Novel forms of ventilation in neonates: Neurally adjusted ventilatory assist and proportional assist ventilation.

Patient-triggered modes of ventilation are currently the standard of practice in the care of term and preterm infants. Maintaining spontaneous breathing during mechanical ventilation promotes earlier weaning and possibly reduces ventilator-induced diaphragmatic dysfunction. A further development of assisted ventilation provides support in proportion to the respiratory effort and enables the patient to have full control of their ventilatory cycle. In this paper we will review the literature on two of these modes of ventilation: neurally adjusted ventilatory assist (NAVA) and proportional assist ventilation (PAV), propose future studies and suggest clinical applications of these modes.

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.

Bubble and ventilator-derived nasal continuous positive airway pressure in premature infants: work of breathing and gas exchange.

OBJECTIVE: During bubble nasal continuous positive airway pressure (B-NCPAP), gas flows through the expiratory limb of CPAP tubing submerged underwater to a depth in centimeters considered equal to the desired end expiratory pressure. Ventilator-derived NCPAP (V-NCPAP) controls the delivered pressure at the expiratory orifice. Limited data exist comparing the two forms of NCPAP on work of breathing (WOB) and other short-term respiratory outcomes. We compared WOB and gas exchange between B-NCPAP and V-NCPAP at equivalent delivered nasal prong pressures among a cohort of preterm infants on NCPAP. STUDY DESIGN: We performed a randomized crossover study in 18 premature infants <1500 g (BW 1101±254 g, GA 28±2 weeks, study age 13±8 days (means±s.d.)), who were already on NCPAP for mild respiratory distress, comparing B-NCPAP to V-NCPAP. Each infant was studied at a constant flow rate and varying pressures of 3, 5, 7, 4 and 2 cm H(2)O in that order. Tidal volumes were obtained by calibrated respiratory inductance plethysmography. Intrapleural pressure was estimated by an esophageal catheter. WOB (inspiratory, elastic and resistive) was calculated from pressure volume data. Breathing asynchrony was assessed with phase angle. Comparisons of respiratory rate, heart rate, tidal volume, minute ventilation, breathing asynchrony, lung compliance, oxygen saturation and transcutaneous (Tc) O(2) and CO(2) were also made. RESULT: WOB and most respiratory parameters were not different between B-NCPAP and V-NCPAP. TcO(2) was higher with B-NCPAP compared to V-NCPAP (P=0.01). TcCO(2) was not different. None of the other measured parameters was significantly different between the two devices. CONCLUSION: WOB and ventilation with B-NCPAP and V-NCPAP are similar when equivalent delivered prong pressures are assured. Improved oxygenation with B-NCPAP is intriguing and requires further investigation.

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.

Work of breathing during constant- and variable-flow nasal continuous positive airway pressure in preterm neonates.

BACKGROUND: Constant-flow nasal continuous positive airway pressure (NCPAP) often is used in preterm neonates to recruit and maintain lung volume. Physical model studies indicate that a variable-flow NCPAP device provides more stable volume recruitment with less imposed work of breathing (WOB). Although superior lung recruitment with variable-flow NCPAP has been demonstrated in preterm neonates, corroborating WOB data are lacking. OBJECTIVE: To measure and compare WOB associated with the use of variable-flow versus constant-flow NCPAP in preterm neonates. METHODS: Twenty-four preterm infants who were receiving constant-flow NCPAP (means, SD) and had birth weight of 1024 +/- 253 g, gestational age of 28 +/- 1.7 weeks, age of 14 +/- 13 days, and FIO(2) of 0.3 +/- 0.1 were studied. Variable-flow and constant-flow NCPAP were applied in random order. We measured changes in lung volume and tidal ventilation (V(T)) by DC-coupled/calibrated respiratory inductance plethysmography as well as esophageal pressures at NCPAP of 8, 6, 4, and 0 cm H(2)O. Inspiratory WOB (WOB(I)) and lung compliance were calculated from the esophageal pressure and V(T) data using standard methods. WOB was divided by V(T) to standardize the results. RESULTS: WOB(I) decreased at all CPAP levels with variable-flow NCPAP, with a maximal decrease at 4 cm H(2)O. WOB(I) increased at all CPAP levels with constant-flow CPAP. Lung compliance increased at all NCPAP levels with variable-flow, with a relative decrease at 8 cm H(2)O, whereas it increased only at 8 cm H(2)O with constant-flow NCPAP. Compared with constant-flow NCPAP, WOB(I) was 13% to 29% lower with variable-flow NCPAP. CONCLUSION: WOB(I) is decreased with variable-flow NCPAP compared with constant-flow NCPAP. The increase in WOB(I) with constant-flow NCPAP indicates the presence of appreciable imposed WOB with this device. Our study, performed in neonates with little lung disease, indicates the possibility of lung overdistention at CPAP of 6 to 8 cm H(2)O with the variable-flow device. Further study is necessary to determine the efficacy of variable-flow NCPAP in neonates with significant lung disease and its use over extended periods of time.continuous-flow and variable-flow NCPAP, work of breathing, premature neonates, lung compliance.

Early high-frequency oscillatory ventilation versus synchronized intermittent mandatory ventilation in very low birth weight infants: a pilot study of two ventilation protocols.

OBJECTIVE: To evaluate the feasibility of conducting a prospective, randomized trial comparing early high-frequency oscillatory ventilation (HFOV) to synchronized intermittent mandatory ventilation (SIMV) in very low birth weight (VLBW) premature infants. This pilot study evaluated two ventilator management protocols to determine how well they could be implemented in a multicenter clinical trial. Although this pilot study was not powered to detect differences in outcome, we also collected outcome data. DESIGN: Prospective, multicenter, randomized pilot study. SETTING: Seven tertiary-level intensive care nurseries with previous experience with both HFOV and flow-triggered SIMV. PATIENTS: Fifty infants weighing 501 to 1200 g, less than 4 hours of age, who had received one dose of surfactant and required ventilation with mean airway pressure > or =6 cm H2O and F(I)O2 > or =0.25, and had an anticipated duration of ventilation greater than 24 hours. INTERVENTIONS: Patients were stratified by birth weight and prenatal steroid status, then randomized to either HFOV or SIMV with tidal volume monitoring. Ventilator management for patients in both study arms was strictly governed by protocols that included optimizing lung inflation and blood gases, weaning strategies, and extubation criteria. MEASUREMENTS: Data were collected using the tools planned for the larger collaborative study. Protocol compliance was closely monitored, with successive changes in the protocol made as necessary to improve clarity and increase compliance. The incidence of major neonatal adverse outcomes was recorded. MAIN RESULTS: Data are presented for 24 HFOV and 24 SIMV infants (two infants, twins, were withdrawn from the study at parent's request). Nineteen of the 24 HFOV infants and 20 of the 24 SIMV infants survived to 36 weeks corrected age. Age at final extubation for survivors was 16+/-16 (mean+/-SD) days for HFOV infants and 24+/-24 days for SIMV infants. At 36 weeks corrected age, 14 of the 19 HFOV survivors were extubated and in room air, whereas 5 required supplemental oxygen. In comparison, 6 of the 20 SIMV survivors were extubated and in room air, whereas 14 required supplemental oxygen. Grade III/IV IVH and/or periventricular leukomalacia occurred in 2 HFOV and 2 SIMV patients. Overall compliance with the ventilator protocols was 82% for the SIMV protocol, and 88% for the HFOV protocol. CONCLUSIONS: The preliminary outcome data supports conducting the large randomized trial, which began in July of 1998. The protocols for the ventilator management of VLBW infants, both with HFOV and with SIMV were easily implemented and consistently followed, and are presented here.

Lung recruitment and breathing pattern during variable versus continuous flow nasal continuous positive airway pressure in premature infants: an evaluation of three devices.

OBJECTIVE: To determine whether lung volume changes and breathing pattern parameters differ among 3 devices for delivery of nasal continuous positive airway pressure (CPAP) in premature infants. METHODS: Thirty-two premature infants receiving nasal CPAP for apnea or mild respiratory distress were enrolled. Birth weight was (mean +/- standard deviation) 1081 +/- 316 g, gestational age 29 +/- 2 weeks, age at study 13 +/- 12 days, and fraction of inspired oxygen (FIO(2)) at study.29 +/-.1. Three devices, applied in random order, were studied in each infant: continuous flow nasal CPAP via CPAP prongs, continuous flow nasal CPAP via modified nasal cannula, and variable flow nasal CPAP. After lung recruitment to standardize volume history, changes in lung volume (DeltaV(L)) were assessed at nasal CPAP of 8, 6, 4, and 0 cm H(2)O using calibrated direct current-coupled respiratory inductance plethysmography. RESULTS: DeltaV(L) was significantly greater overall with the variable flow device compared with both the nasal cannula and CPAP prongs. However, DeltaV(L) was not different between the cannula and the prongs. Respiratory rate, tidal volume, thoraco-abdominal asynchrony, and FIO(2) were greater with the modified cannula than for either of the other 2 devices. CONCLUSION: Compared with 2 continuous flow devices, the variable flow nasal CPAP device leads to greater lung recruitment. Although a nasal cannula is able to recruit lung volume, it does so at the cost of increased respiratory effort and FIO(2).

Detecting lung overdistention in newborns treated with high-frequency oscillatory ventilation.

Positive airway pressure (Paw) during high-frequency oscillatory ventilation (HFOV) increases lung volume and can lead to lung overdistention with potentially serious adverse effects. To date, no method is available to monitor changes in lung volume (DeltaVL) in HFOV-treated infants to avoid overdistention. In five newborn piglets (6-15 days old, 2.2-4.2 kg), we investigated the use of direct current-coupled respiratory inductive plethysmography (RIP) for this purpose by evaluating it against whole body plethysmography. Animals were instrumented, fitted with RIP bands, paralyzed, sedated, and placed in the plethysmograph. RIP and plethysmography were simultaneously calibrated, and HFOV was instituted at varying Paw settings before (6-14 cmH(2)O) and after (10-24 cmH(2)O) repeated warm saline lung lavage to induce experimental surfactant deficiency. Estimates of Delta VL from both methods were in good agreement, both transiently and in the steady state. Maximal changes in lung volume (Delta VL(max)) from all piglets were highly correlated with Delta VL measured by RIP (in ml) = 1.01 x changes measured by whole body plethysmography - 0.35; r(2) = 0.95. Accuracy of RIP was unchanged after lavage. Effective respiratory system compliance (Ceff) decreased after lavage, yet it exhibited similar sigmoidal dependence on Delta VL(max) pre- and postlavage. A decrease in Ceff (relative to the previous Paw setting) as Delta VL(max) was methodically increased from low to high Paw provided a quantitative method for detecting lung overdistention. We conclude that RIP offers a noninvasive and clinically applicable method for accurately estimating lung recruitment during HFOV. Consequently, RIP allows the detection of lung overdistention and selection of optimal HFOV from derived Ceff data.

Lung resistance and elastance in spontaneously breathing preterm infants: effects of breathing pattern and demographics.

Reported values of lung resistance (RL) and elastance (EL) in spontaneously breathing preterm neonates vary widely. We hypothesized that this variability in lung properties can be largely explained by both inter- and intrasubject variability in breathing pattern and demographics. Thirty-three neonates receiving nasal continuous positive airway pressure [weight 606-1,792 g, gestational age (GA) of 25-33 wk, 2-49 days old] were studied. Transpulmonary pressure was measured by esophageal manometry and airway flow by face mask pneumotachography. Breath-to-breath changes in RL and EL in each infant were estimated by Fourier analysis of impedance (Z) and by multiple linear regression (MLR). RL(MLR) (RL(MLR) = 0.85 x RL(Z) -0.43; r(2) = 0.95) and EL(MLR) (EL(MLR) = 0.97 x EL(Z) + 8.4; r(2) = 0.98) were highly correlated to RL(Z) and EL(Z), respectively. Both RL (mean +/- SD; RL(Z) = 70 +/- 38, RL(MLR) = 59 +/- 36 cm H(2)O x s x l(-1)) and EL (EL(Z) = 434 +/- 212, EL(MLR) = 436 +/- 210 cm H(2)O/l) exhibited wide intra- and intersubject variability. Regardless of computation method, RL was found to decrease as a function of weight, age, respiratory rate (RR), and tidal volume (VT) whereas it increased as a function of RR. VT and inspiratory-to-expiratory time ratio (TI/TE). EL decreased with increasing weight, age, VT and female gender and increased as RR and TI/TE increased. We conclude that accounting for the effects of breathing pattern variability and demographic parameters on estimates of RL and EL is essential if they are to be of clinical value. Multivariate statistical models of RL and EL may facilitate the interpretation of lung mechanics measurements in spontaneously breathing infants.

Double-blind 1-year follow-up of 1540 infants with respiratory distress syndrome randomized to rescue treatment with two doses of synthetic surfactant or air in four clinical trials. American and Canadian Exosurf Neonatal Study Groups.

Synthetic surfactant has been shown to reduce neonatal and 1-year mortality and neonatal morbidity in infants with respiratory distress syndrome. However, less is known about the effects of synthetic surfactant on developmental outcome and long-term morbidity. Four multicenter, randomized, placebo-controlled trials of synthetic surfactant administered as rescue therapy were conducted in the United States and Canada, with a total enrollment of 2224 patients. Double-blind developmental evaluations of survivors were conducted at 1 year of age (adjusted for prematurity) in all four trials. Of the 1802 patients enrolled in the placebo-controlled rescue trials who survived to 1 year, 1540 (85%) completed the 1-year follow-up evaluation. Height, weight, and head circumference measurements were not different in the treatment and control groups. Mean and median Bayley Scores of Infant Development for both the Mental Development Index and the Psychomotor Development Index were also equivalent. The incidence of impairments was not different in the two groups (mild to moderate impairment, 12% (92 of 745) for the air placebo group vs 11% (86 of 771) for the synthetic surfactant group; severe impairment, 15% (114 of 745) for the air placebo group vs 13% (102 of 771) for the synthetic surfactant group). No differences in rates of retinopathy of prematurity or hearing impairment were found in the treatment groups. The need for surgery after day 28 of life (relative risk, 0.779; 95% confidence interval, 0.665, 0.927) and the need for respiratory support at 1 year (relative risk, 0.525; 95% confidence intervals, 0.303, 0.911) were both reduced in the synthetic surfactant group. These results indicate that developmental outcome at 1 year of age is at least as good among infants with respiratory distress syndrome who received rescue therapy with synthetic surfactant as it is in infants who received air placebo; the results also indicate that the incidence of long-term morbidity is reduced.

Effects of dexamethasone on pulmonary function following extubation.

Dexamethasone is often given to intubated neonates to facilitate successful extubation. To study the effects of dexamethasone on pulmonary function immediately following extubation, we conducted a randomized, blinded, placebo-controlled trial in 51 infants. All infants had been intubated for a minimum of 3 days but no more than 30 days. Mean weight at extubation was 2.41 kg in treated infants, 2.25 kg in control infants. When infants were deemed ready for extubation, dexamethasone 0.5 mg/kg/dose or an equal volume of normal saline was given in three doses 8 hours apart. The final dose was given 1 hour before extubation. Esophageal pressure, air flow integrated to tidal volume (Vt), respiratory rate, and heart rate were measured before extubation, immediately following extubation, and every 20 minutes for 80 minutes. Total pulmonary resistance (RTP), dynamic lung compliance (CL), and minute ventilation (VE) were calculated. Forty-two infants completed the study; 19 infants received dexamethasone and 23 received placebo. There was no difference between the two groups in gestational age, weight at study, or length of intubation. Vt, RTP, VE, and CL were not significantly different between the two groups over time; however, RTP increased over time in the placebo group. Heart rate was significantly lower in the dexamethasone group. We conclude that dexamethasone appears to have limited effect on pulmonary function immediately following extubation in the population studied. Further studies should evaluate the drug effect beginning at least 1 hour after extubation.

Cardiorespiratory effects of changing inspiratory to expiratory ratio during high-frequency oscillation in an animal model of respiratory failure.

To examine the effects of varying inspiratory/expiratory ratio (I/E) on cardiorespiratory function during high-frequency oscillation (HFO), 11 saline-lavaged rabbits were ventilated at I/E = 1:2, 1:1.5, 1.5:1, and 2:1 in a paired comparison to a baseline of I/E = 1:1. HFO was delivered by a SensorMedics model 3100 oscillator at a frequency of 10 Hz. Pressure amplitude and proximal mean airway pressure (PPaw) were held constant as I/E was varied from baseline to the experimental I/E. During each paired observation, PaO2, PaCO2, cardiac output, blood pressure, and distal mean airway pressure (DPaw) were measured. We found that as I/E was increased or decreased from 1:1, no significant changes in PaO2, PaCO2, blood pressure, or cardiac output occurred. We conclude that in this model, varying I/E has no significant effect on oxygenation, ventilation, or cardiovascular function.

An infant and toddler feeding group program.

At Children's Medical Center of Dayton, Ohio, several children whose early oral feedings were delayed or especially difficult due to physical problems became resistant and exhibited aversive behaviors when oral feeding was introduced. A support group, which lasted for 9 months, was initiated with six of these children and their families. In the group, professionals provided the families with general information about nutrition and behavior and with individualized intervention strategies for the nutritional and behavioral management of their child's specific problems. The families contributed mutual support and problem solving strategies through the group process. Each child demonstrated progress during the 9-month period, which suggests that intervention in a support-group format can be a successful alternative to an individual inpatient program for eating disorders in some young children.

Measurement of tidal volume using a pneumotachometer during high-frequency oscillation.

To assess the accuracy of a pneumotachometer (PN) for tidal volume (VT) measurements during high-frequency oscillation (HFO), we determined simultaneously VT using a PN and a full body plethysmograph (PL) in 12 rabbits. HFO was delivered with an oscillator at a frequency of 10 Hz, mean airway pressure of 8 cm H2O, and inspiratory time of 50%. Pressure amplitude (delta P) was varied as follows: 40, 60, 80, 20, 100, 40 cm H2O. Finally, in ten rabbits a spacer equal in deadspace (VD) to that of the PN (15 ml) was left in-line for 5 min. Blood gases were obtained before and after the spacer was added. We found that VT-PN correlates well with VT-PL (r = .92), although the difference between VT-PN and VT-PL is greater at large VT. Significant respiratory acidosis developed with the spacer in-line. PN may be used to trend VT during HFO but PN must not be left in-line, as increased VD seriously affects ventilation.

Capillary blood gases in the neonate. A reassessment and review of the literature.

Heel puncture capillary blood gas (CBG) measurements continue to be used in neonates for estimating arterial blood gas values. Review of the literature reveals general agreement that CBG PO2 values are of little use in predicting arterial PO2 and that CBG pH values are reliable predictors of arterial pH; opinion varies regarding CBG PCO2. We conducted a two-part study comparing postductal arterial and CBG values. First, 50 infants were studied, each only once. All infants had umbilical arterial catheters in place. Blood was obtained simultaneously from the umbilical artery catheter and the warmed heels. Results demonstrated poor predictability of arterial values from CBG pH and PCO2 as well as for PO2. Second, to determine if variation both within and among individuals was similar, repeated measurements were made in 27 additional infants comparable to the first group. We obtained 3 to 28 simultaneous postductal arterial and CBG samples from each infant. A random-effects nested analysis of variance indicated that for pH, variation was largely the result of between-subject or within-subject replicates effects, while for PO2 and PCO2, most variation was explained by differences between the two techniques (umbilical artery catheter vs CBG). The results indicate that CBG measurements do not accurately predict arterial values in neonates. Extreme caution should be used when management decisions are based on CBG values.

Cardiopulmonary effects of high frequency positive-pressure ventilation versus jet ventilation in respiratory failure.

Conventional ventilators are frequently used at high rates in the intensive care nursery to achieve adequate oxygenation and ventilation with reduced peak inspiratory pressure. The efficacy and limitations of high frequency positive-pressure ventilation (HFPPV) using a conventional ventilator were studied by comparing the cardiopulmonary effects of HFPPV with those of high frequency jet ventilation (HFJV) in an animal model of respiratory failure. Sixteen saline-lavaged rabbits were ventilated with either HFPPV or HFJV for 2 h using rates of 200 breaths/min, inspiratory to expiratory ratio of 1:2, and FIO2 of 1.0. As controls an additional eight lavaged rabbits were ventilated at conventional rates (40 to 60 breaths/min). Proximal peak inspiratory pressure as indicated on the ventilator manometer or drive pressure was adjusted to maintain acceptable blood gases. Cardiac output (CO) was measured by thermodilution. Although there was a significant decrease in cardiac function over time, there were no significant differences between the groups in CO or stroke volume. Satisfactory oxygenation and ventilation were maintained in all groups. Static respiratory system compliance and mean airway pressure were similar among the groups. Histologic examination of the lungs revealed no differences between the three ventilator groups. The results of this study indicate that both HFPPV and HFJV are effective in short-term maintenance of normal blood gases in respiratory failure without any discernable differences in their effects on cardiovascular function. At very high rates, however, increases in VT are not possible with HFPPV, which limits its usefulness and flexibility in respiratory failure.

Effect of racemic epinephrine on ventilatory function in the neonate postextubation.

The use of nebulized racemic epinephrine to improve ventilatory function in the newborn postextubation was studied. Forty-five infants intubated for more than 3 days were randomized to receive racemic epinephrine by nebulization immediately postextubation or to receive only warmed, humidified gas. Measurements of air flow, esophageal pressure, tidal volume, respiratory rate, and heart rate were made before treatment and every 10 min for 1 h after treatment. Resistance was calculated from recorded data. Changes from baseline values were calculated for each time period. Analysis of variance of these variables for treatment, sex, and time main effects and their interactions, with appropriate adjustments for covariables, was performed. Although some sex interactions were seen, there were no significant time effects or interactions. This study provides no evidence that using nebulized racemic epinephrine in infants postextubation improves ventilatory function.