Developmental Changes in the Response of the Newborn to Sustained Ventilatory Elastic Loads'?
WILLIAM A. LAFRAMBOISE, THOMAS A. STANDAERT, J. ROSS MILLEY, and DAVID E. WOODRUM
Introduction
The newborn is assumed to be at a disadvantage when confronted with a respiratory mechanical load such as an added airway resistance or elastance (1). This assumption is supported by the fact that mechanoreflex systems critical for stabilizing ventilation are immature at birth and require a postnatal transition period before they reach maturity (2-5). Werecently studied the response of newborn monkeys to added external airway resistances in order to obtain direct evidence of immaturity in their response to mechanical loading (6). Contrary to our expectations, normal neonates exhibited a robust compensatory response and defended blood gas composition much like more mature subjects. The present study was undertaken to determine the neonatal response to sustained elastic loads. Studies of elastic loading in human infants have primarily been restricted to observations of inspiratory pressure changes during a complete airway occlusion (2, 7-9) or brief exposure to an external elastic loading system (4,8-11). Investigations conducted to date in newborn animals have been compromised by the need for anesthesia in order to obtain more invasive measurements of parameters involved in the loading response such as phrenic nerve output or respiratory muscle electromyograms(12). To overcome these restrictions, we studied a monkey species (Macaca nemestrina) that exhibits a similar postnatal potentiation ofchemosensory and mechanoreflex systems as the human infant (13-15). In this animal model, we have been able to obtain direct electromyographic recordings from the diaphragm without the need for surgery or general anesthesia (16). Immediate load compensation exists in human infants subjected to elastic loads (10), but it is not known whether load compensation takes place during sustained elastic loading. By comparing 752
.
SUMMARY Postnatal development of the steady-state response to Inspiratory elastic loading was studied In eight 48-h-old and eight 24-day-old unanesthetized, tracheostomlzed monkeys. Both age groups exhibited a fall In minute ventilation (VE)with loads of two to five times baseline respiratory elastance. There was no statistical difference In the ventilatory response between age groups. The response patterns of both groups were characterized by a fall In both tidal volume (VT) and mean Inspiratory flow (VTITI) associated with a prolongation of TI and Tlmot. All subJects demonstrated a significant load compensatory response both In terms of neural drive (diaphragmatic EMGoutput) and force output (Inspiratory work production). Arterial CO2 Increased significantly during loading In the older subjects In linear correlation with the decline In VE, but the newborns did not exhibit a statistically significant alteration In PaC0 2 throughout the range of elastic loads. These data Indicate that normal newborns are capable of responding to an external elastic load and that the newborn response Is comparable to that of more mature subjects. AM REV RESPIR DIS 1990; 141:752-757
the steady-state response of neonatal and mature subjects to a range of elastic loads, weundertook to determine whether the neonatal response to a sustained loading challenge was immature compared with that in older subjects. Methods Subjects Sixteen infant monkeys were delivered via cesarean section at 156 days of gestation (0.93 of term). A cannula was placed in an umbilical artery at delivery and blood gas measurements were obtained to determine whether an adequate Pao2 (Pao2 > 50 mm Hg) could be maintained without supplemental oxygen. No studies were undertaken until 48 h after birth to allow for lung fluid clearance and elimination of major fetal shunts (17). Eight infants were studied at 48 h of age and eight subjects were studied at 21 to 24 days of postnatal age. Infants assigned to the older group had their umbilical cannula removed and were reared in a primate nursery according to standard protocol (18). All subjects exhibited a regular respiratory pattern and normal arterial gases in room air at the time of study, ·indicating that they had established stable airways and lung volume (15, 19).
Measurements The details of our system for studying these infants have been previously published (15, 16). The infants were studied in the supine position on a sponge rubber mattress while lightly restrained with thin velcro straps across each arm and leg. These newborns, like hu-
mans, are very quiescent in the first few days of life, and the restraints served primarily to secure them in a constant position. A flexible tracheostomy tube (resistance, 0.25 em H 20/L/min at 3 L/min) was inserted after infiltrating the incision site with a topical anesthetic (chloroprocaine Hel). It was necessary to use ketamine (10 mg/kg) in the older monkeys to achieve appropriate sedation for this surgical procedure and for the placement of a femoral artery cannula. A water-filled catheter with an inner diameter of 1.5 mm was positioned in the esophagus to determine esophageal pressure for caleulation of chest wall and pulmonary elastance values. The catheter tip was located so as to obtain maximal pressure excursions in phase with inspiratory flow but with minimal interference from cardiac pulsations. As in previous studies (20), this was consistently found in the distal esophagus approximately
(Received in original form October 13, 1988 and in revised form August 21, 1989) 1 From the Department of Pediatrics, Division of Neonatal and Respiratory Diseases, University of Washington, Seattle, Washington, and the Department of Pediatrics, Division of Neonatology, University of Pittsburgh, Pittsburgh, Pennsylvania. 2 Supported by Grants HL-19187 and RR-OOI66 from the National Institutes of Health and by Grant 18273from the National Institute of Mental Health. 3 Correspondence and requests for reprints should be addressed to William A. LaFramboise, Department of Pediatrics, Magee-Womens Hospital, Forbes Avenue and Halket Street, Pittsburgh, PA 15213.
753
OEVELOPMENTAL RESPONSE TO ELASTIC LOADING IN THE NEWBORN
I em above the cardiac sphincter as determined by fluoroscopy and by direct measurement. After the infant was connected to the nonrebreathing valve, the accuracy of the esophagealpressure measurements was further substantiated with the "occlusion test" (21). Passive chest wall elastance was determined before connecting the infants to the valve for .he loading protocol by hyperventilating them Nith 100070 oxygen until they become apneic. Measured volumes of oxygen were introduced nto the respiratory system raising tracheal pressure in increments of 5 em H 20 from FRC :0 a maximal respiratory system recoil pressure of 30 em H 20. The volume increments olotted against the corresponding esophageal oressure changes delineated the pressurefolume curve for the chest wall. This measurement was checked throughout the day by Iisconnecting the subject from the loading rystem and injecting the necessary volume of ~as to obtain an airway pressure of 30 cm H 20. I'he corresponding esophageal pressure change divided by the injected volume gave 1 rapid estimate of chest wall elastance to cor.oborate earlier measurements. Pulmonary elastance was determined while .he infants breathed spontaneously through .he non-rebreathing valve with the esophageal cannula in place. A hot wire anemometer olaced in line with the inspiratory circuit in:licated changes in background flow, which vere integrated (HP-8811A; Hewlett-Packard, Waltham, MA) to obtain tidal volume (22). Ihe elastic pressure differential divided by the .nspired tidal volume represented dynamic nilmonary elastance. This pressure difference Nas obtained by transecting the esophageal oressure trace from the zero flow point at end sxpiration to the zero flow point at end inspiation. The area of the esophageal pressure .race exceeding this elastic recoil line was coniidered to be the resistive pressure increment aecessary to generate flow through the respiatory system during inspiration (20). Pulmorary resistance was calculated by integrating .his resistive pressure increment by planime:ry and then dividing that value by the concomitant integral of inspiratory flow (VT).A ninimum of 50 such determinations were nade during unloaded breathing, and the redstance of the valve and tracheal tube were mbtracted to give the average pulmonary inipiratory resistance of each subject. Resistance
was calculated in this manner to offset the tendency for increasing lung volume to decrease resistance within a breath. The measurements of pulmonary and chest wall mechanics were made preliminary to the loading study to assure that each subject fell within the range for normal newborns established in a previous population (15, 19). The design of the valve and loading chamber used to present the added elastance was previously published in detail (23). A unique feature of the system is that a constant elastic load is presented to each inspiration by venting the loading chamber during each expiration. The loads chosen were 1.3,2.1, 3.0,4.6, and 6.6 em H 20/ml, which were added to a mean internal elastance (Behest wall plus Elung) in our subjects of 1.85 ± 0.23 em H 20/ml on Day 2 and 1.55 ± 0.37 em H 20/ml on Day 24. To switch from the free-breathing circuit to the loading circuit required a 90-degree rotation of a silent rotary valve, which could be completed while the infant exhaled and without altering the expiratory pathway. Volumetric ventilatory data were obtained by integration of flow changes in the expiratory circuit of the non-rebreathing valve during baseline and loaded conditions. These flow changes were determined by the hot-wire anemometer located downstream from the expiratory port (22). Ventilatory components derived from flow changes, e.g., tidal volume and mean inspiratory flow (VT/TI) and from timing changes, e.g., inspiratory duration (TI), expiratory duration (Ts), and inspiratory duty cycle (TI/Uot) were resolved from the flow trace by operating the chart recorder at speeds as much as 150 mm/s for maximal resolution. A direct index of neural activity was obtained by percutaneously placing two insulated stainless steel wires in the crural diaphragm of our subjects under local anesthesia (16).A differential recording configuration was used for comparison, with a reference electrode placed subdermally at the base of the buttocks. EMG signals were amplified 5,000 times (Model P511J; Grass Instruments, Quincy, MA) prior to recording on FM tape (No. 5600C; Honeywell, Denver, CO). Further signal processing utilized a Service Associates 414 analog processor where the raw signal was filtered between 30 and 3,000 Hz with 60 and 120 Hz notch filters activated. Moving average EMG was obtained by full
wave rectification of the filtered signal and R-C integration with a time constant of 50 ms. In order to maintain VE during loading, compensatory efforts that serve to increase inspiratory force generation are necessary. To obtain an indication of such compensatory output, inspiratory work rate was measured once a steady state was achieved. Work was partitioned into an external and an internal component. The external work component was defined as the work involved in moving air through the external encumbrances of the measurement system, i.e., the tracheal tube, the non-rebreathing valve, and the elastic loading chamber. It was calculated as the integral of the product of inspiratory air flow and airway pressure measured at the tracheal tube opening (6). The pulmonary work of breathing during inspiration was calculated using the values for pulmonary elastance, inspiratory resistance, tidal volume, and respiratory rate using the same formulation applied in the external work an.alysis. Similarly, the work of moving the chest wall was computed and added to the pulmonary work to obtain total internal inspiratory work. The sum of these internal and external work components was taken to represent the total inspiratory work of breathing for the preload state and the various trial conditions. Baseline respiratory values for the two age groups in this study are presented in table 1. These values are consistent with previous studies from our laboratory (6, 13-16, 19,20).
Protocol The protocol for this study required that the infants be exposed to a range of elastic loads while in NREM sleep until a ventilatory plateau was achieved. The distinction of NREM sleep from rapid eye movement sleep or the awake state was determined using standard behavioral criteria adapted for infants (13). Baseline ventilation was recorded over a stable 10-min period before imposition of one of the loads, the magnitude of which was randomly assigned. One minute was allowed for adjustment on the part of the subject after a load was added to inspiration, and then ventilation was followed each minute for a minimum of 10 and a maximum of 20 min. Preliminary analysis indicated that the 5-, 10-, and 20-min VE values were not different. The oxygen concentration in the loading cham-
TABLE 1 BASELINE RESPIRATORY VALUES·
(mllmin)
VT (ml)
f (breaths/min)
TI (s)
Ecw (em H2O/ml)
EL (em H2O/ml)
Pa02 (mmHg)
Paco2 (mmHg)
Respiratory Work (g-em·min-1)
150 23 251 71
2.37 0.49 4.12 0.62
65.4 15.3 61.3 16.4
0.48 0.12 0.50 0.13
0.18 0.11 0.31 0.06
1.67 0.64 1.23 0.52
72.4 9.5 99.5 14.5
35.4 4.0 34.2 2.3
443 118 1,228 454
Ve Day
2
X SO
24
X SO
Definition of abbreviations: \IE = minute ventilation; VT = tidal volume; f = respiratory frequency in breaths per minute; TI = inspiratory time; Ecw = chest wall elastance; EL = dynamic pulmonary elastance. * The effect of maturation on critical baseline variables in this study. Values are mean ± 1 SO for n = 8 on Day 2 and n = 8 on Day 24.
754
LAFRAMBOISE, STANDAERT, MILLEY, AND WOODRUM
ber was adjusted to maintain Pao 2 during baseline and loading at approximately the same level.At the end of each 5-min interval, arterial blood gases were drawn to correlate with ventilatory, mechanical, and electromyographic data. If the infants aroused or exhibited REM sleep characteristics, data were not collected. Thirty minutes of recovery time were allowed between trials.
20
o
f
Results
The 2-day-old infants slept throughout the loading period on all levels of added elastance. This was not the case for the older subjects, who often aroused on the largest load, forcing premature termination of that run. When the subjects remained asleep for the duration of the loading challenge, a ventilatory steady state was attained within the first 3 min, and data were collected over a 10-to 20min time span. There were no statistical changes in the response obtained at 10 versus 20 min of loaded breathing, so we have chosen to present the former as a representative steady state since all subjects breathed against each load for at least 10 min. VE fell significantly in both age groups during elastic loading (figure 1). When the slopes were compared between age groups, there was no statistically significant difference present. Even though VE consistently fell, Pac02 values did not change during loading in the youngest infants. Pac02 was significantly elevated in the older age group (figure 2). When the changes in Paco, were compared be-
Day 24 (.)
~
o
"#
Statistics Volumetric and timing components of ventilation, the respiratory mechanics, work data, and electromyographic responses were tested to determine the effect of loading by using analysis of covariance (ANOCOVA).Because of maturational changes in VE, VT, and lung and chest wall elastance, these variables collected during elastic loading werenormalized as a percentage difference from baseline to focus on the effects of the loading regimen with age apart from baseline changes. Conversion to percent change did not alter the distribution of the loading data around baseline. The linear relationship of the dependent variables to added elastance was calculated, and the slope of these relationships was then compared with zero using the t distribution to establish whether the added elastances had an effect on a given dependent variable. In order to discriminate an effect of postnatal maturation on the response to loading, we tested the slopes of the two age group relationships for differences by comparison to the t distribution. A p < 0.05 was considered to represent a statistically significant difference.
* *
o
*
-40
-80
-80
* ~
_ _'---_ _. L -_ _..l....-_ _..l....-_-----J
3
1
4
Fig. 1. Changes in ventilation during elastic loading. The baseline elastance was standardized for both age groups as a value of 1, and the elastic loads were scaled as a multiple of this baseline value (see table 1 and METHODS for actual values). TwO-dayold subjActs are represented as circles and 24-day-old subjects are crosses. Slope on Day 2: X ± SE = 2.5 ± 1.2, P < 0.03 when compared with null effect; Day 24: X ± SE = 5.0 ± 1.5,p < 0.003 when compared with null effect. Compared with one another, these slopes were not different (p = 0.21).
MUltiple. of Ba.ellne Ela.tance
tween age groups, there was a significant difference attributable to age. Conversion to a percentile scale did not alter these findings, Le., Paco, was not significantly altered during loading in the neonatal group, whereas it increased in the older subjects for the same range of elastic loads. The volumetric and timing components of ventilation demonstrated neither quantitative nor qualitative changes with age during loading. Loaded inspiratory times wereconsistently longer than control values (Day 2 slope: mean ± SE = 0.017 ± 0.005 s/unit added elastance, p < 0.003 compared with no change; Day 24 = 0.014 ± 0.004, p < 0.006; no difference across age), but they were not associated with any statistical change in respiratory rate. VT fellduring loading (Day 2 slope: mean ± SE = -0.042 ± 0.015 ml/unit added elastance, p < 0.01 compared with no change; Day 24 = --0.110 ± 0.025, p < 0.0001), but no statistical differences were discernible across age groups. Similarly, no statistical age effects could be demonstrated for the progressivedeclinein VT/TIthat occurred at both ages (Day 2 slope: mean ± SE = -0.202 t 0.035 ml/s/unit added elastance, p < 0.0001 compared with no changes; Day 24 = -0.387 ± 0.087, p< 0.0001).There were no maturational differences in Ti/Ttot during loading al-
though this index increased slightly in both age groups. All indices of diaphragmatic electromyographic output (slope movingaverage: EMGo•2 s, rate moving average: EMG/TI, peak EMG activity, and minute EMG output: EMGpeak times frequency) rose progressively during incremental increases in elastic loads regardless of age. The increase in EMG output per minute (figure 3) was significantly higher in the older subjects for the addition of an equivalent elastic load whether the values were analyzed as raw values, as a difference from baseline, or as a percentage change from baseline. This was not the case for single-breath EMG indices of slope-moving average and rate-moving average, which rose markedly during loading but were not different between age groups. Respiratory work output or inspiratory power (i,e., work output over time) rose consistently in both age groups during loading. The increases at either age were predominantly the result of changes in the external work comporent of total inspiratory work. Because external work output is negligiblein the unloaded state, the absolute valuesobtained during loading are compared in figure 4. The older subjects generated a significantly higher external work output at each levelof added elastance.
70
* 80
50
o
Day 24 (-)
20
10 O'-----L....----L....----.L---.L---...J
1
3
4
Multiple. of SUellne Ela.tance
Fig. 2. Changes in Paco2 levels during elastic loading. There was no statistical effect on Day 2 (slope: X ± SE = 0.59 ± 0.30, p < 0.1), whereas Day 24 subjects underwent a significant rise in Paco2 (X ± SE = 2.02 ± 0.53, p < 0.0005). There was a significant group difference at p < 0.05.
755
DEVELOPMENTAL RESPONSE TO ELASTIC LOADING IN THE NEWBORN
1000
Fig. 3. Changes in neural minute output (Peak EMG times respiratory frequency in breaths per minute) during elastic loading trials. There was a significant increase at both ages (Day2 slope: X ± SE = 72.6 ± 10.1, p < 0.0001 when compared with null effect; Day 24: X ± SE = 120.0 ± 16.3, P < 0.0001 whencomparedwith null effect). Groupdifferencewassignificantat p < 0.02.
i
~
800
o
•
.2I
800
!
I z
1;
J
-
400
•
..
..
•
200
·0···.... i - >
..
Day 1 (0)
8 I
0
_ _~_ _---L..._ _.....J
a
2
1
Dayl4(-)
···········~··········:············
..o
oL-.r..:..:~~~_--L
0
..
4
a
8
Multiple. of SU.I.... Elutanc.
Discussion
Paco1 values statistically better than did the older subjects, who demonstrated a small but significant increase in Paoo, during loading. The conclusion apparent in these ventilatory, arterial, and electromyographic findings is that the normal newborn primate is equipped from birth with a mature mechanoreflex system regarding its capacity to respond to a sustained elastic loading challenge.
This study is the first to characterize the neonatal steady-state respiratory response to an added external elastance. We were able to perform this investigation with the same measurement system in neonatal and mature subjects without anesthesia while obtaining arterial blood samples and an electromyographic index of respiratory neural activity. Contrary to our expectations, the 2-day-old infants displayed a remarkably similar ventilatory response to that recorded in their more mature counterparts. Adjustments in the volumetric and timing characteristics of respiration did not differ between age groups during loaded breathing. A strong compensatory response was present at 48 h of age both in terms of neural drive (EMG) and force output (external work). Thus, the newborn was not at a disadvantage by virtue of its age when confronted with a respiratory elastic loading challenge. We previously reported that the neonate had an unusual ability to defend Paco11evelsduring airway resistiveloading (6). This observation can now be extended to include elastic loading. The newborns maintained a constant Paco, throughout the range of addedelastances despite a consistent decline in VEe In fact, they actually defended their baseline
Critique The precautions cited in our earlier study of the response to resistive loading apply similarly to this investigation (6). First, a tracheostomy tube was employed to eliminate the possibilityof leakage and rebreathing associated with the use of a face mask or nasal prongs. Consequently, postnatal differences in the loading responses occurred apart from any influence of upper airway structures. Second, elastic loads were apportioned as a multiple of the total internal elastance for each age group. This approach, while common in adult studies, may not be appropriate during development when growth and neuronal maturation (13, 15) cause ventilatory demand and work requirements to differ markedly despite the presence of equivalent elastic loads. Third, measurements of internal respiratory work in the newborn may signifi-
aooo c i
4000
ii
aooo
E
Fig. 4. Externalworkcomponentof total respiratoryworkoutputduringelasticloading. Day2 slope = 242.3 ± 13.6, differencefrom baseline: p < 0.0001. Day24 slope = 440.0 ± 53.6, differencefrombaseline: p < 0.0001. The older subjects generatedsignificantly more work output: p < 0.01.
i
M
..
2000
ii c:
!
.
Day 14 (.)
. . . 0:..•. '--.. . . . . . .•. . . . . . . .· •· · · · ·
~
o
1000
1&1
o .1
..
a Multiple. of
•
su.,....
4 Ela.tance
I
~.~ 8
(0)
cantly underestimate actual work performance during loaded breathing if chest wall distortion or "paradoxical breathing" is present (24). . In addition, we wereparticularly concerned that the developmental differences in the present study might be dependent on "outlying" data points in the older subject group. To test for this possibility,weanalyzed the data after removing 1, 2, and then 3 extreme values in the VE, Paco1, EMG/min, and external work plots. While these manipulations did alter the slope of the Day 24 results, at no time were the statistical relationships to baseline altered, i.e., VE, Paco., EMG/ min, and external work output remained significantly different from baseline. These data are included in the analysis since the statistical significance of the results is not entirely dependent on them, since these points were not consistently from the same animal, and because we have no experimental basis for their exclusion.
Load Compensation Both age groups exhibited a vigorous compensatory response to loading as indicated by consistent increases in external and total respiratory work output. The compensatory response was the result of enhanced neural drive at each age since all EMG indices consistently increased during loading and rose in proportion to the magnitude of the externalload. Thus, the neonatal subjects demonstrated a proficient neural response even though chemosensory and mechanoreflex systems are immature at this time (13-15). The effectiveness of the neonatal response was surprising since the ability of the newborn to convert neural drive into force output is thought to be compromised compared with that in mature subjects. Characteristics purported to impede force generation in the newborn include (1) high chest wall compliance (5, 25), (2) immature muscle fiber composition (26, 27), (3) poor coordination of diaphragm efforts with intercostal and accessory muscles (10), and (4) immature pulmonary, muscle, and joint receptors involved in stabilization of the chest wall (28, 29). At the outset of this study, we anticipated that a sustained elastic loading challenge would exacerbatethese neonatal inadequacies and highlight any incompetence of the respiratory apparatus. To obtain an index of the effectiveness of the respiratory system in our subjects during loading, minute EMG activity was
756
LAFRAMBOISE, STANDAERT, MILLEY, AND WOODRUM
correlated with inspiratory work output per animal. An ineffective newborn respiratory "pump" would be expected to generate reduced pressures and air flows (i.e., work output) during loading for a given level of inspiratory "drive" (i.e., EMG output) compared with that in mature subjects. It was interesting that there was no difference with age in the conversion of EMG activity into either total or external work output during loading (slope of total inspiratory work per minute versus EMG output per minute: mean ± SE, Day 2 = 0.17 ± 0.016; Day 24 = 0.17 ± 0.038). In fact, the fidelity with which neural drive was translated into work output among the young subjects was surprising. Regression coefficients exceeded 0.95 within individual subjects and r = 0.89 for the group whether EMG was plotted against total or external work output. These data indicate that the newborn is not singularly susceptible during elastic loading to any mechanical instability in converting neural drive to compensatory force output when compared with mature subjects. Furthermore, these data reinforce the conclusion that the newborn compensatory response approximates that of mature subjects since both groups exhibited elevated neural and force output and an equally effective defense of ventilation. These findings do not rule out the possibility that chest wall distortion occurred during loaded breathing in these infants, but if distortion occurred, it affected both age groups equally.
Developmental Effects The most significant effect of age in this study concerned the maintenance of arterial CO 2 homeostasis during elastic loading. It was previously demonstrated in a similar population of these infants that arterial homeostasis could be preserved despite a nearly 300/0 reduction of VE induced by resistive loading (6). The data obtained in this study corroborate the earlier findings since consistent decreases in VE (mean ± SO = -12 ± 90/0 on largest load) did not alter Paeo, in the newborn group. Unlike the previous study, the older subjects were unable to maintain ventilation during elastic loading, and VE values fell approximately 300/0 below baseline on the largest load. But Paco, rose in direct correlation reaching values nearly 300/0 above baseline. Thus, whatever mechanisms are employed by the newborn to maintain Paoo, are unavailable to or ineffective in older subjects whose Paoo, and VE are linearly coupled. We can only speculate as to
the nature of these mechanisms. In principle, a reduction in physiologic dead space or in metabolic rate can account for this phenomenon in the newborn. However, it is known that increases in external work during loaded breathing are associated with elevated oxygen consumption in adult humans and anesthetized dogs (30, 31). Therefore, a fall in metabolic rate seems unlikely, but there are no definitive measurements available for the newborn during loading to address this issue. A specific examination of this phenomenon in the newborn is necessary to elucidate the mechanisms responsible for Paco, stability despite significant alterations in VE. The data obtained in this and in our previous study support the hypothesis that newborns preserve Paoo, and conserve energy output in preference to strictly defending ventilation during loaded breathing (6). Although the data suggest that neonates employ this strategy with considerable success, it is important to recognize that there are limits to the newborn's ability to maintain Paco2 • During preliminary selection of loads to be used in this study and a prolonged resistive loading study (32), a broad range of added elastances and resistances were tested. Once a sufficiently large load was added to the airway, Paco2 did indeed rise in the newborns just as for more mature subjects. However, the newborns tolerated 3.5 times the added resistance and 1.5 times the added elastance required to elicit CO2 retention in the older subjects. These loads invariably awakened the subjects, and they did not meet the criterion to be included in this study. But these data provide further reinforcement to the idea that the healthy neonate has a unique capacity to defend arterial blood gas composition during loaded breathing. The young infants displayed an equivalent ventilatory response (figure 1)despite a relatively lower compensatory drive, i.e., smaller increases in EMG/min and external work output (figures 3 and 4). These differences may be explained by the doubling of baseline VTthat occurred with maturation, thereby increasing the baseline elastic work output per breath by four times in the older subject group (33). Doubling the intrinsic elastance by loading in the older subjects required that they do twice as much external work as the newborns to maintain VT.By this interpretation, the process of maturation appeared to be disadvantageous to the older subjects. It necessitated that they perform significantly more work and ex-
pend more energy than the newborns to accomplish a comparable ventilatory defense. A correlative argument can be made to explain the elevated EMG results in the older subjects since increased work requires augmented muscle force generation and the recruitment of additional muscle motor units. It is tempting to speculate that the increased work output (external or total inspiratory work) at a given load in the older subjects accounts for differences in their hemodynamic responses compared with those in the newborns. The 24-dayold subjects performed more work in mounting a defense of ventilation equal to that of the neonates, but at a higher metabolic cost and an increase in Paco.. One impression, then, is that the response of older subjects was less "efficient" than that in the newborns, who defended VE to the same degree with a smaller work and energy expenditure. On the other hand, it is important to recognize that maturation confers obvious advantages on older subjects in terms of gas exchange, muscular performance, and mechanical properties of the respiratory apparatus such that they are capable of meeting additional work demands. Perhaps scaling the loads as a multiple of intrinsic elastance put the older subjects at a disadvantage since they were required to defend a higher ventilation. We attempted to control for this possibility by normalizing the data as a percent change or based on body weight, but neither manipulation markedly altered the results. Furthermore, it is not established whether absolute or relative changes in these variables, e.g., work output, should be used to compare subjects with age and size differences during loaded breathing. Additional knowledge of the relationship between work rate, energy expenditure, and Paoo, during loaded breathing in the newborn is necessary to determine whether they actually function at a physiologic "advantage" compared with mature subjects. However, several studies now indicate that the response of the newborn to airway loading includes an attenuated effect on arterial CO 2 accumulation compared with that in older subjects (6, 34). In conclusion, the hypothesis that the neonate is particularly susceptible to ventilatory compromise during loaded breathing is not supported by this study. It may be that clinical observation of the hospitalized neonatal population was the source of this impression of vulnerability. Variables such as prematurity, reduced birth weight, cardiopulmonary disease,
DEVELOPMENTAL RESPONSE 10 ELASTIC LOADING IN THE NEWBORN
and nutritional deficits could put a hospitalized infant at a disadvantage compared with normal newborns. Investigation of the role of these variables in the loading response is warranted. However, the conclusion evident from this investigation is that the normal newborn primate, when confronted with an elastic load, is endowed with a sufficiently mature mechanoreflex system to generate a sustained response that is comparable to more mature subjects. Acknowledgment The writers thank Krishna Fells and Richard Tuck for excellent technical assistance in the performance of these studies. Thanks also to Etta Yolk for compiling the graphs, and Karen Zak for preparation of the manuscript. References 1. Cherniack NS,Altose MD. Respiratoryresponses to ventilatoryloading. In: Hornbein 00.Regulation of breathing. Part II. NewYork:MarcelDekker, 1981; 905-64. 2. Adler SM, Thach m; Frantz ID III. Maturational changes of effective elastance in the first 10 days of life. J Appl Physiol 1976; 40:539-42. 3. Gerhardt T, Bancalari E. Components of effective elastance and their maturational changes in human newborns. J Appl Physio11982; 53:766-9. 4. Kosch PC, Davenport PW, Wozniak JA, Stark AR. Reflexcontrol of inspiratory duration. J Appl Physiol 1986; 60:2007-14. 5. Heldt G. Development of stability of the respiratory system in preterm infants. J Appl Physiol 1988; 65:441-4. 6. LaFramboise WA, Standaert TA, Guthrie RD, Woodrum DE. Developmental changes in the ventilatory response of the newborn to added airway resistance. Am Rev Respir Dis 1987; 136:1075-83. 7. Frantz 10, Milic-Emili J. The progressive response of the newborn infant to added respiratory loads. Respir Physiol 1975; 24:233-9. 8. Olinsky A, Bryan MH, Bryan AC. Response
m
of newborn infants to added respiratory loads. J Appl Physiol 1974; 37:190-3. 9. 'Iaeusch HW, Carson S, Frantz ID, Milic-Emili J. Respiratory regulation after elastic loading and COl rebreathing in normal term infants. J Pediatr 1976; 88:102-11. 10. Knill R, Andrews W, Bryan AC, Bryan MH. Respiratory load compensation in infants. J Appl Physiol 1976; 40:357-61. 11. Boychuk RB, Seshia MM, Rigatto H. The immediate ventilatory response to added inspiratory elastic and resistive loads in preterm infants. Pediatr Res 1977; 11:276-9. 12. 'Irippenbach T, KellyG. Phrenic activity and intercostal muscle EMG during inspiratory loading in newborn kittens. J Appl Physiol 1983; 54:496-501. 13. Guthrie RD, Standaert TA, Hodson WA, Woodrum DE. Development of COl' sensitivity: effects of gestational age, postnatal age, and sleep state. J Appl Physiol 1981; 50:956-61. 14. Woodrum DE, Standaert TA, Mayock DE, Guthrie RD. Hypoxic ventilatory response in the newborn monkey. Pediatr Res 1981; 15:367-70. 15. LaFramboise WA, lUck RE, Woodrum DE, Guthrie RD. Maturation of eupneic respiration in the neonatal monkey. Pediatr Res 1984; 18:943-8. 16. LaFramboise WA,Woodrum DE. Elevateddiaphragm electromyogram during neonatal hypoxic ventilatory depression. J Appl Physiol 1985; 59:1040-5. 17. Nelson NM. Respiration and circulation after birth. In: Smith CA, Nelson NM, OOs. The physiology of the newborn infant. Springfield, IL: Charles C Thomas, 1976; 117-262. 18. Ruppenthal Ge. Survey of protocols for nursery-rearing infant macaques. In: Ruppenthal OC, 00. Nursery care of nonhuman primates. New York: Plenum Press, 1979; 165-85. 19. Standaert TA, Truog WE, Guthrie RD, et al. Growth and development of the term and premature monkey Macaca nemestrina: cardiovascular and respiratory changes during the first 3 weeks of life. Am J Primatol 1984; 19:528-33. 20. LaFramboise WA, Guthrie RO, Standaert TA, Woodrum DE. Pulmonary mechanics during the ventilatory response to hypoxemia in the newborn monkey. J Appl Physiol 1983; 55:1008-14. 21. Asher MI, Coates AL, Collinge JM, MilicEmili J. Measurements of pleural pressure in neo-
757 nates. J Appl Physiol 1982; 52:491-4. 22. Godal A, Belenky DA, Standaert TA, Woodrum DE, Grimsrud L, Hodson WA. Application of the hot-wire anemometer to respiratory measurements in small animals. J Appl Physiol 1976; 40:275-7. 23. LaFramboise WA, lUck RE, Standaert TA, Woodrum DE. An elastic loading system for ventilatory studies in small animals. J Appl Physiol 1983; 54:314-7. 24. Guslits BG, Gaston SE, Bryan MH, England SJ, Bryan AC. Diaphragmatic work of breathing in premature human infants. J Appl Physiol1988; 1410-5. 25. Avery ME, Cook CD. VOlume-pressure relationships of lungs and thorax in fetal, newborn, and adult goats. J Appl Physiol1961; 16:1034-8. 26. KeensTO, Bryan AC, LevisonH, lanuzzo CD. Developmental pattern of muscle fiber types in human ventilatory muscles. Am J Physiol 1978; 44:909-13. 27. Maxwell tc, McCarter RJM, Kuehl TJ, Robstham JL. Development of histochemicaland functional properties of baboon respiratory muscles. J Appl Physiol 1983; 54:551-61. 28. Kalia M. Visceral and somatic reflexes produced by J pulmonary receptors in newborn kittens. J Appl Physiol 1976; 41:1-6. 29. Duron B, Jung-Caillol MC, Marlot D. Myelinated nerve fiber supply and muscle spindles in the respiratory muscles of cat: quantitative study. Anat Embryol (Bert) 1978; 152:171-92. 30. Collet PW, Perry C, Engel LA. Pressure-time product, flow, and oxygen cost of resistivebreathing in humans. J Appl Physiol 1985; 58:1263-72. 31. Robertson CH, Foster GH, Johnson RL. The relationshipof respiratory failureto the oxygenconsumption of lactate production by and distribution of blood flow among respiratory muscles during increasing inspiratory resistance. J Clin Invest 1977; 59:31-42. 32. Watchko JF, Standaert TA, Mayock DE, 1\viggs G, Woodrum DE. Ventilatory failure during loaded breathing: the role of central neural failure. J Appl Physiol 1988; 65:249-55. 33. Otis AB, Fenn WA, Rahn H. Mechanics of breathing in man. J Appl Physiol1950; 2:592-607. 34. Abbasi S, Duara S, Shaffer T, Fox W. Effect of external inspiratory loading on ventilation of premature infants. Pediatr Res 1984; 18:150-4.
WILLIAM A. LAFRAMBOISE, THOMAS A. STANDAERT, J. ROSS MILLEY, and DAVID E. WOODRUM
Introduction
The newborn is assumed to be at a disadvantage when confronted with a respiratory mechanical load such as an added airway resistance or elastance (1). This assumption is supported by the fact that mechanoreflex systems critical for stabilizing ventilation are immature at birth and require a postnatal transition period before they reach maturity (2-5). Werecently studied the response of newborn monkeys to added external airway resistances in order to obtain direct evidence of immaturity in their response to mechanical loading (6). Contrary to our expectations, normal neonates exhibited a robust compensatory response and defended blood gas composition much like more mature subjects. The present study was undertaken to determine the neonatal response to sustained elastic loads. Studies of elastic loading in human infants have primarily been restricted to observations of inspiratory pressure changes during a complete airway occlusion (2, 7-9) or brief exposure to an external elastic loading system (4,8-11). Investigations conducted to date in newborn animals have been compromised by the need for anesthesia in order to obtain more invasive measurements of parameters involved in the loading response such as phrenic nerve output or respiratory muscle electromyograms(12). To overcome these restrictions, we studied a monkey species (Macaca nemestrina) that exhibits a similar postnatal potentiation ofchemosensory and mechanoreflex systems as the human infant (13-15). In this animal model, we have been able to obtain direct electromyographic recordings from the diaphragm without the need for surgery or general anesthesia (16). Immediate load compensation exists in human infants subjected to elastic loads (10), but it is not known whether load compensation takes place during sustained elastic loading. By comparing 752
.
SUMMARY Postnatal development of the steady-state response to Inspiratory elastic loading was studied In eight 48-h-old and eight 24-day-old unanesthetized, tracheostomlzed monkeys. Both age groups exhibited a fall In minute ventilation (VE)with loads of two to five times baseline respiratory elastance. There was no statistical difference In the ventilatory response between age groups. The response patterns of both groups were characterized by a fall In both tidal volume (VT) and mean Inspiratory flow (VTITI) associated with a prolongation of TI and Tlmot. All subJects demonstrated a significant load compensatory response both In terms of neural drive (diaphragmatic EMGoutput) and force output (Inspiratory work production). Arterial CO2 Increased significantly during loading In the older subjects In linear correlation with the decline In VE, but the newborns did not exhibit a statistically significant alteration In PaC0 2 throughout the range of elastic loads. These data Indicate that normal newborns are capable of responding to an external elastic load and that the newborn response Is comparable to that of more mature subjects. AM REV RESPIR DIS 1990; 141:752-757
the steady-state response of neonatal and mature subjects to a range of elastic loads, weundertook to determine whether the neonatal response to a sustained loading challenge was immature compared with that in older subjects. Methods Subjects Sixteen infant monkeys were delivered via cesarean section at 156 days of gestation (0.93 of term). A cannula was placed in an umbilical artery at delivery and blood gas measurements were obtained to determine whether an adequate Pao2 (Pao2 > 50 mm Hg) could be maintained without supplemental oxygen. No studies were undertaken until 48 h after birth to allow for lung fluid clearance and elimination of major fetal shunts (17). Eight infants were studied at 48 h of age and eight subjects were studied at 21 to 24 days of postnatal age. Infants assigned to the older group had their umbilical cannula removed and were reared in a primate nursery according to standard protocol (18). All subjects exhibited a regular respiratory pattern and normal arterial gases in room air at the time of study, ·indicating that they had established stable airways and lung volume (15, 19).
Measurements The details of our system for studying these infants have been previously published (15, 16). The infants were studied in the supine position on a sponge rubber mattress while lightly restrained with thin velcro straps across each arm and leg. These newborns, like hu-
mans, are very quiescent in the first few days of life, and the restraints served primarily to secure them in a constant position. A flexible tracheostomy tube (resistance, 0.25 em H 20/L/min at 3 L/min) was inserted after infiltrating the incision site with a topical anesthetic (chloroprocaine Hel). It was necessary to use ketamine (10 mg/kg) in the older monkeys to achieve appropriate sedation for this surgical procedure and for the placement of a femoral artery cannula. A water-filled catheter with an inner diameter of 1.5 mm was positioned in the esophagus to determine esophageal pressure for caleulation of chest wall and pulmonary elastance values. The catheter tip was located so as to obtain maximal pressure excursions in phase with inspiratory flow but with minimal interference from cardiac pulsations. As in previous studies (20), this was consistently found in the distal esophagus approximately
(Received in original form October 13, 1988 and in revised form August 21, 1989) 1 From the Department of Pediatrics, Division of Neonatal and Respiratory Diseases, University of Washington, Seattle, Washington, and the Department of Pediatrics, Division of Neonatology, University of Pittsburgh, Pittsburgh, Pennsylvania. 2 Supported by Grants HL-19187 and RR-OOI66 from the National Institutes of Health and by Grant 18273from the National Institute of Mental Health. 3 Correspondence and requests for reprints should be addressed to William A. LaFramboise, Department of Pediatrics, Magee-Womens Hospital, Forbes Avenue and Halket Street, Pittsburgh, PA 15213.
753
OEVELOPMENTAL RESPONSE TO ELASTIC LOADING IN THE NEWBORN
I em above the cardiac sphincter as determined by fluoroscopy and by direct measurement. After the infant was connected to the nonrebreathing valve, the accuracy of the esophagealpressure measurements was further substantiated with the "occlusion test" (21). Passive chest wall elastance was determined before connecting the infants to the valve for .he loading protocol by hyperventilating them Nith 100070 oxygen until they become apneic. Measured volumes of oxygen were introduced nto the respiratory system raising tracheal pressure in increments of 5 em H 20 from FRC :0 a maximal respiratory system recoil pressure of 30 em H 20. The volume increments olotted against the corresponding esophageal oressure changes delineated the pressurefolume curve for the chest wall. This measurement was checked throughout the day by Iisconnecting the subject from the loading rystem and injecting the necessary volume of ~as to obtain an airway pressure of 30 cm H 20. I'he corresponding esophageal pressure change divided by the injected volume gave 1 rapid estimate of chest wall elastance to cor.oborate earlier measurements. Pulmonary elastance was determined while .he infants breathed spontaneously through .he non-rebreathing valve with the esophageal cannula in place. A hot wire anemometer olaced in line with the inspiratory circuit in:licated changes in background flow, which vere integrated (HP-8811A; Hewlett-Packard, Waltham, MA) to obtain tidal volume (22). Ihe elastic pressure differential divided by the .nspired tidal volume represented dynamic nilmonary elastance. This pressure difference Nas obtained by transecting the esophageal oressure trace from the zero flow point at end sxpiration to the zero flow point at end inspiation. The area of the esophageal pressure .race exceeding this elastic recoil line was coniidered to be the resistive pressure increment aecessary to generate flow through the respiatory system during inspiration (20). Pulmorary resistance was calculated by integrating .his resistive pressure increment by planime:ry and then dividing that value by the concomitant integral of inspiratory flow (VT).A ninimum of 50 such determinations were nade during unloaded breathing, and the redstance of the valve and tracheal tube were mbtracted to give the average pulmonary inipiratory resistance of each subject. Resistance
was calculated in this manner to offset the tendency for increasing lung volume to decrease resistance within a breath. The measurements of pulmonary and chest wall mechanics were made preliminary to the loading study to assure that each subject fell within the range for normal newborns established in a previous population (15, 19). The design of the valve and loading chamber used to present the added elastance was previously published in detail (23). A unique feature of the system is that a constant elastic load is presented to each inspiration by venting the loading chamber during each expiration. The loads chosen were 1.3,2.1, 3.0,4.6, and 6.6 em H 20/ml, which were added to a mean internal elastance (Behest wall plus Elung) in our subjects of 1.85 ± 0.23 em H 20/ml on Day 2 and 1.55 ± 0.37 em H 20/ml on Day 24. To switch from the free-breathing circuit to the loading circuit required a 90-degree rotation of a silent rotary valve, which could be completed while the infant exhaled and without altering the expiratory pathway. Volumetric ventilatory data were obtained by integration of flow changes in the expiratory circuit of the non-rebreathing valve during baseline and loaded conditions. These flow changes were determined by the hot-wire anemometer located downstream from the expiratory port (22). Ventilatory components derived from flow changes, e.g., tidal volume and mean inspiratory flow (VT/TI) and from timing changes, e.g., inspiratory duration (TI), expiratory duration (Ts), and inspiratory duty cycle (TI/Uot) were resolved from the flow trace by operating the chart recorder at speeds as much as 150 mm/s for maximal resolution. A direct index of neural activity was obtained by percutaneously placing two insulated stainless steel wires in the crural diaphragm of our subjects under local anesthesia (16).A differential recording configuration was used for comparison, with a reference electrode placed subdermally at the base of the buttocks. EMG signals were amplified 5,000 times (Model P511J; Grass Instruments, Quincy, MA) prior to recording on FM tape (No. 5600C; Honeywell, Denver, CO). Further signal processing utilized a Service Associates 414 analog processor where the raw signal was filtered between 30 and 3,000 Hz with 60 and 120 Hz notch filters activated. Moving average EMG was obtained by full
wave rectification of the filtered signal and R-C integration with a time constant of 50 ms. In order to maintain VE during loading, compensatory efforts that serve to increase inspiratory force generation are necessary. To obtain an indication of such compensatory output, inspiratory work rate was measured once a steady state was achieved. Work was partitioned into an external and an internal component. The external work component was defined as the work involved in moving air through the external encumbrances of the measurement system, i.e., the tracheal tube, the non-rebreathing valve, and the elastic loading chamber. It was calculated as the integral of the product of inspiratory air flow and airway pressure measured at the tracheal tube opening (6). The pulmonary work of breathing during inspiration was calculated using the values for pulmonary elastance, inspiratory resistance, tidal volume, and respiratory rate using the same formulation applied in the external work an.alysis. Similarly, the work of moving the chest wall was computed and added to the pulmonary work to obtain total internal inspiratory work. The sum of these internal and external work components was taken to represent the total inspiratory work of breathing for the preload state and the various trial conditions. Baseline respiratory values for the two age groups in this study are presented in table 1. These values are consistent with previous studies from our laboratory (6, 13-16, 19,20).
Protocol The protocol for this study required that the infants be exposed to a range of elastic loads while in NREM sleep until a ventilatory plateau was achieved. The distinction of NREM sleep from rapid eye movement sleep or the awake state was determined using standard behavioral criteria adapted for infants (13). Baseline ventilation was recorded over a stable 10-min period before imposition of one of the loads, the magnitude of which was randomly assigned. One minute was allowed for adjustment on the part of the subject after a load was added to inspiration, and then ventilation was followed each minute for a minimum of 10 and a maximum of 20 min. Preliminary analysis indicated that the 5-, 10-, and 20-min VE values were not different. The oxygen concentration in the loading cham-
TABLE 1 BASELINE RESPIRATORY VALUES·
(mllmin)
VT (ml)
f (breaths/min)
TI (s)
Ecw (em H2O/ml)
EL (em H2O/ml)
Pa02 (mmHg)
Paco2 (mmHg)
Respiratory Work (g-em·min-1)
150 23 251 71
2.37 0.49 4.12 0.62
65.4 15.3 61.3 16.4
0.48 0.12 0.50 0.13
0.18 0.11 0.31 0.06
1.67 0.64 1.23 0.52
72.4 9.5 99.5 14.5
35.4 4.0 34.2 2.3
443 118 1,228 454
Ve Day
2
X SO
24
X SO
Definition of abbreviations: \IE = minute ventilation; VT = tidal volume; f = respiratory frequency in breaths per minute; TI = inspiratory time; Ecw = chest wall elastance; EL = dynamic pulmonary elastance. * The effect of maturation on critical baseline variables in this study. Values are mean ± 1 SO for n = 8 on Day 2 and n = 8 on Day 24.
754
LAFRAMBOISE, STANDAERT, MILLEY, AND WOODRUM
ber was adjusted to maintain Pao 2 during baseline and loading at approximately the same level.At the end of each 5-min interval, arterial blood gases were drawn to correlate with ventilatory, mechanical, and electromyographic data. If the infants aroused or exhibited REM sleep characteristics, data were not collected. Thirty minutes of recovery time were allowed between trials.
20
o
f
Results
The 2-day-old infants slept throughout the loading period on all levels of added elastance. This was not the case for the older subjects, who often aroused on the largest load, forcing premature termination of that run. When the subjects remained asleep for the duration of the loading challenge, a ventilatory steady state was attained within the first 3 min, and data were collected over a 10-to 20min time span. There were no statistical changes in the response obtained at 10 versus 20 min of loaded breathing, so we have chosen to present the former as a representative steady state since all subjects breathed against each load for at least 10 min. VE fell significantly in both age groups during elastic loading (figure 1). When the slopes were compared between age groups, there was no statistically significant difference present. Even though VE consistently fell, Pac02 values did not change during loading in the youngest infants. Pac02 was significantly elevated in the older age group (figure 2). When the changes in Paco, were compared be-
Day 24 (.)
~
o
"#
Statistics Volumetric and timing components of ventilation, the respiratory mechanics, work data, and electromyographic responses were tested to determine the effect of loading by using analysis of covariance (ANOCOVA).Because of maturational changes in VE, VT, and lung and chest wall elastance, these variables collected during elastic loading werenormalized as a percentage difference from baseline to focus on the effects of the loading regimen with age apart from baseline changes. Conversion to percent change did not alter the distribution of the loading data around baseline. The linear relationship of the dependent variables to added elastance was calculated, and the slope of these relationships was then compared with zero using the t distribution to establish whether the added elastances had an effect on a given dependent variable. In order to discriminate an effect of postnatal maturation on the response to loading, we tested the slopes of the two age group relationships for differences by comparison to the t distribution. A p < 0.05 was considered to represent a statistically significant difference.
* *
o
*
-40
-80
-80
* ~
_ _'---_ _. L -_ _..l....-_ _..l....-_-----J
3
1
4
Fig. 1. Changes in ventilation during elastic loading. The baseline elastance was standardized for both age groups as a value of 1, and the elastic loads were scaled as a multiple of this baseline value (see table 1 and METHODS for actual values). TwO-dayold subjActs are represented as circles and 24-day-old subjects are crosses. Slope on Day 2: X ± SE = 2.5 ± 1.2, P < 0.03 when compared with null effect; Day 24: X ± SE = 5.0 ± 1.5,p < 0.003 when compared with null effect. Compared with one another, these slopes were not different (p = 0.21).
MUltiple. of Ba.ellne Ela.tance
tween age groups, there was a significant difference attributable to age. Conversion to a percentile scale did not alter these findings, Le., Paco, was not significantly altered during loading in the neonatal group, whereas it increased in the older subjects for the same range of elastic loads. The volumetric and timing components of ventilation demonstrated neither quantitative nor qualitative changes with age during loading. Loaded inspiratory times wereconsistently longer than control values (Day 2 slope: mean ± SE = 0.017 ± 0.005 s/unit added elastance, p < 0.003 compared with no change; Day 24 = 0.014 ± 0.004, p < 0.006; no difference across age), but they were not associated with any statistical change in respiratory rate. VT fellduring loading (Day 2 slope: mean ± SE = -0.042 ± 0.015 ml/unit added elastance, p < 0.01 compared with no change; Day 24 = --0.110 ± 0.025, p < 0.0001), but no statistical differences were discernible across age groups. Similarly, no statistical age effects could be demonstrated for the progressivedeclinein VT/TIthat occurred at both ages (Day 2 slope: mean ± SE = -0.202 t 0.035 ml/s/unit added elastance, p < 0.0001 compared with no changes; Day 24 = -0.387 ± 0.087, p< 0.0001).There were no maturational differences in Ti/Ttot during loading al-
though this index increased slightly in both age groups. All indices of diaphragmatic electromyographic output (slope movingaverage: EMGo•2 s, rate moving average: EMG/TI, peak EMG activity, and minute EMG output: EMGpeak times frequency) rose progressively during incremental increases in elastic loads regardless of age. The increase in EMG output per minute (figure 3) was significantly higher in the older subjects for the addition of an equivalent elastic load whether the values were analyzed as raw values, as a difference from baseline, or as a percentage change from baseline. This was not the case for single-breath EMG indices of slope-moving average and rate-moving average, which rose markedly during loading but were not different between age groups. Respiratory work output or inspiratory power (i,e., work output over time) rose consistently in both age groups during loading. The increases at either age were predominantly the result of changes in the external work comporent of total inspiratory work. Because external work output is negligiblein the unloaded state, the absolute valuesobtained during loading are compared in figure 4. The older subjects generated a significantly higher external work output at each levelof added elastance.
70
* 80
50
o
Day 24 (-)
20
10 O'-----L....----L....----.L---.L---...J
1
3
4
Multiple. of SUellne Ela.tance
Fig. 2. Changes in Paco2 levels during elastic loading. There was no statistical effect on Day 2 (slope: X ± SE = 0.59 ± 0.30, p < 0.1), whereas Day 24 subjects underwent a significant rise in Paco2 (X ± SE = 2.02 ± 0.53, p < 0.0005). There was a significant group difference at p < 0.05.
755
DEVELOPMENTAL RESPONSE TO ELASTIC LOADING IN THE NEWBORN
1000
Fig. 3. Changes in neural minute output (Peak EMG times respiratory frequency in breaths per minute) during elastic loading trials. There was a significant increase at both ages (Day2 slope: X ± SE = 72.6 ± 10.1, p < 0.0001 when compared with null effect; Day 24: X ± SE = 120.0 ± 16.3, P < 0.0001 whencomparedwith null effect). Groupdifferencewassignificantat p < 0.02.
i
~
800
o
•
.2I
800
!
I z
1;
J
-
400
•
..
..
•
200
·0···.... i - >
..
Day 1 (0)
8 I
0
_ _~_ _---L..._ _.....J
a
2
1
Dayl4(-)
···········~··········:············
..o
oL-.r..:..:~~~_--L
0
..
4
a
8
Multiple. of SU.I.... Elutanc.
Discussion
Paco1 values statistically better than did the older subjects, who demonstrated a small but significant increase in Paoo, during loading. The conclusion apparent in these ventilatory, arterial, and electromyographic findings is that the normal newborn primate is equipped from birth with a mature mechanoreflex system regarding its capacity to respond to a sustained elastic loading challenge.
This study is the first to characterize the neonatal steady-state respiratory response to an added external elastance. We were able to perform this investigation with the same measurement system in neonatal and mature subjects without anesthesia while obtaining arterial blood samples and an electromyographic index of respiratory neural activity. Contrary to our expectations, the 2-day-old infants displayed a remarkably similar ventilatory response to that recorded in their more mature counterparts. Adjustments in the volumetric and timing characteristics of respiration did not differ between age groups during loaded breathing. A strong compensatory response was present at 48 h of age both in terms of neural drive (EMG) and force output (external work). Thus, the newborn was not at a disadvantage by virtue of its age when confronted with a respiratory elastic loading challenge. We previously reported that the neonate had an unusual ability to defend Paco11evelsduring airway resistiveloading (6). This observation can now be extended to include elastic loading. The newborns maintained a constant Paco, throughout the range of addedelastances despite a consistent decline in VEe In fact, they actually defended their baseline
Critique The precautions cited in our earlier study of the response to resistive loading apply similarly to this investigation (6). First, a tracheostomy tube was employed to eliminate the possibilityof leakage and rebreathing associated with the use of a face mask or nasal prongs. Consequently, postnatal differences in the loading responses occurred apart from any influence of upper airway structures. Second, elastic loads were apportioned as a multiple of the total internal elastance for each age group. This approach, while common in adult studies, may not be appropriate during development when growth and neuronal maturation (13, 15) cause ventilatory demand and work requirements to differ markedly despite the presence of equivalent elastic loads. Third, measurements of internal respiratory work in the newborn may signifi-
aooo c i
4000
ii
aooo
E
Fig. 4. Externalworkcomponentof total respiratoryworkoutputduringelasticloading. Day2 slope = 242.3 ± 13.6, differencefrom baseline: p < 0.0001. Day24 slope = 440.0 ± 53.6, differencefrombaseline: p < 0.0001. The older subjects generatedsignificantly more work output: p < 0.01.
i
M
..
2000
ii c:
!
.
Day 14 (.)
. . . 0:..•. '--.. . . . . . .•. . . . . . . .· •· · · · ·
~
o
1000
1&1
o .1
..
a Multiple. of
•
su.,....
4 Ela.tance
I
~.~ 8
(0)
cantly underestimate actual work performance during loaded breathing if chest wall distortion or "paradoxical breathing" is present (24). . In addition, we wereparticularly concerned that the developmental differences in the present study might be dependent on "outlying" data points in the older subject group. To test for this possibility,weanalyzed the data after removing 1, 2, and then 3 extreme values in the VE, Paco1, EMG/min, and external work plots. While these manipulations did alter the slope of the Day 24 results, at no time were the statistical relationships to baseline altered, i.e., VE, Paco., EMG/ min, and external work output remained significantly different from baseline. These data are included in the analysis since the statistical significance of the results is not entirely dependent on them, since these points were not consistently from the same animal, and because we have no experimental basis for their exclusion.
Load Compensation Both age groups exhibited a vigorous compensatory response to loading as indicated by consistent increases in external and total respiratory work output. The compensatory response was the result of enhanced neural drive at each age since all EMG indices consistently increased during loading and rose in proportion to the magnitude of the externalload. Thus, the neonatal subjects demonstrated a proficient neural response even though chemosensory and mechanoreflex systems are immature at this time (13-15). The effectiveness of the neonatal response was surprising since the ability of the newborn to convert neural drive into force output is thought to be compromised compared with that in mature subjects. Characteristics purported to impede force generation in the newborn include (1) high chest wall compliance (5, 25), (2) immature muscle fiber composition (26, 27), (3) poor coordination of diaphragm efforts with intercostal and accessory muscles (10), and (4) immature pulmonary, muscle, and joint receptors involved in stabilization of the chest wall (28, 29). At the outset of this study, we anticipated that a sustained elastic loading challenge would exacerbatethese neonatal inadequacies and highlight any incompetence of the respiratory apparatus. To obtain an index of the effectiveness of the respiratory system in our subjects during loading, minute EMG activity was
756
LAFRAMBOISE, STANDAERT, MILLEY, AND WOODRUM
correlated with inspiratory work output per animal. An ineffective newborn respiratory "pump" would be expected to generate reduced pressures and air flows (i.e., work output) during loading for a given level of inspiratory "drive" (i.e., EMG output) compared with that in mature subjects. It was interesting that there was no difference with age in the conversion of EMG activity into either total or external work output during loading (slope of total inspiratory work per minute versus EMG output per minute: mean ± SE, Day 2 = 0.17 ± 0.016; Day 24 = 0.17 ± 0.038). In fact, the fidelity with which neural drive was translated into work output among the young subjects was surprising. Regression coefficients exceeded 0.95 within individual subjects and r = 0.89 for the group whether EMG was plotted against total or external work output. These data indicate that the newborn is not singularly susceptible during elastic loading to any mechanical instability in converting neural drive to compensatory force output when compared with mature subjects. Furthermore, these data reinforce the conclusion that the newborn compensatory response approximates that of mature subjects since both groups exhibited elevated neural and force output and an equally effective defense of ventilation. These findings do not rule out the possibility that chest wall distortion occurred during loaded breathing in these infants, but if distortion occurred, it affected both age groups equally.
Developmental Effects The most significant effect of age in this study concerned the maintenance of arterial CO 2 homeostasis during elastic loading. It was previously demonstrated in a similar population of these infants that arterial homeostasis could be preserved despite a nearly 300/0 reduction of VE induced by resistive loading (6). The data obtained in this study corroborate the earlier findings since consistent decreases in VE (mean ± SO = -12 ± 90/0 on largest load) did not alter Paeo, in the newborn group. Unlike the previous study, the older subjects were unable to maintain ventilation during elastic loading, and VE values fell approximately 300/0 below baseline on the largest load. But Paco, rose in direct correlation reaching values nearly 300/0 above baseline. Thus, whatever mechanisms are employed by the newborn to maintain Paoo, are unavailable to or ineffective in older subjects whose Paoo, and VE are linearly coupled. We can only speculate as to
the nature of these mechanisms. In principle, a reduction in physiologic dead space or in metabolic rate can account for this phenomenon in the newborn. However, it is known that increases in external work during loaded breathing are associated with elevated oxygen consumption in adult humans and anesthetized dogs (30, 31). Therefore, a fall in metabolic rate seems unlikely, but there are no definitive measurements available for the newborn during loading to address this issue. A specific examination of this phenomenon in the newborn is necessary to elucidate the mechanisms responsible for Paco, stability despite significant alterations in VE. The data obtained in this and in our previous study support the hypothesis that newborns preserve Paoo, and conserve energy output in preference to strictly defending ventilation during loaded breathing (6). Although the data suggest that neonates employ this strategy with considerable success, it is important to recognize that there are limits to the newborn's ability to maintain Paco2 • During preliminary selection of loads to be used in this study and a prolonged resistive loading study (32), a broad range of added elastances and resistances were tested. Once a sufficiently large load was added to the airway, Paco2 did indeed rise in the newborns just as for more mature subjects. However, the newborns tolerated 3.5 times the added resistance and 1.5 times the added elastance required to elicit CO2 retention in the older subjects. These loads invariably awakened the subjects, and they did not meet the criterion to be included in this study. But these data provide further reinforcement to the idea that the healthy neonate has a unique capacity to defend arterial blood gas composition during loaded breathing. The young infants displayed an equivalent ventilatory response (figure 1)despite a relatively lower compensatory drive, i.e., smaller increases in EMG/min and external work output (figures 3 and 4). These differences may be explained by the doubling of baseline VTthat occurred with maturation, thereby increasing the baseline elastic work output per breath by four times in the older subject group (33). Doubling the intrinsic elastance by loading in the older subjects required that they do twice as much external work as the newborns to maintain VT.By this interpretation, the process of maturation appeared to be disadvantageous to the older subjects. It necessitated that they perform significantly more work and ex-
pend more energy than the newborns to accomplish a comparable ventilatory defense. A correlative argument can be made to explain the elevated EMG results in the older subjects since increased work requires augmented muscle force generation and the recruitment of additional muscle motor units. It is tempting to speculate that the increased work output (external or total inspiratory work) at a given load in the older subjects accounts for differences in their hemodynamic responses compared with those in the newborns. The 24-dayold subjects performed more work in mounting a defense of ventilation equal to that of the neonates, but at a higher metabolic cost and an increase in Paco.. One impression, then, is that the response of older subjects was less "efficient" than that in the newborns, who defended VE to the same degree with a smaller work and energy expenditure. On the other hand, it is important to recognize that maturation confers obvious advantages on older subjects in terms of gas exchange, muscular performance, and mechanical properties of the respiratory apparatus such that they are capable of meeting additional work demands. Perhaps scaling the loads as a multiple of intrinsic elastance put the older subjects at a disadvantage since they were required to defend a higher ventilation. We attempted to control for this possibility by normalizing the data as a percent change or based on body weight, but neither manipulation markedly altered the results. Furthermore, it is not established whether absolute or relative changes in these variables, e.g., work output, should be used to compare subjects with age and size differences during loaded breathing. Additional knowledge of the relationship between work rate, energy expenditure, and Paoo, during loaded breathing in the newborn is necessary to determine whether they actually function at a physiologic "advantage" compared with mature subjects. However, several studies now indicate that the response of the newborn to airway loading includes an attenuated effect on arterial CO 2 accumulation compared with that in older subjects (6, 34). In conclusion, the hypothesis that the neonate is particularly susceptible to ventilatory compromise during loaded breathing is not supported by this study. It may be that clinical observation of the hospitalized neonatal population was the source of this impression of vulnerability. Variables such as prematurity, reduced birth weight, cardiopulmonary disease,
DEVELOPMENTAL RESPONSE 10 ELASTIC LOADING IN THE NEWBORN
and nutritional deficits could put a hospitalized infant at a disadvantage compared with normal newborns. Investigation of the role of these variables in the loading response is warranted. However, the conclusion evident from this investigation is that the normal newborn primate, when confronted with an elastic load, is endowed with a sufficiently mature mechanoreflex system to generate a sustained response that is comparable to more mature subjects. Acknowledgment The writers thank Krishna Fells and Richard Tuck for excellent technical assistance in the performance of these studies. Thanks also to Etta Yolk for compiling the graphs, and Karen Zak for preparation of the manuscript. References 1. Cherniack NS,Altose MD. Respiratoryresponses to ventilatoryloading. In: Hornbein 00.Regulation of breathing. Part II. NewYork:MarcelDekker, 1981; 905-64. 2. Adler SM, Thach m; Frantz ID III. Maturational changes of effective elastance in the first 10 days of life. J Appl Physiol 1976; 40:539-42. 3. Gerhardt T, Bancalari E. Components of effective elastance and their maturational changes in human newborns. J Appl Physio11982; 53:766-9. 4. Kosch PC, Davenport PW, Wozniak JA, Stark AR. Reflexcontrol of inspiratory duration. J Appl Physiol 1986; 60:2007-14. 5. Heldt G. Development of stability of the respiratory system in preterm infants. J Appl Physiol 1988; 65:441-4. 6. LaFramboise WA, Standaert TA, Guthrie RD, Woodrum DE. Developmental changes in the ventilatory response of the newborn to added airway resistance. Am Rev Respir Dis 1987; 136:1075-83. 7. Frantz 10, Milic-Emili J. The progressive response of the newborn infant to added respiratory loads. Respir Physiol 1975; 24:233-9. 8. Olinsky A, Bryan MH, Bryan AC. Response
m
of newborn infants to added respiratory loads. J Appl Physiol 1974; 37:190-3. 9. 'Iaeusch HW, Carson S, Frantz ID, Milic-Emili J. Respiratory regulation after elastic loading and COl rebreathing in normal term infants. J Pediatr 1976; 88:102-11. 10. Knill R, Andrews W, Bryan AC, Bryan MH. Respiratory load compensation in infants. J Appl Physiol 1976; 40:357-61. 11. Boychuk RB, Seshia MM, Rigatto H. The immediate ventilatory response to added inspiratory elastic and resistive loads in preterm infants. Pediatr Res 1977; 11:276-9. 12. 'Irippenbach T, KellyG. Phrenic activity and intercostal muscle EMG during inspiratory loading in newborn kittens. J Appl Physiol 1983; 54:496-501. 13. Guthrie RD, Standaert TA, Hodson WA, Woodrum DE. Development of COl' sensitivity: effects of gestational age, postnatal age, and sleep state. J Appl Physiol 1981; 50:956-61. 14. Woodrum DE, Standaert TA, Mayock DE, Guthrie RD. Hypoxic ventilatory response in the newborn monkey. Pediatr Res 1981; 15:367-70. 15. LaFramboise WA, lUck RE, Woodrum DE, Guthrie RD. Maturation of eupneic respiration in the neonatal monkey. Pediatr Res 1984; 18:943-8. 16. LaFramboise WA,Woodrum DE. Elevateddiaphragm electromyogram during neonatal hypoxic ventilatory depression. J Appl Physiol 1985; 59:1040-5. 17. Nelson NM. Respiration and circulation after birth. In: Smith CA, Nelson NM, OOs. The physiology of the newborn infant. Springfield, IL: Charles C Thomas, 1976; 117-262. 18. Ruppenthal Ge. Survey of protocols for nursery-rearing infant macaques. In: Ruppenthal OC, 00. Nursery care of nonhuman primates. New York: Plenum Press, 1979; 165-85. 19. Standaert TA, Truog WE, Guthrie RD, et al. Growth and development of the term and premature monkey Macaca nemestrina: cardiovascular and respiratory changes during the first 3 weeks of life. Am J Primatol 1984; 19:528-33. 20. LaFramboise WA, Guthrie RO, Standaert TA, Woodrum DE. Pulmonary mechanics during the ventilatory response to hypoxemia in the newborn monkey. J Appl Physiol 1983; 55:1008-14. 21. Asher MI, Coates AL, Collinge JM, MilicEmili J. Measurements of pleural pressure in neo-
757 nates. J Appl Physiol 1982; 52:491-4. 22. Godal A, Belenky DA, Standaert TA, Woodrum DE, Grimsrud L, Hodson WA. Application of the hot-wire anemometer to respiratory measurements in small animals. J Appl Physiol 1976; 40:275-7. 23. LaFramboise WA, lUck RE, Standaert TA, Woodrum DE. An elastic loading system for ventilatory studies in small animals. J Appl Physiol 1983; 54:314-7. 24. Guslits BG, Gaston SE, Bryan MH, England SJ, Bryan AC. Diaphragmatic work of breathing in premature human infants. J Appl Physiol1988; 1410-5. 25. Avery ME, Cook CD. VOlume-pressure relationships of lungs and thorax in fetal, newborn, and adult goats. J Appl Physiol1961; 16:1034-8. 26. KeensTO, Bryan AC, LevisonH, lanuzzo CD. Developmental pattern of muscle fiber types in human ventilatory muscles. Am J Physiol 1978; 44:909-13. 27. Maxwell tc, McCarter RJM, Kuehl TJ, Robstham JL. Development of histochemicaland functional properties of baboon respiratory muscles. J Appl Physiol 1983; 54:551-61. 28. Kalia M. Visceral and somatic reflexes produced by J pulmonary receptors in newborn kittens. J Appl Physiol 1976; 41:1-6. 29. Duron B, Jung-Caillol MC, Marlot D. Myelinated nerve fiber supply and muscle spindles in the respiratory muscles of cat: quantitative study. Anat Embryol (Bert) 1978; 152:171-92. 30. Collet PW, Perry C, Engel LA. Pressure-time product, flow, and oxygen cost of resistivebreathing in humans. J Appl Physiol 1985; 58:1263-72. 31. Robertson CH, Foster GH, Johnson RL. The relationshipof respiratory failureto the oxygenconsumption of lactate production by and distribution of blood flow among respiratory muscles during increasing inspiratory resistance. J Clin Invest 1977; 59:31-42. 32. Watchko JF, Standaert TA, Mayock DE, 1\viggs G, Woodrum DE. Ventilatory failure during loaded breathing: the role of central neural failure. J Appl Physiol 1988; 65:249-55. 33. Otis AB, Fenn WA, Rahn H. Mechanics of breathing in man. J Appl Physiol1950; 2:592-607. 34. Abbasi S, Duara S, Shaffer T, Fox W. Effect of external inspiratory loading on ventilation of premature infants. Pediatr Res 1984; 18:150-4.
