Until then the ventilator used for brief or augmented ventilatory support is a reasonable alternative to administering MAV by inconsistent standards.

Evaluation of neonatal pulmonary mechanics and energetics: a two factor least mean square analysis.

Pulmonary mechanics, using a two factor least mean square analysis technique, were determined in 22 preterm neonates with respiratory failure. The respiratory system is modelled as a linear mechanical system. Concurrent signals of airflow and transpulmonary pressure were utilized to calculate values of dynamic lung compliance and pulmonary resistances; these determinations were made over the entire tidal volume range. In addition, values of resistive work of breathing, pulmonary time constants, scalar records of sequential breaths, pressure-volume and flow-volume relationships were available for data review and interpretation. The mean +/- SEM value of tidal volume was 7.4 +/- 0.6 ml/kg; dynamic lung compliance was 0.44 +/- 0.04 ml/cmH2O/kg; and the pulmonary resistance of the whole breath was 106 +/- 9.1 cmH2O/liter/s. The resistive work of breathing (hysteresis) was 41.8 +/- 5.9 gm.cm/kg. In correlating the measured values of pressure and flow to those predicted by the model, the mean value of the correlation coefficient for the least mean square analysis for all 22 studies was 0.995 +/- 0.001; the standard error of estimate of the predicted pressure was less than 4.4% of the range of pressures measured. Thereby, the model was considered to be appropriate for the neonatal respiratory system. In addition to the traditional procedures of evaluating the respiratory status of a sick neonate, bedside analysis of pulmonary mechanics provide graphical information, and quantitative data which should be useful in day-to-day pulmonary management.

Clinical use of pulmonary mechanics and waveform graphics.

Decades of research have led to the understanding of neonatal pulmonary physiology and have influenced the clinical care that neonatologists provide to the sick newborn. Advances in microprocessor technology have allowed for clinical access of the research-based measurements of neonatal pulmonary functions. These evaluations are not only the integrated evaluation of the three primary vectors of respiration (driving pressure, air flow, and volume measured over time) but also values calculated by known physiologic equations. Clinical use of these data may not only be relevant and helpful in the bedside management, but also provides a uniquely objective and research-oriented data collection for individual newborns.

Clinical report from the pilot USA Kernicterus Registry (1992 to 2004).

To identify antecedent clinical and health services events in infants (>/=35 weeks gestational age (GA)) who were discharged as healthy from their place of birth and subsequently sustained kernicterus. We conducted a root-cause analysis of a convenience sample of 125 infants >/=35 weeks GA cared for in US healthcare facilities (including off-shore US military bases). These cases were voluntarily reported to the Pilot USA Kernicterus Registry (1992 to 2004) and met the eligibility criteria of acute bilirubin encephalopathy (ABE) and/or post-icteric sequelae. Multiple providers at multiple sites managed this cohort of infants for their newborn jaundice and progressive hyperbilirubinemia. Clinical signs of ABE, verbalized by parents, were often inadequately elicited or recorded and often not recognized as an emergency. Clinical signs of ABE were reported in 7 of 125 infants with a subsequent diagnosis of kernicterus who were not re-evaluated or treated for hyperbilirubinemia, although jaundice was noted at outpatient visits. The remaining infants (n=118) had total serum bilirubin (TSB) levels >20 mg per 100 ml (342 micromol l(-1); range: 20.7 to 59.9 mg per 100 ml). No specific TSB threshold coincided with onset of ABE. Of infants <37 weeks GA with kernicterus, 34.9% were LGA (large for gestational age) as compared with 24.7% of term infants (>37 weeks GA). Although >90% mothers initiated breast-feeding, assessment of milk transfer and lactation support was suboptimal in most. Mortality was 4% (5 of 125) in infants readmitted at age 0.2 mg per 100 ml per hour), contributing factors, alone or in combination, included undiagnosed hemolytic disease, excessive bilirubin production related to extra-vascular hemolysis and delayed bilirubin elimination (including increased enterohepatic circulation, diagnosed and undiagnosed genetic disorders) in the context of known late prematurity (<37 weeks), glucose 6-phosphate-dehydrogenase deficiency, infection and dehydration. Readmission was at age 35 mg per 100 ml had post-icteric sequelae (n=73). There was a narrow margin of safety between birthing hospital discharge or home birth and readmission to a tertiary neonatal/pediatric facility. Progression of hyperbilirubinemia to hazardous levels and onset of neurological signs were often not identified as infant's care and medical supervision transitioned during the first week after birth. The major underlying root cause for kernicterus was systems failure of services by multiple providers at multiple sites and inability to identify the at-risk infant and manage severe hyperbilirubinemia in a timely manner.

Energetics and mechanics of nutritive sucking in the preterm and term neonate.

Energetics and mechanics of sucking in preterm and term neonates were determined by simultaneous records of intraoral pressure, flow, volume, and work of individual sucks. Nine term infants (mean postconceptional age: 38.6 +/- 0.7 SD weeks; mean postnatal age: 18.4 +/- 6.1 SD days) and nine preterm infants (mean postconceptional age: 35.2 +/- 0.7 SD weeks; mean postnatal age: 21.9 +/- 5.4 SD days) were studied under identical feeding conditions. Preterm infants generated significantly lower peak pressure (mean values of 48.5 cm H2O compared with 65.5 cm H2O in term infants; P less than 0.01), and the volume ingested per such was generally less than or equal to 0.5 mL. Term infants demonstrated a higher frequency of sucking, a well-defined suck-pause pattern, and a higher minute consumption of formula. Energy and caloric expenditure estimations revealed significantly lower work performed by preterm infants for isovolumic feeds (1190 g/cm/dL in preterm infants compared with 2030 g.cm/dL formula ingested in term infants; P less than 0.01). Furthermore, work performed by term infants was disproportionately higher for volumes greater than or equal to 0.5 mL ingested. This study indicates that preterm infants expend less energy than term infants to suck the same volume of feed and also describes an objective technique to evaluate nutritive sucking during growth and development.

Instrumentation for measuring cardiac output by direct Fick method during liquid ventilation.

A closed-circuit fluorocarbon oxygenation system was designed and incorporated into an existing liquid breathing system (LBS) to allow measurement of an animal's oxygen consumption during liquid ventilation. This enabled simultaneous determination of cardiac output by the direct Fick method. A series of seven in-vivo experiments were conducted in which the oxygen consumption and cardiac output of adult cats (2.3 +/- 0.1 kg body wt SEM) were measured during both spontaneous gas breathing (Fio2 = 0.80 in the control animals) and fluorocarbon liquid (FC-80) ventilation using the LBS. On conversion to liquid ventilation, cardiac output and oxygen consumption were found to decrease significantly, by 40% (P less than 0.02) and 18.6% (P less than 0.05), respectively, from control values for gas breathing. Use of the closed-loop fluorocarbon oxygenation system provided for total recovery of vaporized fluorocarbon (greater than 750 ml/h) and of oxygen (18 liter/min STPD), which were otherwise discarded in previous experiments with liquid ventilation.

Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns.

OBJECTIVE: To assess the predictive ability of a universal predischarge serum bilirubin measurement to screen for risk of subsequent significant hyperbilirubinemia in the direct Coombs negative healthy term and near-term newborn during the first postnatal week. METHODS: Total serum bilirubin (TSB) levels were obtained at the time of the routine metabolic screen in all term and near-term newborns cared for in the Pennsylvania Hospital Well Baby Nursery (n = 13 003). Postnatal age (in hours) at the time of TSB measurement was recorded. A percentile-based bilirubin nomogram for the first week was constructed from hour-specific predischarge and postdischarge TSB values of newborns (n = 2840; median BW = 3230 g and median gestational age = 39 weeks) who met classification criteria for healthy newborns (excluding those with a positive direct Coombs test or those requiring phototherapy before age 60 hours) and who were enrolled in a hospital supervised home or outpatient follow-up program. The accuracy of the predischarge TSB as a predictor of subsequent degree of hyperbilirubinemia was determined. RESULTS: The study patients in the nomogram were racially diverse. Nearly 60% were breastfed. Predischarge, 6.1% of the study population (172/2840) had TSB values in the high-risk zone (>/=95th percentile) at 18 to 72 hours; of these, 39.5% (68/172) remained in that zone (likelihood ratio [LR] = 14.08, sensitivity = 54%; specificity = 96.2%, probability = 39.5%). Predischarge, 32.1% of the population (912/2840) had TSB values in the intermediate-risk zone. In a clinically significant minority of these newborns (58/912 or 6.4%), the postdischarge TSB moved into the high-risk zone (LR of this move: 3.2 from the upper-intermediate zone and.48 from the lower-intermediate risk zone). The predischarge TSB in 61.8% of the newborns (1756/2840) was in the low-risk zone (<40th percentile) and there was no measurable risk for significant hyperbilirubinemia (LR = 0, sensitivity = 100%; specificity = 64.7%; probability = 0%). CONCLUSIONS: An hour-specific TSB before hospital discharge can predict which newborn is at high, intermediate or low risk for developing clinically significant hyperbilirubinemia (specifically defined as TSB levels >/=95th percentile for age in hours). Risk designation and subsequent increases or decreases of in TSB can be easily monitored on an hour-specific percentile based predictive bilirubin nomogram. A predischarge TSB measured as a universal policy would facilitate targeted intervention and follow-up in a safe, cost-effective manner. In conjunction with bilirubin practice parameter of the American Academy of Pediatrics, it could reduce the potential risk for bilirubin-induced neurologic dysfunction.

Cardiopulmonary function in very preterm lambs during liquid ventilation.

Cardiopulmonary function was evaluated in very preterm lambs (106 +/- 0.7 S.E. days gestation, 1.66 +/- 0.12 S.E. kg birth weight) during fluorocarbon ventilation. Lambs were delivered by cesarean section after epidural anesthesia. Indwelling arterial, venous, and tracheal cannulae were placed before clamping the cord. Lambs were then mechanically ventilated with oxygenated fluorocarbon for approximately 2 h. During this period it was possible to maintain adequate gas exchange and stable cardiac function. Transpulmonary pressure, liquid flow, and tidal volume tracings enabled determination of lung compliance, CL = 0.58 +/- 0.12 S.E. ml X cmH2O-1 X kg-1, inspiratory resistance, RI = 3600 +/- 604 S.E. cmH2O X liter-1 X sec-1, and expiratory resistance, RE = 4034 +/- 2183 S.E. cmH2O/liter/sec. Lung compliance of the 106-day-old fluorocarbon-filled lung is similar to the more mature 138-143-day-old air-filled lung in preterm lambs. Based on the data presented herein we have extended the viability of the preterm lamb to the limit of pulmonary capillary development rather than that of the pulmonary surfactant system.

Liquid ventilation: cardiovascular adjustments with secondary hyperlactatemia and acidosis.

Cardiovascular adjustments during liquid ventilation were investigated in seven cats. Cardiac output (CO) and regional blood flow were measured with radioactive microspheres during both spontaneous air breathing (control) and ventilation with fluorocarbon liquid, FC-80. CO was found to decrease 48% (P less than 0.05) during liquid breathing as compared to control. This decrease largely reflected a reduced stroke volume. Despite the decreased CO, mean arterial pressure remained unchanged, indicating a 48% increase (P less than 0.002) in total peripheral resistance (TPR). Secondary to the reduced CO and increased TPR, extensive redistribution of blood flow occurred during liquid ventilation. The arterial lactate concentration and lactate-to-pyruvate ratio (L/P) were significantly increased (P less than 0.02). Furthermore, the increase in L/P correlated with the decrease in CO (r = 0.70; P less than 0.01). In turn, the significant decrease in pH during liquid breathing was found to correlate with the increase in L/P (r = 0.85; P less than 0.001). These data clearly demonstrate signficant alterations in cardiovascular dynamics during liquid ventilation with secondary hyperlactatemia and acidosis.

Sequential effects of acute meconium obstruction on pulmonary function.

The relationship between pulmonary function and the migration of meconium to distal airways was determined in 10 rabbits (mean weight 2.6 kg) after insufflation of a meconium-saline mixture (1--2 ml/kg). Animals were anesthetized, cannulated, intubated, and mechanically ventilated with 100% oxygen. Lung mechanical dysfunction was most severe during the early phase of meconium migration, 15 min postinsufflation. Substantial increases in inspiratory lung resistance (RI) and expiratory lung resistance (RE) suggest that the site of obstruction at 15 min was the large airways. A decrease in dynamic lung compliance with unchanged static compliance characterizes the obstruction as partial. At 15 min and throughout the migration process, RE was greater than RI, demonstrating a check-valve effect. This phenomenon was substantiated by an increased functional residual capacity (FRC) in all rabbits, presumably due to gas trapping. Secondary to these changes, marked hypoxemia, hypercapnea, and acidosis developed in spite of assisted ventilation with 100% oxygen. At 60 and 120 min postinsufflation, both RI and RE decreased as compared to 15 min. This suggests that the predominant site of obstruction shifted to medium and small airways concomitant with the migration of meconium. Widespread and uneven distribution of meconium still produced significant frequency dependence of lung compliance. Static compliance remained unchanged, indicating that meconium does not affect surface-active or tissue properties of the lung within 120 min postinsufflation. These data suggest that effective respiratory management after meconium aspiration is dependent on the degree of meconium migration, as reflected by pulmonary mechanics.