Non-invasive inhaled nitric oxide in the treatment of hypoxemic respiratory failure in term and preterm infants.

OBJECTIVES: Inhaled nitric oxide (iNO) is effective in conjunction with tracheal intubation (TI) and mechanical ventilation (MV) for treating arterial pulmonary hypertension and hypoxemic respiratory failure (HRF) in near-term and term newborns. Non-invasive respiratory support with nasal continuous positive airway pressure (CPAP) is increasingly used to avoid morbidity associated with TI and MV, yet the effectiveness of iNO delivery via nasal CPAP remains unknown. To evaluate the effectiveness of iNO delivered via the bubble nasal CPAP system in term and preterm newborns with HRF. STUDY DESIGN: Electronic medical records from all infants admitted to the neonatal intensive care unit (NICU) during 2005 to 2014 (n=10, 895) were screened for treatment with iNO therapy for HRF. Detailed data on population characteristics and cardiorespiratory, iNO and respiratory support indices were abstracted for all infants, who were administered iNO non-invasively using bubble nasal CPAP. Change in relevant indices at baseline (before initiating non-invasive iNO) and at 3, 6, 12 and 24 h after non-invasive iNO therapy were analyzed using repeated measures analysis of variance. RESULTS: Of 795 infants treated with iNO (7.3% of total NICU admissions) over a 10-year period, 107 infants (13.4% of iNO treated) with birth weight 2448±1112 g and gestational age 35.3±5.8 weeks received iNO non-invasively. 25 infants received iNO exclusively non-invasively, whereas in remaining 82 infants non-invasive route followed invasive delivery via TI and MV. Indications for using non-invasive iNO included idiopathic pulmonary hypertension (39%), congenital heart disease (37%), bronchopulmonary dysplasia (10%), meconium aspiration syndrome (9%) and congenital diaphragmatic hernia (5%). Over the 24 h following initiation of non-invasive iNO, fractional oxygen requirements decreased (0.38 to 0.32; P<0.0005) and SpO2 increased (90.7 to 91.6%; P<0.01) with no significant changes in heart rate, respiratory rate, blood pressure, pH and PaCO2. On average non-invasive iNO was initiated on day of life 9 with a maximal dose was 20 p.p.m. The average duration of iNO therapy and the duration over which it was weaned off were 134 and 51 h, respectively. Analysis of environmental gases during non-invasive iNO therapy revealed median ambient nitrogen dioxide and nitric oxide levels of 0.30 and 0.01 p.p.m., respectively. CONCLUSIONS: Initiation of iNO in infants on bubble nasal CPAP or continuation of iNO in infants transitioning from MV to bubble nasal CPAP is associated with improved oxygenation during HRF in term and preterm infants. Non-invasive iNO may have a synergistic effect with airway recruitment strategies such as nasal CPAP.

Interactions among peripheral perfusion, cardiac activity, oxygen saturation, thermal profile and body position in growing low birth weight infants.

AIMS: To investigate the correlation between the 'perfusion index' (PI) and other commonly used estimates of cutaneous blood flow [heart rate (HR), surface temperatures (ST) and central-to-peripheral thermal gradients (C-P grad)] and to use this new non-invasive tool to compare differences between prone and supine sleep position in low birth weight (LBW) infants. METHODS: Six-hour continuous recordings of pulse oximetry, cardiac activity and absolute ST from three sites (flank, forearm and leg), along with minute-to-minute assessment of behavioural states were performed in 31 LBW infants. Infants were randomly assigned to the prone or supine position for the first 3 h and then reversed for the second 3 h. PI data were correlated with HR and C-P grad, and compared across sleep positions during quiet sleep (QS) and active sleep (AS). RESULTS: Perfusion index correlated significantly with HR (r(2) = 0.40) and flank-to-forearm thermal gradient (r(2) = 0.28). In the prone position during QS, infants exhibited higher PI (3.7 +/- 0.9 vs. 3.1 +/- 0.7), HR (158.4 +/- 8.9 vs. 154.1 +/- 8.8 bpm), SpO(2) (95.8 +/- 2.6 vs. 95.2 +/- 2.6%), flank (36.7 +/- 0.4 vs. 36.5 +/- 0.4 degrees C), forearm (36.1 +/- 0.6 vs. 35.5 +/- 0.4 degrees C) and leg (35.4 +/- 0.7 vs. 34.7 +/- 0.7 degrees C) temperatures and narrower flank-to-forearm (0.6 +/- 0.4 vs. 0.9 +/- 0.3 degrees C) and flank-to-leg (1.3 +/- 0.6 vs. 1.8 +/- 0.7 degrees C) gradients, compared to those of the supine position. Similar differences were observed during AS. CONCLUSION: Perfusion index is a good non-invasive estimate of tissue perfusion. Prone sleeping position is associated with a higher PI, possibly reflecting thermoregulatory adjustments in cardiovascular control. The effects of these position-related changes may have important implications for the increased risk for sudden infant death syndrome in prone position.

Sleeping position and electrocortical activity in low birthweight infants.

OBJECTIVE: To evaluate the effects of prone and supine sleeping positions on electrocortical activity during active (AS) and quiet (QS) sleep in low birthweight infants. DESIGN: Randomised/crossover study. SETTING: Infant Physiology Laboratory at Children's Hospital of New York. PATIENTS: Sixty three healthy, growing, low birthweight (birth weight 795-1600 g) infants, 26-37 weeks gestational age. INTERVENTIONS: Six hour continuous two channel electrocortical recordings, together with minute by minute behavioural state assignment, were performed. The infants were randomly assigned to prone or supine position during the first three hours, and positions were reversed during the second three hours. OUTCOME MEASURES AND RESULTS: Fast Fourier transforms of electroencephalograms (EEGs) were performed each minute and the total EEG power (TP), spectral edge frequency (SEF), absolute (AP) and relative (RP) powers in five frequency bands (0.01-1.0 Hz, 1-4 Hz, 4-8 Hz, 8-12 Hz, 12-24 Hz) were computed. Mean values for TP, SEF, AP, and RP in the five frequency bands in the prone and supine positions during AS and QS were then compared. In the prone sleeping position, during AS, infants showed significantly lower TP, decreased AP in frequency bands 0.01-1.0 Hz, 4-8 Hz, 8-12 Hz, 12-24 Hz, increased RP in 1-4 Hz, and a decrease in SEF. Similar trends were observed during QS, although they did not reach statistical significance. CONCLUSIONS: The prone sleeping position promotes a shift in EEG activity towards slower frequencies. These changes in electrocortical activity may be related to mechanisms associated with decreased arousal in the prone position and, in turn, increased risk of sudden infant death syndrome.

Motion resistant pulse oximetry in neonates.

BACKGROUND: Pulse oximetry is widely used in neonates. However, its reliability is often affected by motion artefact. Clinicians confronted with questionable oxygen saturation (SpO(2)) values often estimate the reliability by correlating heart rate (HR) obtained with the oximeter with that obtained by electrocardiogram. OBJECTIVE: To compare the effects of motion on SpO(2) and HR measurements made with Masimo signal extraction technology and those made with a Nellcor N-200. DESIGN: Continuous pulse oximetry and HR monitoring were performed in 15 healthy, term infants (mean (SD) birth weight 3408 (458) g) undergoing circumcision, using Masimo and Nellcor pulse oximeters and a standard HR monitor (Hewlett-Packard). Simultaneous minute by minute behavioural activity codes were also assigned. Baseline data were collected for 10 minutes when the infant was quietly asleep and then continued during and after circumcision for a total duration of one hour. The oximeter HR and SpO(2) values were compared and related to HR values obtained by ECG during all three periods. The effect of behavioural activity on SpO(2) and HR was also evaluated. RESULTS: When compared with results obtained with the Nellcor, the mean SpO(2) and HR were higher and the incidence of artefact lower with the Masimo during all three periods. Masimo HR more accurately predicted HR obtained with a standard monitor, with lower residual error. SpO(2) and HR values obtained with the Nellcor were lower and more variable during all behavioural states, especially crying, when excessive motion artefact was most likely. CONCLUSIONS: The data suggest that Masimo signal extraction technology may offer improvement in pulse oximetry performance, particularly in clinical situations in which extreme motion artefacts are likely.

Effects of quality of energy intake on growth and metabolic response of enterally fed low-birth-weight infants.

Carbohydrate and fat may vary in their ability to support protein accretion and growth. If so, variations in the source of nonprotein energy might be used to therapeutic advantage in enterally fed low-birth-weight infants. To test the hypothesis that high-carbohydrate diets are more effective than isocaloric high-fat diets in promoting growth and protein accretion, low-birth-weight infants weighing 750-1600 g at birth were randomized in a double blind study to receive one of five formulas differing only in the quantity and quality of nonprotein energy. Groups 1, 2, and control received 130 kcal x kg(-1) x d(-1) with 35, 65, and 50% of the nonprotein energy as carbohydrate. Groups 3 and 4 received energy intake of 155 kcal x kg(-1) x d(-1) with 35 and 65% of the nonprotein energy as carbohydrate. Protein intake of all groups was 4 g x kg(-1) x d(-1). Growth and metabolic responses were followed weekly, and macronutrient balances including 6-h indirect calorimetry were performed biweekly. Greater rates of weight gain and nitrogen retention were observed at high-carbohydrate intake compared with high-fat intake at both gross energy intakes. Greater rates of energy storage and an increase in skinfold thickness were observed in group 4 (high-energy high-carbohydrate diet) despite higher rates of energy expenditure. These data support the hypothesis that at isocaloric intakes, carbohydrate is more effective than fat in enhancing growth and protein accretion in enterally fed low-birth-weight infants. However, a diet with high-energy and high-carbohydrate content also results in increased fat deposition.

Effects of quality of energy on substrate oxidation in enterally fed, low-birth-weight infants.

BACKGROUND: Carbohydrate and fat may differ in their ability to support energy-requiring physiologic processes, such as protein synthesis and growth. If so, varying the constituents of infant formula might be therapeutically advantageous. OBJECTIVE: We tested the hypothesis that low-birth-weight infants fed a diet containing 65% of nonprotein energy as carbohydrate oxidize relatively more carbohydrate and relatively less protein than do infants fed an isoenergetic, isonitrogenous diet containing 35% of nonprotein energy as carbohydrate. DESIGN: Sixty-two low-birth-weight infants weighing from 750 to 1600 g at birth were assigned randomly and blindly to receive 1 of 5 formulas that differed only in the quantity and quality of nonprotein energy. Formula containing 544 kJ x kg(-1) x d(-1) with either 50%, 35%, or 65% of nonprotein energy as carbohydrate was administered to control subjects, group 1, and group 2, respectively. Groups 3 and 4 received gross energy intakes of 648 kJ x kg(-1) x d(-1) with 35% and 65% of nonprotein energy as carbohydrate. Protein intake was targeted at 4 g x kg(-1) x d(-1). Substrate oxidation was estimated from biweekly, 6-h measurements of gas exchange and 24-h urinary nitrogen excretion. RESULTS: Carbohydrate oxidation was positively (r = 0.71, P < 0.0001) and fat oxidation was negatively (r = -0.46, P < 0.001) correlated with carbohydrate intake. Protein oxidation was negatively correlated with carbohydrate oxidation (r = -0.42, P < 0.001). Fat oxidation was not correlated with protein oxidation. Protein oxidation was less in infants receiving 65% of nonprotein energy as carbohydrate than in groups receiving 35% nonprotein energy as carbohydrate. CONCLUSION: These data support the hypothesis that energy supplied as carbohydrate is more effective than energy supplied as fat in sparing protein oxidation in enterally fed low-birth-weight infants.

Maturational changes in heart rate and heart rate variability in low birth weight infants.

To provide insight into the maturation of neural mechanisms responsible for variability in heart rate during quiet and active sleep, 6-hour continuous electrocardiographic recordings and simultaneous minute-by-minute behavioral activity state assignments were performed in 61 healthy, growing low birth weight infants. The infants weighed 795-1600 g at birth and ranged between 31-38 weeks in postconceptional age. During this age interval there was a decrease in heart rate during quiet sleep and an increase in both time domain and frequency domain measures of the variability in cardiac interbeat intervals. In quiet sleep, global variability, measured as SD of R-R intervals, increased in relation to age, as did higher frequency variability, measured as the square root of the mean of squared successive differences in R-R intervals. Developmental changes in the 0.5-2.0 Hz spectral power band of RR-interval variability, another measure of high frequency variability, paralleled the changes seen in the time domain measure. Evaluation of patterns of changes in the magnitude and direction of successive interbeat intervals provided evidence that the incidence of sustained accelerations or decelerations increased whereas the incidence of no change in consecutive RR-intervals decreased as infants matured. Among the various measures of heart rate variability, the incidence of sustained change and no change in successive interbeat intervals were most closely related to postconceptional age in both sleep states. The overall decrease in heart rate, increase in heart rate variability, and increase in the pattern of changes in interbeat interval with postconceptional age are consistent with the maturation of the autonomic cardio-regulatory activity from 31-38 weeks age.

Body position, sleep states, and cardiorespiratory activity in developing low birth weight infants.

The objective of this study was to determine the effects of body position (supine vs prone) on cardiorespiratory activity during quiet and active sleep in growing low birth weight (LBW) infants. The effect of postconceptional age on cardiorespiratory activity in the two positions was also evaluated. Fifty-one healthy, growing, appropriate for gestational age LBW infants (795-1600 g), ranging from 26-37 weeks in gestational age, were evaluated. All subjects were enrolled in an ongoing study of the effects of quality of dietary energy on the rate and composition of weight gain. Infants were randomly assigned to the supine or prone position for the first 3 h of the 6-h studies; the position was reversed for the second 3 h. Continuous recordings of cardiorespiratory activity were performed along with simultaneous minute by minute assignment of behavioral sleep state. Measurements of heart rate (HR), heart period variability (RR-SD), respiratory rate (f), and respiratory variability (fSD) were made each minute. Low birth weight infants had higher HR and f and lower RR-SD and fSD in the prone position compared to the supine position, during both quiet and active sleep. With increasing postconceptional age, positional differences in HR increased during quiet sleep and differences in RR-SD increased during both sleep states. These data demonstrate systematic differences in cardiorespiratory control related to body position during sleep. We speculate that such positional differences are due to variations in autonomic control, and may, in turn, contribute to variations in susceptibility to sudden infant death syndrome.

Postural differences in cardiac dynamics during quiet and active sleep in low birthweight infants.

To study the effects of body position (supine versus prone) on changes in cardiac inter-beat interval during quiet and active sleep, 6-h continuous electrocardiographic recordings and simultaneous minute-by-minute behavioural activity state assignments were made in 61 healthy, growing, low birthweight infants. The infants weighed 795-1600 g at birth and ranged between 30-38 wk in postconceptual age. Infants were randomly assigned to the supine or prone position for the first 3 h of each study; the position was reversed for the second 3 h. Higher heart rates and lower time and frequency domain measures of inter-beat interval variability were observed in the prone position as compared to the supine position, during both quiet and active sleep. In addition, an analysis of consecutive increases and decreases in the instantaneous heart rate revealed a lower incidence of sustained accelerations or decelerations in the prone position. Although consistent findings concerning inter-beat interval variability and sleeping position were obtained from all analytic techniques, the differences derived from analysis of consecutive inter-beat changes were the most robust. These differences in multiple measures of cardiac rate and rhythm between prone and supine positions suggest that autonomic control of the heart is altered by body position, the net effect on heart rate being increased sympathetic dominance.

Effects of sleeping position and time after feeding on the organization of sleep/wake states in prematurely born infants.

Epidemiologic studies provide strong evidence for the conclusion that sleeping in the prone position places infants at greater risk for sudden infant death syndrome (SIDS). Prior studies in newborn infants found that in the prone sleeping position there is less time awake and more quiet sleep, but little change in the amount of active sleep. To determine whether the effects of sleeping position on state distribution vary with time after feeding, we studied prematurely born infants in both the prone and supine sleeping positions. Sleep states were recorded each minute during interfeed intervals. Results demonstrate expected effects of sleep position on state distribution: prone sleeping is associated with a 79% increase in quiet sleep and a 71% decrease in time awake. While the decreases in time awake are seen throughout the interfeed interval, increases in quiet sleep in the prone position are found only within the first hour and again near the end of the interfeed interval. These results are consistent with the hypothesis that prone sleeping could increase risk for SIDS by altering the organization of sleep, and that time after feeding may play an important role in the expression of these effects.