Biol. Neonate 36: 10 -17 (1979)
Assessment of Ventilation-Perfusion Inequality by aADN2 in Newborn Infants A.J.S. Corbet, J.A. Ross, P.H. Beaudry and L. Stern Departments of Newborn Medicine and Respiratory Function, Montreal Children’s Hospital and McGill University, Montreal, P.Q.
Key Words. Arterial-alveolar differences • Venous admixture • Low VA/Qc • Premature infants • Transient tachypnea Abstract. The contribution (Qo/Qt) of gas-filled air spaces with reduced ventilation-perfusion ratio (VA/Qc) to the production of total venous admixture in nondistressed premature infants and newborn infants with transient tachypnea was assessed by the aADNj and AaD0 j . The mean value for Qo/Qt in both nondistressed prematures and infants with transient tachypnea was 0.08. In both groups this represented about 30% of total venous admixture.
AaDoj PAco P,\N Paq aAD(jo; aADf^ PaCOj Pajsj ^ PaQ; E-'Iq Pv'cOj Pvo; R Qva/Qt Qs/Qt Qo/Qt Qo/Qc
Va /Q c
Alveolar arterial oxygen difference Alveolar carbon dioxide tension Alveolar nitrogen tension Alveolar oxygen tension Arterial alveolar carbon dioxide difference Arterial alveolar nitrogen difference Arterial carbon dioxide tension Arterial nitrogen tension Arterial oxygen tension Fractional inspired oxygen Mixed venous carbon dioxide tension Mixed venous oxygen tension Respiratory exchange ratio Total venous admixture Venous admixture due to true venoarterial shunt Venous admixture of low VA/Qc compart ment Venous admixture of low VA/Qc compart ment expressed as fraction of effective pulmonary blood flow (Qc) Ventilation-perfusion ratio
Introduction
Though in older children and adults a major cause of hypoxemia is ventilation-perfusion (Va /Q c) imbalance in open poorly ventilated regions of the lung, in newborn and premature infants a true venoarterial shunt is thought to be more important (23). After closure of fetal vascular channels such as the foramen ovale and ductus arteriosus, the true shunt must be situ ated in the lungs, either through vessels accom panying nonventilated air spaces, or through vascular channels not associated with air spaces (26). Whereas measurements of the AaDo2 reflect total venous admixture including the true veno arterial shunt, measurements of the aADNj allow an estimate of venous admixture in poor ly ventilated regions of the lung (8). In infants with hyaline membrane disease and relatively large true venoarterial shunts, a surprisingly
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List of recurring abbreviations
small fraction of total venous admixture is caused directly by perfusion of poorly venti lated regions of the lung (9). In the present study we have examined whether the same may be true of nondistressed premature infants and newborn infants with transient tachypnea, a common condition thought to be associated with abnormal postnatal retention of fetal lung fluid (5).
Materials, Methods and Calculations The 16 newborn infants included in this study were admitted to the Montreal Children’s Hospital for reasons associated with prematurity or respiratory distress. There were 6 nondistressed premature infants with normal chest radiographs and breathing room air at the time of study, aged 1-10 days. The remaining 10 infants had transient tachypnea which started at birth, required oxygen supplementation in 9 up to a maximum of 30-40% to relieve hypoxemia, and settled after 2 -5 days. At the time of study, at the age of 1-4 days, all but 1 infant with transient tachypnea breathed supplemental oxygen of 29-40%. The chest radiograph showed diffuse coarse linear densities with hyperaeration, consistent with abnormal retention of fetal lung fluid in all cases (31). Infants in the study were managed in standard incubators with abdominal skin temperature servo-controlled at 36.5 °C to mini mize oxygen consumption. All were receiving intra vascular infusions of glucose in water, and nondis tressed infants were commenced on milk formula feedings. None required constant positive pressure or mechanical ventilation, none had clinical evidence of patent ductus arteriosus or pneumonia, and all sur vived. In the case of infants breathing room air, the study was performed not less than 6 h after any temporary oxygen supplementation. Those receiving oxygen ther apy, after maintenance of relatively stable ambient levels for a period of at least 3 -4 h, were given a similar mixture of oxygen and nitrogen (within 5%) from a cylinder of compressed gas. This was delivered at a rate of 10 litcrs/min, warmed and humidified by a heated nebulizer, into a transparent plastic bag which enclosed the infant’s head and was tied loosely about the neck. In this way absolute constancy of
11
inspired nitrogen was obtained for as long as desired in a system which effectively prevented rebreathing. To avoid exchange of nitrogen across the skin (14), incubator oxygen was adjusted to that in the head bag. All oxygen concentrations were measured with a paramagnetic oxygen analyzer and rectal temperature with a mercury thermometer. After 2.0-2.5 h breath ing in the head bag, during which time precautions were taken to prevent all disturbance, anaerobic arte rial blood samples were drawn, 1.7 ml into a glassdisposable syringe and 1.2 ml into a calibrated Hamil ton gas-tight syringe for analysis of blood gases, pH and hemoglobin. The blood samples were drawn from indwelling umbilical artery catheters with the tip placed in the descending aorta at the level of the diaphragm, except in 3 infants in which the blood sample was collected by radial artery puncture under local anesthesia with procaine to prevent disturbance. All measurements of Pa^ ^ were made in duplicate with a gas chromatograph. The reproducibility of repeated measurements on the same samples was within ± 2 Torr. Gases were first extracted under vacuum in a Van Slyke apparatus modified in the manner suggested by Farhi et al. (12), and then analyzed in a gas chromatograph modeled after that described by Klocke (18). The gas thermal conduc tivity detector (Carle Instruments, Model 100) had a linear voltage response over the desired range. Thor oughly mixed 0.5 ml samples from the Hamilton gas-tight syringe were used. Care was taken to elimi nate even the tiniest bubbles of gas if present as these caused inconsistencies in the height of chromato graphic peaks. A small correction dependent on the level of inspired oxygen was made for the nitrogen content of heparin solution used to fill the syringe dead space before sampling. This ranged between 0 and 1.5% in our subjects. Calibration of the instru ment was performed by identical analyses of blood tonometered at 37.4 °C with humidified gas from the same cylinder breathed by the subject or with room air when appropriate. For this purpose 1.2 ml blood from the disposable syringe and a tonometer similar to that described by Finley et al. (13) was used. The nitrogen fraction of mixtures breathed by subjects was analyzed with the gas chromatograph using room air (P[sj 3 = 0.78) as the standard. The Paj^ was calculated from the equation (19): PaN j = H a/H t X F i N j X (P b - P H j O)
(1-0.012 |T t- T r ))
x
(I)
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aADjvj2 jn Newborn Infants
Corbet/Ross/Beaudry/Stem
12
where Ha = mean chromatographic peak height for nitrogen from the anaerobic arterial sample, H( = mean peak height for nitrogen from the tonometered sample, F in = fractional inspired nitrogen, Pu = barometric pressure, Ph ; o = water vapor pressure (47 Torr), and (1-0.012 |T t- T r |) is a correction factor for the difference (in °C) between rectal (Tr) and tonometer (Tt) temperatures, 0.012 being the Bunsen solubility coefficient for nitrogen in whole blood (12). The remaining blood from the disposable syringe was used for analysis of hemoglobin, Paoj; pH and P aco2The Pa0 j was measured polarographically using a Clarke-type electrode (Radiometer, E5016) calibrated at 2 points around the predicted value with gases of known oxygen composition analyzed by the method of Scholander (29). The values for PaQ; were cor rected for the few minutes delay before measurement, and for the difference between rectal and electrode temperatures (17). Arterial P aco 2 and pH were mea sured by the Astrup technique (Radiometer, Copen hagen). Arterial oxygen saturation was calculated from knowledge of the Pao2 and pH using the oxygen dissociation curve for neonatal blood (24). The standard alveolar gas equations (11) were used to calculate ideal Pa 0 and ideal Pan • 11 was as sumed that the Pa ^ q was the samc as P aço 2, that the overall R was 0.8 (1), and that rectal temperature was the same as alveolar temperature. The differences between ideal alveolar and arterial nitrogen and oxy gen tensions were then calculated:
Qo/Qc =
PaN 2 PA|\i 2
(5)
(Pb - P h 20 -Pvo 2 Pvco 2)-P a Nj
Qo/Qt = O '» /» < ! - * " * » >
(6)
1- Qo/Qc where Qo/Qc is the venous admixture due to the open poorly ventilated compartment expressed as a fraction of effective pulmonary blood flow (Qc), the Pv q ), was assumed to be 6 Torr more than the P aco 2>P^02 represents the mixed venous oxygen tension derived from the oxygen saturation curve (24), Pu is atmo spheric pressure and Ph 2o *s water vapor pressure at body temperature. Equation 5 is derived by comparing the measured aAD^j with the aADj^ if all blood perfused lung which was open but nonventilated, in which case Pa^, would be represented by (PgPh 2o - P v0 j -P vco 2) (22, 25). Equation 6 is derived from first principles by assuming that nitrogen in arterial blood is equal to the sum of nitrogen in blood passing through well-ventilated lung, blood passing through open but poorly ventilated lung and blood which constitutes a true shunt (9). The Qs/Qt could be calculated from the following equation:
( 2)
Qs/Qt = Qva/Qt- Qo/Qt aADNj = PaN 2- Pa n 2
Further, assuming that there was no diffusion defect, the AaD0 j was converted to Qva/Qt, which was calculated from the following equation (6): C co2-C a o 2 Qva/Qt =
(7)
(3)
(4)
C cO j - C v q ,
where Ccq 2, C ao; and Cvq 2 arc the oxygen contents of pulmonary end-capillary, arterial and mixed venous blood, respectively. These were calculated using a value of 1.34 ml oxygen for each gram of hemoglobin, a value of 0.003 m l/100 ml/Torr for oxygen dissolved in blood, and assuming that the difference between arterial and mixed venous oxygen saturation was 4 vol% (26, 28).
Table I. Data in newborn infants (mean ± SD)
GA weeks
BW g
Age days
Fi0 ;
Pao 2 Torr
Nondistressed premature infants (n = 6) 1,982 32.6 5.3 0.21 ± 4.0 ± 0.00 ± 2.6 ± 788
74 ± 10
Infants with transient tachypnea (n = 10) 2,644 2.0 0.32 37.1 ±1.4 ±0.06 ± 3.0 ± 588
75 ± 17
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AaD0 j = PAo2-P a0 ;
Making the same assumptions and in addition that Va /Q c of the open poorly ventilated compartment was essentially zero, the venous admixture due to this compartment (Qo/Qt) was calculated as follows (9, 25):
13
aAD[y|2 in Newborn Infants
The gestational age (GA) and birth weight (BW) of the 2 groups of infants, the age at study and the inspired oxygen concentration (F i0 ), the values for PaN2, Pao2, PacO j»and [H+], the values for AaDo2 and aADN j, and the calculated values for Qva/Qt, Qo/Qc, Qo/Qt and Qs/Qt are given in table I. In both groups, Qo/Qt was approximately 30% of total venous admixture. The infants with transient tachypnea and supplemental oxygen had higher values for AaDo2 and aA D ^ than nondistressed infants breathing room air, but there was no appre ciable difference in the values for Qva/Qt and Qo/Qt.
Discussion
Errors in Analysis Though the measurements of PaNj were highly reproducible (± 2 Torr), the possible errors are large compared with values for uADn (table I), and therefore reliance should be placed on mean rather than individual val ues. It was previously shown that equilibration at constant inspired nitrogen for 2 h is suffi
PaNj T orr
PaCOj T orr
|H *| nM H
cient to allow body nitrogen stores to stabilize and obtain reliable values for P a ^ in the presence of a venoarterial shunt (9). The most appropriate temperature to indicate the true significance of aADNj would be that of alveolar capillary blood, but since this is not measured, rectal temperature is substituted. As it is rea sonable to assume that alveolar temperature may be up to 0.5 °C higher than rectal (10), true values for aADNj may be 2 -3 Torr higher and AaD0j 2—3 Torr lower, in which case Qo/Qt would be increased by up to 0.03. The values obtained for aA D ^ and AaD0j depend on the assumed R, variation by 0.05 changing both in the same direction by 2—3 Torr. Although the effect on AaD0¡ is small and Qva/Qt negligible, the effect on aADN; is relatively large and the error in Qo/Qt may be as much as 0.03-0.05. All published studies of aADjvj in premature infants have assumed a value for R, usually 0.8 (9, 26) as in the present study, but sometimes 0.7 (21). If we had assumed a value of 0.7, the values for aADNj in at least 5 of 16 infants would have been negative, and all values would have been lower. It is, however, considered improbable that true values for aADj^ would be negative (11). While such results could be due to inaccuracy in the measurement o f PaN; or perhaps lack of steady
AaD0 j T orr
Qva/Qt
aADNj T orr
Qo/Qc
Qo/Qt
Qs/Qt
0.09
570 ±5
±5
43 ±5
29 ±9
0.25 ± 0.04
6 ±5
± 0.05
0.08 ± 0.06
0.17 ± 0 .0 7
489 ± 40
39 ±8
44 ±5
102 ± 35
0.28 ± 0.08
12 ± 11
0.09 ± 0.08
0.08 ± 0.07
0.20 ± 0.12
37
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Results
state conditions, we consider this unlikely in view of the excellent reproducibility in the measurements and precautions taken to prevent physical disturbance. Since all subjects were receiving intravascular infusions of glucose, it is not likely that values for R would be as low as 0.7, reflecting only the metabolism of fat. On the other hand, if we had assumed a value of 0.9 for R the aADNj would be higher, but such values for R would be unusual after the first few hours of life. Nevertheless, it is obvious that individual values for aA D ^ may not be reliable and more confidence should be given the mean, since the mean value for R is unlikely to vary far from the value of 0.8 assumed. There is a further problem with the values for aADN and AaD0 because the aADco in newborn infants may be higher than the as sumed value (21). If the aADco was lOTorr, then aADN2 would increase by 1 Torr and AaD0 would increase by 11 Torr, in which case values for Qva/Qt may be up to 0.03 higher and Qo/Qt increased by 0.01. Because the values for Qo/Qc were small they were not sensitive to Pv0; or PvCOj (see equation 5). Variation in Pv0j is limited because the oxygen dissociation curve is steep, while variation in PvCo 2 is likely in the opposite direction. In crease in both by a total of 10 Torr would be required to increase Qo/Qc by 0.01, and the error in Qo/Qt would be less. If the arterio venous oxygen difference varied from the as sumed value, Qva/Qt could change by as much as 0.1, but it would be accompanied by a change in Qo/Qc in the same direction due to changes in Pvq^ . The effect would reduce the error in Qo/Qt to less than that for Qo/ Qc, significantly less than 0.01 (see equa tion 6). In summary, problems with temperature and aADco may cause underestimation of aADN and Qo/Qt, but assumption of too high a value
Corbet/Ross/Beaudry/Stern
for R may balance this effect. The values for aADNj and Qo/Qt should be regarded only as reasonable estimates. Interpretation o f aADN and Qo/Qt Demonstration of any positive value for aA D ^ in nondistressed prematures and infants with transient tachypnea indicates the presence of open air spaces with reduced VA/Qc (11). Venous admixture due to these air spaces (Qo/Qt) averaged 8% in the nondistressed pre matures studied and those with transient tachy pnea, although in both groups there was consid erable variation, at least partly attributable to methodological problems discussed above, but also to the heterogeneity of infants examined. The contribution of open low VA/Qc units represents about 30% of the calculated total venous admixture (table I), a figure similar to that obtained by Parks et al. (26) in non distressed premature infants. If Qva/Qt is over estimated by assumption of too small an arteriovenous oxygen difference, the relative contribution of open low VA/Qc units is under estimated, but if the assumption is too large an overestimate would occur. The absolute value obtained by Parks et al. (26) for venous admixture due to open low Va /Q c units in normal prematures, namely 3-5% , is lower than the present estimate of 8%. This could represent differences in population since theirs was larger and probably more homogeneous. However, much of the difference may be explained because they obtained lower values for Qva/Qt, possibly because most of their subjects received oxygen supplements. An important assumption was that Qo/Qt is produced by air spaces with VA/Qc = 0, because if Va /Q c exceeds 0 significantly, then Qo/Qt will underestimate perfusion (25), but over estimate venous admixture (22). This assump tion is thought to be reasonable in normal
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14
prematures, but possibly not in transient tachy pnea. Because measurements of thoracic gas vol ume using an infant plethysmograph are con sistently higher than normal values for func tional residual capacity using inert gas mixing techniques, newborn infants and especially pre mature infants are thought to have a substantial very poorly ventilated compartment for up to several days or weeks after birth (4,20). Nitro gen washout techniques have usually demon strated remarkably even distribution in these infants, indicating that if poorly ventilated air spaces are present they must have negligible ventilation (21). In occasional infants an extremely poorly ventilated compartment can be demonstrated near the end of washout (15). This is presumably the result of small airway closure with gas-trapping in the range of tidal volume. At least in younger infants airway closure is probably due to delayed clearance of fetal lung fluid (21), which may compress small airways if interstitial, or directly obstruct if intraluminal. In older infants airway closure is also related to high wall compliance in small airways (7) and to the absence of large negative pleural pressures, especially in dependent areas, due to high chest wall compliance (2). For similar reasons, airway closure with gas-trapping is considered a major problem in the newborn with transient tachypnea (3). These infants have normal functional residual capacity by nitrogen washout (27), but radiological evi dence for hyperinflation (30). There are no appropriate measurements of lung volume in transient tachypnea available, and no definite descriptions of ventilatory distribution. How ever, the infants studied by Nelson et al. (23) probably had transient tachypnea rather than hyaline membrane disease since they breathed room air for the purpose of nitrogen washout with no ill effects. Despite generally rapid
15
nitrogen washout a significant poorly ventilated compartment was demonstrated. Although gas trapping probably occurs (3), this finding sug gests that overall VA/Qc in the low VA/Qc compartment may not be 0 in transient tachy pnea. Thus, Qo/Qt may reliably estimate perfu sion in nondistressed prematures, but it may not do so in transient tachypnea. Estimates of size of the poorly ventilated compartment in normal prematures depend on maturity and age, but in the first 10 days of life vary between 20 and 40% of total lung volume (21), and could be higher in transient tachy pnea although no direct measurements have been made. If such estimates are correct, and perfusion does not change, then values for Qo/Qt higher than 8% would be expected in normal prematures. The possible discrepancy may, of course, be due to differences in the population studied, but an alternative explana tion has been suggested (21). Since Pq 2 in the low Va /Qc compartment is low, hypoxic vaso constriction may limit perfusion (16) and hence venous admixture. This would cause under estimation of the size of the open low VA/Qc compartment by aADNj and Qo/Qt in much the same way as previously proposed in hyaline membrane disease (9). Comparison o f 2 Groups The 2 groups of patients considered in this study were not comparable, so the nondis tressed group does not represent a control for those with transient tachypnea. It may be considered surprising, however, that there were substantial differences in inspired oxygen, AaD0 j and aADNj, yet there was only a small difference in Qva/Qt and none in Qo/Qt (ta ble I). Both groups had similar values for Pa0 2 , while differences in oxygen content of pulmo nary end-capillary blood would be small due to the shape of the oxygen dissociation curve.
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aADfvi2 in Newborn Infants
16
Corbet/Ross/Beaudry/Stern
Acknowledgments This work was supported by Grant MA-3037 from the Medical Research Council of Canada and a grant from the Canadian Cystic Fibrosis Foundation.
References 1 Adams, F.H.; Fujiwara, T.; Spears, R., and Hodge man, J.: Gaseous metabolism in premature infants at 32-34 °C ambient temperature. Pediatrics 33: 75-82(1964). 2 Agostini, E.: Volume-pressure relationships of the thorax and lung in the newborn. J. appl. Physiol. 14: 909-913 (1959). 3 Auld, P.A.M.: Pulmonary physiology of the new born infant; in Scarpelli, Pulmonary physiology of the fetus, newborn and child, p. 152 (Lea & Febiger, Philadelphia 1975). 4 Auld, P.A.M.; Nelson, N.M.; Cherry, R.B.; Rudolph, A.J., and Smith, C.A.: Measurement of thoracic gas volume in the newborn infant. J. clin. Invest. 42: 476-483 (1963). 5 Avery, M.E.; Gatewood, O.G., and Brumley, G.: Transient tachypnea of the newborn. Am. J. Dis. Child. Ill: 380-385 (1966). 6 Berggren, S.M.: The oxygen deficit of arterial blood caused by nonventilating parts of the lung. Acta physiol, scand. 11: suppl., pp. 7-92 (1942). 7 Burnard, E.D.; Grattan-Smith, P.; Picton-Warlow, C.G., and Grauaug, A.: Pulmonary insufficiency in prematurity. Aust. Paediat. J. 1: 12-38 (1965). 8 Canfield, R.E. and Rahn, H.: Arterial-alveolar N2 gas pressure difference due to ventilation-perfusion variations. J. appl. Physiol. 10: 165-172 (1957). 9 Corbet, A.J.S.; Ross, J.A.; Beaudry, P.H., and Stern, L.: Ventilation-perfusion relationships as assessed by aADfg in hyaline membrane disease. J. appl. Physiol. 36: 74-81 (1974). 10 Edwards, A.W.T.; Velasquez, T., and Farhi, L.E.: Determination of alveolar capillary temperature. J. appl. Physiol. 18: 107-113 (1963). 11 Farhi, L.E.: Ventilation-perfusion relationship and its role in alveolar gas exchange; in Caro, Advances in respiratory physiology, pp. 148-197 (Williams & Wilkins, Baltimore 1966). 12 Farhi, L.E.; Edwards, A.W.T., and Homma, T.: Determination of dissolved N2 in blood by gas chromatography and the (a-A)N, difference. J. appl. Physiol. 18: 97-106 (1963). 13 Finley, T.N.; Lenfant, C.; Haab, P.; Piiper, J., and Rahn, H.: Venous admixture in the pulmonary circulation of anesthetized dogs. J. appl. Physiol. 15: 418 424 (1960). 14 Groom, A.C. and Farhi, L.E.: Cutaneous diffusion
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Examination of equation 4 reveals that under these circumstances an appreciable difference in Qva/Qt would not be expected. In the case of Qo/Qt it is known that at constant VA/Qc the value for aADf^ rises with increasing inspired oxygen (9). Increased oxygen causes only a small decrease in the PNj of the low VA/Qc compartment, the major determinant of PaN i. This is because blood perfusing the low VA/Qc compartment is desaturated and changes in P0j depend on the steep portion of the oxygen dissociation curve. On the other hand, increased oxygen causes a large reduction in PAn be cause blood perfusing well-ventilated regions of lung is fully saturated and changes of P0; on the flat portion of the oxygen dissociation curve are large. Thus, it can be readily under stood that values for Qo/Qt could be similar when there were appreciable differences in aADN between the 2 groups. The data obtained do not indicate why the group with transient tachypnea required oxy gen supplementation when they had similar values for Qva/Qt and Qo/Qt to those who did not require additional oxygen (table I). It is reasonable to assume, however, that Qva/Qt in transient tachypnea would be greater in room air and that supplemental oxygen would relieve arterial desaturation and correct Qva/Qt toward more normal values. The behavior of Qo/Qt without oxygen supplementation is not known. Since nitrogen in the low VA/Qc compartment would increase, Qo/Qt might also increase, but further hypoxic vasoconstriction might have the opposite effect of decreasing Qo/Qt.
17
aADNj in Newborn Infants
24 Oh, W.; Arcilla, R.A., and Lind, J.: In vivo oxygen dissociation curve of newborn infants. Biol. Neo nate 8. 241-252 (1965). 25 Olszowka, A. and Markello, R.: ‘Shunt’ fractions using 0 2 versus N2. J. appl. Physiol. 34: 531-533 (1973) . 26 Parks, C.R.; Woodrum, D.E.; Alden, E.R.; Standaut, T.A., and Hodson, W.A.: Gas exchange in the immature lung. Anatomical shunt in the premature infant. J. appl. Physiol. 36: 103-107 (1974) . 27 Prod’hom, L.S.; Levison, H.; Cherry, R.B., and Smith, C.A.: Adjustment of ventilation, intrapulmonary gas exchange and acid-base balance during the first day of life. Pediatrics 35: 662-676 (1965). 28 Rudolph, A.M.; Auld, P.A.M.; Golinko, R.J., and Paul, M.H.: Pulmonary vascular adjustments in the neonatal period. Pediatrics 28: 28-34 (1961). 29 Scholander, P.F.: Analyzer for accurate estimation of respiratory gases in one half cubic centimeter samples. J. biol. Chem. 167: 235-250 (1947). 30 Sundell, H.; Garrott, J.; Blankenship, W.J.; Shepard, F.M., and Stahlman, M.T.: Studies on infants with type II respiratory distress syndrome. J. Pediat. 78: 754-764 (1971). 31 Wesenberg, R.L.: The newborn chest (Harper & Row, New York 1973).
Dr. Anthony Corbet, Department of Pediatrics, Flinders Medical Center, Bedford Park, SA 5042 (Australia)
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of atmospheric N2 during N2 washout in the dog. J. appl. Physiol. 22: 740-745 (1967). 15 Hanson, J.S. and Shinozaki, T.: Hybrid computer studies of ventilatory distribution and lung volume. Normal newborn infants. Pediatrics 46: 900-914 (1970). 16 Hughes, J.M.B.: Local control of blood flow and ventilation; in West, Regional differences in the lung, pp. 419-450 (Academic Press, New York 1977). 17 Kelman, G.R. and Nunn, J.F.: Nomograms for correction of blood Pq ^, P c o 2> and base excess for time and temperature. 18 Klocke, F.J.: Measurement of trace amounts of inert gases in blood by gas chromatography; in Mattick and Szymanski, Lectures on gas chroma tography, pp. 75-87 (Plenum, New York 1967). 19 Klock, F.J. and Rahn, H.: The arterial-alveolar inert gas (N2) difference in normal and emphy sematous subjects as indicated by the analysis of urine. J. appl. Physiol. 40: 286-294 (1961). 20 Krauss, A.N. and Auld, P.A.M.: Pulmonary gas trapping in premature infants. Pediat. Res. 5: 10-16 (1971). 21 Krauss, A.N. and Auld, P.A.M.: Ventilation-perfu sion abnormalities in the premature infant: triple gradient. Pediat. Res. 3: 255-264 (1969). 22 Markello, R.; Winter, P., and Olszowka, A.: Assess ment of ventilation-perfusion inequalities by arte rial-alveolar nitrogen differences in intensive care patients. Anesthesiology 37: 4 -1 5 (1972). 23 Nelson, N.M.; Prod’hom, L.S.; Cherry, R.B.; Lipsitz, P.J., and Smith, C.A.: Pulmonary function in the newborn infant: the alveolar-arterial oxygen gradient. J. appl. Physiol. 18: 534-538 (1963).
Assessment of Ventilation-Perfusion Inequality by aADN2 in Newborn Infants A.J.S. Corbet, J.A. Ross, P.H. Beaudry and L. Stern Departments of Newborn Medicine and Respiratory Function, Montreal Children’s Hospital and McGill University, Montreal, P.Q.
Key Words. Arterial-alveolar differences • Venous admixture • Low VA/Qc • Premature infants • Transient tachypnea Abstract. The contribution (Qo/Qt) of gas-filled air spaces with reduced ventilation-perfusion ratio (VA/Qc) to the production of total venous admixture in nondistressed premature infants and newborn infants with transient tachypnea was assessed by the aADNj and AaD0 j . The mean value for Qo/Qt in both nondistressed prematures and infants with transient tachypnea was 0.08. In both groups this represented about 30% of total venous admixture.
AaDoj PAco P,\N Paq aAD(jo; aADf^ PaCOj Pajsj ^ PaQ; E-'Iq Pv'cOj Pvo; R Qva/Qt Qs/Qt Qo/Qt Qo/Qc
Va /Q c
Alveolar arterial oxygen difference Alveolar carbon dioxide tension Alveolar nitrogen tension Alveolar oxygen tension Arterial alveolar carbon dioxide difference Arterial alveolar nitrogen difference Arterial carbon dioxide tension Arterial nitrogen tension Arterial oxygen tension Fractional inspired oxygen Mixed venous carbon dioxide tension Mixed venous oxygen tension Respiratory exchange ratio Total venous admixture Venous admixture due to true venoarterial shunt Venous admixture of low VA/Qc compart ment Venous admixture of low VA/Qc compart ment expressed as fraction of effective pulmonary blood flow (Qc) Ventilation-perfusion ratio
Introduction
Though in older children and adults a major cause of hypoxemia is ventilation-perfusion (Va /Q c) imbalance in open poorly ventilated regions of the lung, in newborn and premature infants a true venoarterial shunt is thought to be more important (23). After closure of fetal vascular channels such as the foramen ovale and ductus arteriosus, the true shunt must be situ ated in the lungs, either through vessels accom panying nonventilated air spaces, or through vascular channels not associated with air spaces (26). Whereas measurements of the AaDo2 reflect total venous admixture including the true veno arterial shunt, measurements of the aADNj allow an estimate of venous admixture in poor ly ventilated regions of the lung (8). In infants with hyaline membrane disease and relatively large true venoarterial shunts, a surprisingly
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List of recurring abbreviations
small fraction of total venous admixture is caused directly by perfusion of poorly venti lated regions of the lung (9). In the present study we have examined whether the same may be true of nondistressed premature infants and newborn infants with transient tachypnea, a common condition thought to be associated with abnormal postnatal retention of fetal lung fluid (5).
Materials, Methods and Calculations The 16 newborn infants included in this study were admitted to the Montreal Children’s Hospital for reasons associated with prematurity or respiratory distress. There were 6 nondistressed premature infants with normal chest radiographs and breathing room air at the time of study, aged 1-10 days. The remaining 10 infants had transient tachypnea which started at birth, required oxygen supplementation in 9 up to a maximum of 30-40% to relieve hypoxemia, and settled after 2 -5 days. At the time of study, at the age of 1-4 days, all but 1 infant with transient tachypnea breathed supplemental oxygen of 29-40%. The chest radiograph showed diffuse coarse linear densities with hyperaeration, consistent with abnormal retention of fetal lung fluid in all cases (31). Infants in the study were managed in standard incubators with abdominal skin temperature servo-controlled at 36.5 °C to mini mize oxygen consumption. All were receiving intra vascular infusions of glucose in water, and nondis tressed infants were commenced on milk formula feedings. None required constant positive pressure or mechanical ventilation, none had clinical evidence of patent ductus arteriosus or pneumonia, and all sur vived. In the case of infants breathing room air, the study was performed not less than 6 h after any temporary oxygen supplementation. Those receiving oxygen ther apy, after maintenance of relatively stable ambient levels for a period of at least 3 -4 h, were given a similar mixture of oxygen and nitrogen (within 5%) from a cylinder of compressed gas. This was delivered at a rate of 10 litcrs/min, warmed and humidified by a heated nebulizer, into a transparent plastic bag which enclosed the infant’s head and was tied loosely about the neck. In this way absolute constancy of
11
inspired nitrogen was obtained for as long as desired in a system which effectively prevented rebreathing. To avoid exchange of nitrogen across the skin (14), incubator oxygen was adjusted to that in the head bag. All oxygen concentrations were measured with a paramagnetic oxygen analyzer and rectal temperature with a mercury thermometer. After 2.0-2.5 h breath ing in the head bag, during which time precautions were taken to prevent all disturbance, anaerobic arte rial blood samples were drawn, 1.7 ml into a glassdisposable syringe and 1.2 ml into a calibrated Hamil ton gas-tight syringe for analysis of blood gases, pH and hemoglobin. The blood samples were drawn from indwelling umbilical artery catheters with the tip placed in the descending aorta at the level of the diaphragm, except in 3 infants in which the blood sample was collected by radial artery puncture under local anesthesia with procaine to prevent disturbance. All measurements of Pa^ ^ were made in duplicate with a gas chromatograph. The reproducibility of repeated measurements on the same samples was within ± 2 Torr. Gases were first extracted under vacuum in a Van Slyke apparatus modified in the manner suggested by Farhi et al. (12), and then analyzed in a gas chromatograph modeled after that described by Klocke (18). The gas thermal conduc tivity detector (Carle Instruments, Model 100) had a linear voltage response over the desired range. Thor oughly mixed 0.5 ml samples from the Hamilton gas-tight syringe were used. Care was taken to elimi nate even the tiniest bubbles of gas if present as these caused inconsistencies in the height of chromato graphic peaks. A small correction dependent on the level of inspired oxygen was made for the nitrogen content of heparin solution used to fill the syringe dead space before sampling. This ranged between 0 and 1.5% in our subjects. Calibration of the instru ment was performed by identical analyses of blood tonometered at 37.4 °C with humidified gas from the same cylinder breathed by the subject or with room air when appropriate. For this purpose 1.2 ml blood from the disposable syringe and a tonometer similar to that described by Finley et al. (13) was used. The nitrogen fraction of mixtures breathed by subjects was analyzed with the gas chromatograph using room air (P[sj 3 = 0.78) as the standard. The Paj^ was calculated from the equation (19): PaN j = H a/H t X F i N j X (P b - P H j O)
(1-0.012 |T t- T r ))
x
(I)
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aADjvj2 jn Newborn Infants
Corbet/Ross/Beaudry/Stem
12
where Ha = mean chromatographic peak height for nitrogen from the anaerobic arterial sample, H( = mean peak height for nitrogen from the tonometered sample, F in = fractional inspired nitrogen, Pu = barometric pressure, Ph ; o = water vapor pressure (47 Torr), and (1-0.012 |T t- T r |) is a correction factor for the difference (in °C) between rectal (Tr) and tonometer (Tt) temperatures, 0.012 being the Bunsen solubility coefficient for nitrogen in whole blood (12). The remaining blood from the disposable syringe was used for analysis of hemoglobin, Paoj; pH and P aco2The Pa0 j was measured polarographically using a Clarke-type electrode (Radiometer, E5016) calibrated at 2 points around the predicted value with gases of known oxygen composition analyzed by the method of Scholander (29). The values for PaQ; were cor rected for the few minutes delay before measurement, and for the difference between rectal and electrode temperatures (17). Arterial P aco 2 and pH were mea sured by the Astrup technique (Radiometer, Copen hagen). Arterial oxygen saturation was calculated from knowledge of the Pao2 and pH using the oxygen dissociation curve for neonatal blood (24). The standard alveolar gas equations (11) were used to calculate ideal Pa 0 and ideal Pan • 11 was as sumed that the Pa ^ q was the samc as P aço 2, that the overall R was 0.8 (1), and that rectal temperature was the same as alveolar temperature. The differences between ideal alveolar and arterial nitrogen and oxy gen tensions were then calculated:
Qo/Qc =
PaN 2 PA|\i 2
(5)
(Pb - P h 20 -Pvo 2 Pvco 2)-P a Nj
Qo/Qt = O '» /» < ! - * " * » >
(6)
1- Qo/Qc where Qo/Qc is the venous admixture due to the open poorly ventilated compartment expressed as a fraction of effective pulmonary blood flow (Qc), the Pv q ), was assumed to be 6 Torr more than the P aco 2>P^02 represents the mixed venous oxygen tension derived from the oxygen saturation curve (24), Pu is atmo spheric pressure and Ph 2o *s water vapor pressure at body temperature. Equation 5 is derived by comparing the measured aAD^j with the aADj^ if all blood perfused lung which was open but nonventilated, in which case Pa^, would be represented by (PgPh 2o - P v0 j -P vco 2) (22, 25). Equation 6 is derived from first principles by assuming that nitrogen in arterial blood is equal to the sum of nitrogen in blood passing through well-ventilated lung, blood passing through open but poorly ventilated lung and blood which constitutes a true shunt (9). The Qs/Qt could be calculated from the following equation:
( 2)
Qs/Qt = Qva/Qt- Qo/Qt aADNj = PaN 2- Pa n 2
Further, assuming that there was no diffusion defect, the AaD0 j was converted to Qva/Qt, which was calculated from the following equation (6): C co2-C a o 2 Qva/Qt =
(7)
(3)
(4)
C cO j - C v q ,
where Ccq 2, C ao; and Cvq 2 arc the oxygen contents of pulmonary end-capillary, arterial and mixed venous blood, respectively. These were calculated using a value of 1.34 ml oxygen for each gram of hemoglobin, a value of 0.003 m l/100 ml/Torr for oxygen dissolved in blood, and assuming that the difference between arterial and mixed venous oxygen saturation was 4 vol% (26, 28).
Table I. Data in newborn infants (mean ± SD)
GA weeks
BW g
Age days
Fi0 ;
Pao 2 Torr
Nondistressed premature infants (n = 6) 1,982 32.6 5.3 0.21 ± 4.0 ± 0.00 ± 2.6 ± 788
74 ± 10
Infants with transient tachypnea (n = 10) 2,644 2.0 0.32 37.1 ±1.4 ±0.06 ± 3.0 ± 588
75 ± 17
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AaD0 j = PAo2-P a0 ;
Making the same assumptions and in addition that Va /Q c of the open poorly ventilated compartment was essentially zero, the venous admixture due to this compartment (Qo/Qt) was calculated as follows (9, 25):
13
aAD[y|2 in Newborn Infants
The gestational age (GA) and birth weight (BW) of the 2 groups of infants, the age at study and the inspired oxygen concentration (F i0 ), the values for PaN2, Pao2, PacO j»and [H+], the values for AaDo2 and aADN j, and the calculated values for Qva/Qt, Qo/Qc, Qo/Qt and Qs/Qt are given in table I. In both groups, Qo/Qt was approximately 30% of total venous admixture. The infants with transient tachypnea and supplemental oxygen had higher values for AaDo2 and aA D ^ than nondistressed infants breathing room air, but there was no appre ciable difference in the values for Qva/Qt and Qo/Qt.
Discussion
Errors in Analysis Though the measurements of PaNj were highly reproducible (± 2 Torr), the possible errors are large compared with values for uADn (table I), and therefore reliance should be placed on mean rather than individual val ues. It was previously shown that equilibration at constant inspired nitrogen for 2 h is suffi
PaNj T orr
PaCOj T orr
|H *| nM H
cient to allow body nitrogen stores to stabilize and obtain reliable values for P a ^ in the presence of a venoarterial shunt (9). The most appropriate temperature to indicate the true significance of aADNj would be that of alveolar capillary blood, but since this is not measured, rectal temperature is substituted. As it is rea sonable to assume that alveolar temperature may be up to 0.5 °C higher than rectal (10), true values for aADNj may be 2 -3 Torr higher and AaD0j 2—3 Torr lower, in which case Qo/Qt would be increased by up to 0.03. The values obtained for aA D ^ and AaD0j depend on the assumed R, variation by 0.05 changing both in the same direction by 2—3 Torr. Although the effect on AaD0¡ is small and Qva/Qt negligible, the effect on aADN; is relatively large and the error in Qo/Qt may be as much as 0.03-0.05. All published studies of aADjvj in premature infants have assumed a value for R, usually 0.8 (9, 26) as in the present study, but sometimes 0.7 (21). If we had assumed a value of 0.7, the values for aADNj in at least 5 of 16 infants would have been negative, and all values would have been lower. It is, however, considered improbable that true values for aADj^ would be negative (11). While such results could be due to inaccuracy in the measurement o f PaN; or perhaps lack of steady
AaD0 j T orr
Qva/Qt
aADNj T orr
Qo/Qc
Qo/Qt
Qs/Qt
0.09
570 ±5
±5
43 ±5
29 ±9
0.25 ± 0.04
6 ±5
± 0.05
0.08 ± 0.06
0.17 ± 0 .0 7
489 ± 40
39 ±8
44 ±5
102 ± 35
0.28 ± 0.08
12 ± 11
0.09 ± 0.08
0.08 ± 0.07
0.20 ± 0.12
37
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Results
state conditions, we consider this unlikely in view of the excellent reproducibility in the measurements and precautions taken to prevent physical disturbance. Since all subjects were receiving intravascular infusions of glucose, it is not likely that values for R would be as low as 0.7, reflecting only the metabolism of fat. On the other hand, if we had assumed a value of 0.9 for R the aADNj would be higher, but such values for R would be unusual after the first few hours of life. Nevertheless, it is obvious that individual values for aA D ^ may not be reliable and more confidence should be given the mean, since the mean value for R is unlikely to vary far from the value of 0.8 assumed. There is a further problem with the values for aADN and AaD0 because the aADco in newborn infants may be higher than the as sumed value (21). If the aADco was lOTorr, then aADN2 would increase by 1 Torr and AaD0 would increase by 11 Torr, in which case values for Qva/Qt may be up to 0.03 higher and Qo/Qt increased by 0.01. Because the values for Qo/Qc were small they were not sensitive to Pv0; or PvCOj (see equation 5). Variation in Pv0j is limited because the oxygen dissociation curve is steep, while variation in PvCo 2 is likely in the opposite direction. In crease in both by a total of 10 Torr would be required to increase Qo/Qc by 0.01, and the error in Qo/Qt would be less. If the arterio venous oxygen difference varied from the as sumed value, Qva/Qt could change by as much as 0.1, but it would be accompanied by a change in Qo/Qc in the same direction due to changes in Pvq^ . The effect would reduce the error in Qo/Qt to less than that for Qo/ Qc, significantly less than 0.01 (see equa tion 6). In summary, problems with temperature and aADco may cause underestimation of aADN and Qo/Qt, but assumption of too high a value
Corbet/Ross/Beaudry/Stern
for R may balance this effect. The values for aADNj and Qo/Qt should be regarded only as reasonable estimates. Interpretation o f aADN and Qo/Qt Demonstration of any positive value for aA D ^ in nondistressed prematures and infants with transient tachypnea indicates the presence of open air spaces with reduced VA/Qc (11). Venous admixture due to these air spaces (Qo/Qt) averaged 8% in the nondistressed pre matures studied and those with transient tachy pnea, although in both groups there was consid erable variation, at least partly attributable to methodological problems discussed above, but also to the heterogeneity of infants examined. The contribution of open low VA/Qc units represents about 30% of the calculated total venous admixture (table I), a figure similar to that obtained by Parks et al. (26) in non distressed premature infants. If Qva/Qt is over estimated by assumption of too small an arteriovenous oxygen difference, the relative contribution of open low VA/Qc units is under estimated, but if the assumption is too large an overestimate would occur. The absolute value obtained by Parks et al. (26) for venous admixture due to open low Va /Q c units in normal prematures, namely 3-5% , is lower than the present estimate of 8%. This could represent differences in population since theirs was larger and probably more homogeneous. However, much of the difference may be explained because they obtained lower values for Qva/Qt, possibly because most of their subjects received oxygen supplements. An important assumption was that Qo/Qt is produced by air spaces with VA/Qc = 0, because if Va /Q c exceeds 0 significantly, then Qo/Qt will underestimate perfusion (25), but over estimate venous admixture (22). This assump tion is thought to be reasonable in normal
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14
prematures, but possibly not in transient tachy pnea. Because measurements of thoracic gas vol ume using an infant plethysmograph are con sistently higher than normal values for func tional residual capacity using inert gas mixing techniques, newborn infants and especially pre mature infants are thought to have a substantial very poorly ventilated compartment for up to several days or weeks after birth (4,20). Nitro gen washout techniques have usually demon strated remarkably even distribution in these infants, indicating that if poorly ventilated air spaces are present they must have negligible ventilation (21). In occasional infants an extremely poorly ventilated compartment can be demonstrated near the end of washout (15). This is presumably the result of small airway closure with gas-trapping in the range of tidal volume. At least in younger infants airway closure is probably due to delayed clearance of fetal lung fluid (21), which may compress small airways if interstitial, or directly obstruct if intraluminal. In older infants airway closure is also related to high wall compliance in small airways (7) and to the absence of large negative pleural pressures, especially in dependent areas, due to high chest wall compliance (2). For similar reasons, airway closure with gas-trapping is considered a major problem in the newborn with transient tachypnea (3). These infants have normal functional residual capacity by nitrogen washout (27), but radiological evi dence for hyperinflation (30). There are no appropriate measurements of lung volume in transient tachypnea available, and no definite descriptions of ventilatory distribution. How ever, the infants studied by Nelson et al. (23) probably had transient tachypnea rather than hyaline membrane disease since they breathed room air for the purpose of nitrogen washout with no ill effects. Despite generally rapid
15
nitrogen washout a significant poorly ventilated compartment was demonstrated. Although gas trapping probably occurs (3), this finding sug gests that overall VA/Qc in the low VA/Qc compartment may not be 0 in transient tachy pnea. Thus, Qo/Qt may reliably estimate perfu sion in nondistressed prematures, but it may not do so in transient tachypnea. Estimates of size of the poorly ventilated compartment in normal prematures depend on maturity and age, but in the first 10 days of life vary between 20 and 40% of total lung volume (21), and could be higher in transient tachy pnea although no direct measurements have been made. If such estimates are correct, and perfusion does not change, then values for Qo/Qt higher than 8% would be expected in normal prematures. The possible discrepancy may, of course, be due to differences in the population studied, but an alternative explana tion has been suggested (21). Since Pq 2 in the low Va /Qc compartment is low, hypoxic vaso constriction may limit perfusion (16) and hence venous admixture. This would cause under estimation of the size of the open low VA/Qc compartment by aADNj and Qo/Qt in much the same way as previously proposed in hyaline membrane disease (9). Comparison o f 2 Groups The 2 groups of patients considered in this study were not comparable, so the nondis tressed group does not represent a control for those with transient tachypnea. It may be considered surprising, however, that there were substantial differences in inspired oxygen, AaD0 j and aADNj, yet there was only a small difference in Qva/Qt and none in Qo/Qt (ta ble I). Both groups had similar values for Pa0 2 , while differences in oxygen content of pulmo nary end-capillary blood would be small due to the shape of the oxygen dissociation curve.
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aADfvi2 in Newborn Infants
16
Corbet/Ross/Beaudry/Stern
Acknowledgments This work was supported by Grant MA-3037 from the Medical Research Council of Canada and a grant from the Canadian Cystic Fibrosis Foundation.
References 1 Adams, F.H.; Fujiwara, T.; Spears, R., and Hodge man, J.: Gaseous metabolism in premature infants at 32-34 °C ambient temperature. Pediatrics 33: 75-82(1964). 2 Agostini, E.: Volume-pressure relationships of the thorax and lung in the newborn. J. appl. Physiol. 14: 909-913 (1959). 3 Auld, P.A.M.: Pulmonary physiology of the new born infant; in Scarpelli, Pulmonary physiology of the fetus, newborn and child, p. 152 (Lea & Febiger, Philadelphia 1975). 4 Auld, P.A.M.; Nelson, N.M.; Cherry, R.B.; Rudolph, A.J., and Smith, C.A.: Measurement of thoracic gas volume in the newborn infant. J. clin. Invest. 42: 476-483 (1963). 5 Avery, M.E.; Gatewood, O.G., and Brumley, G.: Transient tachypnea of the newborn. Am. J. Dis. Child. Ill: 380-385 (1966). 6 Berggren, S.M.: The oxygen deficit of arterial blood caused by nonventilating parts of the lung. Acta physiol, scand. 11: suppl., pp. 7-92 (1942). 7 Burnard, E.D.; Grattan-Smith, P.; Picton-Warlow, C.G., and Grauaug, A.: Pulmonary insufficiency in prematurity. Aust. Paediat. J. 1: 12-38 (1965). 8 Canfield, R.E. and Rahn, H.: Arterial-alveolar N2 gas pressure difference due to ventilation-perfusion variations. J. appl. Physiol. 10: 165-172 (1957). 9 Corbet, A.J.S.; Ross, J.A.; Beaudry, P.H., and Stern, L.: Ventilation-perfusion relationships as assessed by aADfg in hyaline membrane disease. J. appl. Physiol. 36: 74-81 (1974). 10 Edwards, A.W.T.; Velasquez, T., and Farhi, L.E.: Determination of alveolar capillary temperature. J. appl. Physiol. 18: 107-113 (1963). 11 Farhi, L.E.: Ventilation-perfusion relationship and its role in alveolar gas exchange; in Caro, Advances in respiratory physiology, pp. 148-197 (Williams & Wilkins, Baltimore 1966). 12 Farhi, L.E.; Edwards, A.W.T., and Homma, T.: Determination of dissolved N2 in blood by gas chromatography and the (a-A)N, difference. J. appl. Physiol. 18: 97-106 (1963). 13 Finley, T.N.; Lenfant, C.; Haab, P.; Piiper, J., and Rahn, H.: Venous admixture in the pulmonary circulation of anesthetized dogs. J. appl. Physiol. 15: 418 424 (1960). 14 Groom, A.C. and Farhi, L.E.: Cutaneous diffusion
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Examination of equation 4 reveals that under these circumstances an appreciable difference in Qva/Qt would not be expected. In the case of Qo/Qt it is known that at constant VA/Qc the value for aADf^ rises with increasing inspired oxygen (9). Increased oxygen causes only a small decrease in the PNj of the low VA/Qc compartment, the major determinant of PaN i. This is because blood perfusing the low VA/Qc compartment is desaturated and changes in P0j depend on the steep portion of the oxygen dissociation curve. On the other hand, increased oxygen causes a large reduction in PAn be cause blood perfusing well-ventilated regions of lung is fully saturated and changes of P0; on the flat portion of the oxygen dissociation curve are large. Thus, it can be readily under stood that values for Qo/Qt could be similar when there were appreciable differences in aADN between the 2 groups. The data obtained do not indicate why the group with transient tachypnea required oxy gen supplementation when they had similar values for Qva/Qt and Qo/Qt to those who did not require additional oxygen (table I). It is reasonable to assume, however, that Qva/Qt in transient tachypnea would be greater in room air and that supplemental oxygen would relieve arterial desaturation and correct Qva/Qt toward more normal values. The behavior of Qo/Qt without oxygen supplementation is not known. Since nitrogen in the low VA/Qc compartment would increase, Qo/Qt might also increase, but further hypoxic vasoconstriction might have the opposite effect of decreasing Qo/Qt.
17
aADNj in Newborn Infants
24 Oh, W.; Arcilla, R.A., and Lind, J.: In vivo oxygen dissociation curve of newborn infants. Biol. Neo nate 8. 241-252 (1965). 25 Olszowka, A. and Markello, R.: ‘Shunt’ fractions using 0 2 versus N2. J. appl. Physiol. 34: 531-533 (1973) . 26 Parks, C.R.; Woodrum, D.E.; Alden, E.R.; Standaut, T.A., and Hodson, W.A.: Gas exchange in the immature lung. Anatomical shunt in the premature infant. J. appl. Physiol. 36: 103-107 (1974) . 27 Prod’hom, L.S.; Levison, H.; Cherry, R.B., and Smith, C.A.: Adjustment of ventilation, intrapulmonary gas exchange and acid-base balance during the first day of life. Pediatrics 35: 662-676 (1965). 28 Rudolph, A.M.; Auld, P.A.M.; Golinko, R.J., and Paul, M.H.: Pulmonary vascular adjustments in the neonatal period. Pediatrics 28: 28-34 (1961). 29 Scholander, P.F.: Analyzer for accurate estimation of respiratory gases in one half cubic centimeter samples. J. biol. Chem. 167: 235-250 (1947). 30 Sundell, H.; Garrott, J.; Blankenship, W.J.; Shepard, F.M., and Stahlman, M.T.: Studies on infants with type II respiratory distress syndrome. J. Pediat. 78: 754-764 (1971). 31 Wesenberg, R.L.: The newborn chest (Harper & Row, New York 1973).
Dr. Anthony Corbet, Department of Pediatrics, Flinders Medical Center, Bedford Park, SA 5042 (Australia)
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of atmospheric N2 during N2 washout in the dog. J. appl. Physiol. 22: 740-745 (1967). 15 Hanson, J.S. and Shinozaki, T.: Hybrid computer studies of ventilatory distribution and lung volume. Normal newborn infants. Pediatrics 46: 900-914 (1970). 16 Hughes, J.M.B.: Local control of blood flow and ventilation; in West, Regional differences in the lung, pp. 419-450 (Academic Press, New York 1977). 17 Kelman, G.R. and Nunn, J.F.: Nomograms for correction of blood Pq ^, P c o 2> and base excess for time and temperature. 18 Klocke, F.J.: Measurement of trace amounts of inert gases in blood by gas chromatography; in Mattick and Szymanski, Lectures on gas chroma tography, pp. 75-87 (Plenum, New York 1967). 19 Klock, F.J. and Rahn, H.: The arterial-alveolar inert gas (N2) difference in normal and emphy sematous subjects as indicated by the analysis of urine. J. appl. Physiol. 40: 286-294 (1961). 20 Krauss, A.N. and Auld, P.A.M.: Pulmonary gas trapping in premature infants. Pediat. Res. 5: 10-16 (1971). 21 Krauss, A.N. and Auld, P.A.M.: Ventilation-perfu sion abnormalities in the premature infant: triple gradient. Pediat. Res. 3: 255-264 (1969). 22 Markello, R.; Winter, P., and Olszowka, A.: Assess ment of ventilation-perfusion inequalities by arte rial-alveolar nitrogen differences in intensive care patients. Anesthesiology 37: 4 -1 5 (1972). 23 Nelson, N.M.; Prod’hom, L.S.; Cherry, R.B.; Lipsitz, P.J., and Smith, C.A.: Pulmonary function in the newborn infant: the alveolar-arterial oxygen gradient. J. appl. Physiol. 18: 534-538 (1963).
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