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Measurements of Pulmonary Flow and Gas Exchange Throughout the Respiratory Cycle in Man

Arthur B. Dubois, Robert Marshall

J Clin Invest. 1957;36(11):1566-1571. https://doi.org/10.1172/JCI103554.

Research Article

Find the latest version: https://jci.me/103554/pdf MEASUREMENTS OF PUL ONARY CAPILLARY BLOOD FLOW AND GAS EXCHA16GE THROUGHOUT THE RESPIRATORY CYCLE IN MAN1 IYARTHURBB. 4OIS 2 AftROBERT MARSHALL ' (FrV^-tA ODepirtnAt of PhPIbeyind Phat*4oloy, _Grdwdte Shool of Medicine, -,~-~ISkGSG~~~~Udvsfyo*-,~etiGU P ,- i - 'P*a)' ' (Subwtkite r publioi May 13, 1957; accepted July 11, 1957) Judging from e iia*tn resic';netr' technique as described previously in the and ! puMQ i (4); 1Figur' I ithistas bhe Spric of the- method. bysWiggis 'An 9mi an4i-'xsti:di.i.~sThe,~n by subjec sits entirely inside b plethyograph Lbyson, B~loomfieW1{l)dandstqldltl (z*?s lge hy 'h;ih hah a tensitive pressure gauge. If -aCth,iCi and.mfie&l, -M6 Coughedit1§K(),_Indi;XGt2W ft ub it seemed entirely possible tInt the pulmonary tM'ibootA flowing through the pulmonary'capilaries. As capillary blood flow might vary appreciably dur- N2O leaves the gas phase, the total gas vohrme and pres- ing the respiratory cycle. sure decrease in the closed box. The blood flow can be Brecher and Hubay (3) reported respiratory calculated by an equation which applies before recircu- AUson, lation, provided the alveolar gas tension and the solubility fluctuations of pulmonary flow i dogs de- of the gas in whole blood are known. termined by implanting a bristle flow meter in the In the technique previously described, the measure- . But if these respiratory varia- ments of N,O uptake were made when the breath was tions of blood flow persisted in the pulmonary held with the glottis open and changes in pressure in the in intact man, they could conceivably box were due almost entirely to the uptake of NO. create a moment-to-moment "unsteady state" BODY PLETHYSMOGRAPH FOR MEASURING which would cause errors in calculation of the re- PULMONARY CAPILLARY BLOOD FLOW spiratory gas exchange and . PRESSURE GAUGE It has recently been shown that the pulmonary capillary blood flow, as measured by a new and VOLUME instantaneous method, is pulsatile in time with the CALIBRATION heart beat (4). It is the object of this study to measure pulmonary capillary blood flow by the instantaneous method throughout the entire re- -(2A spiratory cycle in the normal intact man. Previous attempts to measure alveolar capil- lary gas exchange during the respiratory cycle have been limited to the expiratory phase alone, because expired alveolar gas can be sampled only during expiration. The present method permits measurements to be made of the exchange of gases FIG. 1. DAGAM ILLUSTRATING THE PRINCIPLE OF MFAS- between alveoli and capillaries during both ex- UREMENT OF PULMONARY CAPILLARY BLOOD FLOW piration and inspiration. During normal the pressure in the box is af- METHOD fected by other factors. First, changes in temperature and saturation of the cause fluctuations The rate of absorption of N.O, a gas which is highly respired gas in plethysmographic pressure. These changes were ______soluble in the bloodstream, was measured by a "manor"mano- nated by rebreathing from bags at body temperatureelimi- 1These studies were aided, in part, by a contract be- saturated with water vapor. Secondly, changes in alveo- tween the Office of Naval Research, Department of the lar pressure during airflow also produce changes in box Navy, and the University of Pennsylvania, NR 112-323. pressure (5) but if the airflow is recorded a correction 2This work was done during the tenure of an Estab- can be applied for the pressure changes due to this lished Investigatorship of the American Heart Associa- cause. tion. Apparatus. The body plethysmograph used in these 'Present address: The Dunn Laboratories, St. Barthol- investigations has been described previously (4, 5). A omew's Hospital, London, England. double chamber was used; one half was occupied by the 1566 PULMONARY BLOOD FLOW DURING INSPIRATION AND EXPIRATION 1567

MOUTHPIECE a to and fro stroke of 30 ml. at a rate of 2 cycles per C...... -. TO I -R GAS ANALYZER second. PNWMOACHYGRAPH Procedure. After the subject entered the chamber, it

ENCLOSURE was closed and intermittently vented during a 2-minute A I R 1 TED EMC SURE warm-up period necessary for the thermal pressure drift BREATHING BAGS to become negligible. Wearing a nose clip, he then breathed approximatelIy halfway out, placed his mouth on the rubbir mouthpiece, ua ped the 4-liter bag of FIG. 2. APPARATus UsED FOR REBREATHING AIR OR 80 air, ok a full isprin from the bag, and then re- PER CENT NO SATURATED WITH WATE VAPOR AT breathed at normal rate and depth for a period of 20 sec- 37 C. onds. The clamp was replaced on the neck of the air bag. After 2 minutes of recovery, he again breathed subject while the other half at atmospheric pressure half-way out, put his mouth on the mouthpiece, un- merely served to damp sound waves on the reverse side clamped the other gas bag which contained 4 liters of a of the manometer. A Lilly capacitance manometer meas- mixture of 80 per cent NO and 20 per cent °2, took a ured the differential pressure between the two chambers deep breath of the mixture and then rebreathed at a and responded with a sensitivity of 0.4 mm. deflection per normal rate and depth for a 20-second period. At the ml. change of gas volume in the subject's chamber. The end of that time, he removed his mouth from the mouth- natural frequency of this manometer was approximately piece. Continuous recordings were made during the 200 cps. control period on air and during the experimental pe- Suspended from the roof of the chamber was the heated nod on nitrous oxide. The pressure gauges and nitrous enclosure containing the gases to be rebreathed (Figure oxide meter were calibrated. This procedure was car- 2).4 The enclosure consisted of a wire mesh cage en- ried out during normal quiet breathing and repeated with circled by a heating coiL The enclosure was covered by the subject breathing through added resistance. cloth for thermal insulation and by a polyethylene bag to A breathing resistance consisting of glass wool packed prevent passage of warm air to the outside of the bag as into a 1-inch breathing tube was interposed between the the subject rebreathed. Inside the enclosure were two mouth of the subject and the rebreathing apparatus. 4-liter bags, one containing air and the other The value of this resistance, measured by pressure-flow a mixture of 80 per cent N20 and 20 per cent 02 The tracings at 0.5 L. per second, was 10 cm. H20 per L. per necks of the bags were occluded by clamps and were con- second, which is in the range of moderate to marked ob- nected via a 1-inch bore T piece to a small heated flow struction to breathing. The usual procedures rebreathing meter and mouthpiece. The gases put into the bags had air and Nt0 were carried out, but in addition esophageal been saturated with water vapor by passing them through pressure fluctuations were recorded from an air-filledhal- DeVilbiss nebulizers. The temperature of the heating icon 10 cm. long placed in the lower third of the esopha- coil surrounding the enclosure was controlled by means gus, to show that fluctuations of pleural pressure were of a variable transformer to maintain the air temperature taking place, as seen in Figure 3, and to rule out changes at 370 C. A 1-mm. bore polyethylene tube led from the of resistance which might otherwise affect the correction mouthpiece of the breathing apparatus to a rapid infra- for gas compression during breathing. red gas analyzer. This analyzer had a range of zero The usual respiratory cycle included approximately to 100 per cent and was located outside the N,0 respira- three heart beats during inspiration and three beats dur- tory chamber. ing expiration. Additional experiments were performed After passing through the analyzer, the gas sample was to determine the effect upon blood flow of slow breathing, returned to the chamber by a continuously pumping sys- at the rate of approximately five heart beats during in- tem through a polyethylene tube. Electrocardiograph spiration and five during expiration, i.e., about seven leads and an esophageal pressure tubing passed to the respirations per minute. outside of the chamber for amplification and continuous recording, by Hathaway oscillograph galvanometers of During ordinary breathing, there was but little varia- suitable sensitivity and frequency response, on inch wide tion of throughout the respiratory cycle. suitablesensitivitypae an respos,pe on 6-inch wder However, during slow breathing there was considerable photsenitv f1ic e sinus arrhythmia. Atropine, 1.2 mg., was administered moiga, . second. The subject's chamber was vented to the at- siu rhtma toie gwsamnsee mspeond.rTe subject's camboerod w ras ted to the.at- subcutaneously to two subjects to diminish the sinus plethysmegraphwascalibratedby a s mall pump hadlwhich arrhythmia, in an attempt to separate the mechanical factors from the vagal factors which might affect the pul- 'Previous attempts to heat and saturate the entire air monary capillary blood flow. inside of the plethysmograph had resulted in discomfort Calculation. The first respiratory cycle rebreathing of the subject. However, in the present arrangement the N,0 was neglected, but the next few cycles (Figure 3) air surrounding the body of the subject was not heated. were measured provided they were "on scale" and prior 5 Liston-Becker model 16. Case flushed with 100 per to recirculation. As many as five consecutive cycles were cent CO2 to discriminate against the latter. Lag (Figure sometimes measured. 3) was about 02 second. The type of record obtained is shown in Figure 3. .1568 ARTHUR B. DUBOIS AND) ROBERT MARSHALL AIRFLOW

PLETHYSMOGORAPF PRESSU.RE

Es.~T t I'¢tl l *,lll

I@,~~~~~~~~~~~~~~~~~~~~---I N I 2 0'iO?-; 4% I. I .1I. , iI i Ii.li11 1ili 5 . II.:.! ,' FIG. 3A. SIMULTANEOUS RECORDINGS OF PNEUMOTACHYGRAM, PLETHYSMOGRAPHIC PRESSURE, ESOPHA- GEAL PRESSURE AND ELECTROCARDIOGRAM, WITH 0 PER CENT N.0 IN THE MOUTHPIECE WHILE THE SUB- JECT WAS BREATHING AIR DURING THE CONTROL PERIOD, PRIOR TO BREATHING Nrrous OXIDE (FIG- URE 3B) Calibration factors and paper speed are same as for Figure 3B. The purpose of the record is to show the magnitude of the correction factors discussed in the section on calculations, particularly the relation- ship between plethysmographic pressure and the rate of airflow at the mouth.

During the control period on air there were respiratory air or the foreign gas mixture (approximately 50 per fluctuations of the plethysmographic pressure proportional cent NO0). to the rate of airflow at the mouth of the subject. With The plethysmographic pressure during the rebreathing the low rates of airflow obtained during normal breath- of N,0 was read and the correction subtracted proportional ing (usually less than 0.5 L. per second) this relationship to the rate of airflow. A second correction was applied between recorded airflow and plethysmographic pressure for the trend of the respiratory exchange difference for was linear and could be measured either from the tracing 02 and C02, this trend having been determined during the obtained during normal breathing or during panting at period rebreathing air. In order to avoid the effect of the end of the record. The relationship between deflec- the changes in blood flow which occur during the cardiac tion recorded by the flow meter and plethysmographic cycle (4) the corrections were made at the same phase in pressure was approximately the same whether breathing each (the R wave of the ECG). The blood flow during a given interval of time is given by the following equation which is an application of the Fick principle for bloodflow (4): AP-60 = 470*FA.N20Pp*At where ap is the fall in plethysmographic pressure during an interval of time At; 470 ml. per L. is the solubility coefficient for N,0 in blood at 370 C.; FAN2o is the mean concentrations of N20 in the expired alveolar air; P.e1 is the change in pressure in the plethysmograph for 1 ml. TIM cS 0DS 3 4 a 6 7 * a ID 11~ 6 The mean of expired alveolar N20 was measured at FIG. 3B. SIMULTANEOUS RECORDINGS OF PLETHYSMO- about mid-expiration. Systematic fluctuations of a few GRAPHIC PRESSURE, PNEUMOTACHYGRAM, NO PER CENT per cent N20 from the mean (as in Figure 3) were ob- IN ExPIRm AR, ESOPHAGEAL PRESSURE AND ELcTo- served during the breathing cycle. Like 02 and CO2 (6), CARDIOGRAM the mean during inspiration is probably very nearly the The record reads from left to right. The R waves of same as the mean N20 during expiration. The rate of the ECG have been touched up. Inset is calibration of change of alveolar concentration is about one-half per plethysmographic pressure. This subject had atropine. cent per second, (4), which introduces a slight systematic Dotted line through circles represents plethysmographic error in end-inspiratory and end-expiratory bloodflow. pressure change attributable to gas absorption, a correc- No attempt was made to correct the calculated bloodflow tion having been made for resistance to airflow. for respiratory fluctuations of N20 concentration. PULMONARY BLOOD FLOW DURING INSPIRATION AND EXPIRATION 1569 change in gas volume; and Q is the rate of blood flow in TABLE II L. per minute. Pulmonary capillary blood flow while breathing RESULTS against added resistance Normal quiet breathing Subject's Subject expt. Mean 0 Imp. Q Exp. Q Pulmonary capillary blood flow during inspira- No. L./min. L./min. L./min. tory air flow, expiratory air flow, and for the whole A.B.DB. 3 4.1 4.06 4.3 respiratory cycle is tabulated as measured on five R. M. 3 6.7 6.9 6.4 normal subjects (Table I). Each subject was measured on two different occasions. Beat-by- rate was 74 per minute during slow breathing. beat gas absorption throughout the respiratory There was an increase in blood flow to 7 L. per cycle was plotted. The percentage deviations from minute toward the end of inspiratory gas flow and mean blood flow of inspiratory blood flow and of decrease toward the end of expiratory gas flow to expiratory blood flow are tabulated for individual 5 L. per minute. Cardiac acceleration to 86 also subjects and averaged for the group of subjects. occurred toward end inspiration, and deceleration The results may be summarized as follows: for to 62 toward end expiration. the group of subjects, the deviation of inspiratory blood flow from the mean blood flow was + 1.8 Atropine per cent; S.D., 7.6 per cent; S.E., 2.4 per cent. Of the two subjects given atropine, one per- The deviation of expiratory blood flow from the formed at a normal respiratory rate and exhibited mean blood flow was - 1.0 per cent; S.D., 7.7 per very little fluctuation of blood flow during the cent; S.E., 2.4 per cent. By the "t" test, the dif- respiratory cycle (Figure 3) whereas the other ference from mean blood flow and the difference subject, A. B. DB., breathed slowly and showed between inspiratory and expiratory blood flow are fluctuations of blood flow similar to slow breath- not significant. ing without atropine (see above) except that sinus arrhythmia disappeared. These few measurements Breathing through added resistance seem to indicate that further studies of the effects Similar measurements while breathing through of different breathing patterns, drugs, and disease added resistance are listed in Table II. No sig- may be of interest. nificant fluctuation was found. DISCUSSION Slow breathing The evidence presented above leads directly to In subject A. B. DB., experiment No. 4, the the conclusion that the exchange of inert, soluble mean blood flow was 6 L. per minute, and the heart gas between the alveoli and capillaries continues TABLE I to occur evenly during both inspiration and ex- Pulmonary capillary blood flow during normal piration. Furthermore, it is apparent that pul- quid respiration monary capillary blood flow does not vary, or varies within narrow limits, throughout the re- Sub- ject's Ma Insp.a.EpExo. spiratory cycle in normal man. Subject expt. QChange Change During the "direct Fick" determination of blood No. L./min. L./min. % L./min. % flow it is generally assumed that the respiratory R. M. 1 4.7 4.2 -11 5.2 +11 ten- 2 5.7 6.1 +7 5.4 -5 fluctuations of blood flow and alveolar gas A. B. DB. 1 3.5 3.5 0 3.3 - 6 sions do not cause any appreciable error in the 2 4.2 4.1 -2 4.3 + 5 The above data J.S.- 1 7.0 7.8 +11 6.6 - 6 measurement of blood flow. 2 8.2 8.8 +7 7.6 -7 show that this is a safe assumption for the G. B. 1 7.8 7.9 + 1 7.5 - 4 errors 2 5.4 5.8 + 7 5.1 -6 capillaries, but this does not rule out due P.C. 1 6.6 7.1 + 7 6.3 - 5 to fluctuations of blood flow at other sites of blood 2 5.4 4.9 - 9 6.1 +13 sampling. Mean 5.9 +1.8 -1.0 It has been calculated, assuming constant blood S.D. 1.5 7.6 7.7 S.E. 0.5 2.4 2.4 flow throughout the respiratory cycle, that there are respiratory fluctuations of alveolar P002 and 1570 ARTHUR B. DUBOIS AND ROBERT MARSHALL Po, amounting to a few mm. Hg of partial pres- lar. ristance must be postulated. This increased sure (6). The assumption concerning blood flow resistance is probably not due to vasomotor ac- has now been tested and shown to be reasonably tivity (9) but could be due to mechanical changes accurate for a normal rate of breathing. How- in the lung vessels during inflation. ever, slow, deep breathing may cause a variation of Daly (10) found that inflation of the de- blood flow such as to slightly diminish the pre- creased but most workers have dicted respiratory excursions of alveolar gas ten- found that in the lungs, either isolated or in situ, sion. when the vascular pressure is maintained constant In the introductory paragraphs it was mentioned in relation to intrapleural pressure, the vascular that certain hemodynamic measurements tended to resistance increases on inflation (7, 11, 12). Di- indicate the possibility of respiratory variations of rect observation of the lung capillaries in the pulmonary blood flow and vascular resistance. (13) shows that during inspiration the capillaries We have not made simultaneous determinations of become flatter and the blood flow in them usually pulmonary vascular pressure in our subjects, and diminishes, probably indicating increased vascu- direct measurements of blood velocity in the great lar resistance. During normal inspiration the in- vessels have not been attempted under similar ex- creased output of the right heart must be accom- perimental conditions in humans. Knowledge of modated by distension of the pulmonary . the mechanical properties of the pulmonary ar- During inspiration there is a fall in systemic teries, capillaries and is not yet sufficient to , even when this is measured rela- allow interpretation of pressure and capillary blood tive to intrapleural pressure (2, 7, 12, 14-18), and flow in terms of resistance to flow even had they oncometer and cinematographic studies of the been measured simultaneously, because pressure heart (16) have shown that this is associated with and flow are pulsatile and not exactly simultane- a diminished left ventricular output and left ven- ous with each other. Therefore the following part tricular diastolic volume. A diminished left atrial of the discussion, which is a comparison of our size has also been reported during inspiration results with the results of others, must be con- (14), as would be expected if the diminished left sidered as speculative until further investigation ventricular output is due to decreased filling. of the problems. Since the blood flow into the capillaries is not di- It has been shown that the effective pulmonary minished during inspiration there must be an in- arterial pressure (i.e., in relation to intrapleural crease of in either the pulmonary pressure) is raised during inspiration (2, 7, 8), capillaries or pulmonary veins. The site of this whereas the effective left auricular pressure meas- increase in capacity has not been determined and ured by others (as discussed in Reference 2) the evidence is conflicting. Direct observations shows little change so that pressure difference be- of the lung capillaries (13) show that they are tween these vessels is therefore augmented during flattened during inspiration and their volume does inspiration. The rise in effective pulmonary ar- not appear to increase. Heinbecker (12), in per- terial pressure has been supposed by some (8) to fusion studies in which lungs were inflated with be due entirely to the increased output of the positive pressure, also concluded that the capacity right heart during inspiration, since it still occurs of the capillaries was decreased on inspiration. when sympathetic nerve action is blocked by tetra- Some workers (17, 19) have found an increased ethyl ammonium bromide. An increase in the blood volume in the lungs during inspiration, but cardiac output of normal subjects, or increase in the experiments were carried out under conditions blood flow through one lung due to clamping the such that there was an increased pressure across other pulmonary artery, is accompanied by either the walls of the pulmonary veins during inspira- no rise or only a slight rise in pulmonary arterial tion and dilatation of these may have accounted for pressure. For this reason Brecher and Hubay (3) the increased capacity. In the intact chest there considered that the small increase in cardiac output is no other reason why the increased negative intra- which occurred during inspiration was insufficient thoracic pressure should dilate the part of the pul- to account for the rise in pulmonary arterial pres- monary veins outside the lung parenchyma. sure, and that some increase in pulmonary vascu- In summary, it may be said that the increased PULMONARY BLOOD FLOW DURING INSPIRATION AND EXPIRATION 1571 2. Lauson, H. D., Bloomfield, R. A., and Cournand, A., The influence of the respiration on the circulation in man, with special reference to pressures in the right auricle, right , femoral artery and peripheral veins. Am. J. Med., 1946, 1, 315. 3. Brecher, G. A., and Hubay, C. A., Pulmonary blood flow and venous return during spontaneous res- piration. Circ. Research, 1955, 3, 210. 4. Lee, G. de J., and DuBois, A. B., Pulmonary capil- lary blood flow in man. J. Clin. Invest., 1955, 34, 1380. 5. DuBois, A. B., Botelho, S. Y., and Comroe, J. H., Jr., A new method for measuring airway resistance in man using a body plethysmograph: Values in nor- mal subjects and in patients with respiratory dis- ease. J. Clin. Invest., 1956, 35, 327. 6. DuBois, A. B., Alveolar CO, and 0. during breath FIG. 4. SCHEMATIC REPRESENTATION OF THE BLOOD holding, expiration, and inspiration. J. Applied FLOW THROUGH THE DIFFERENT BLOOD COMPARTMENTS Physiol., 1952, 5, 1. IN THE DURING INSPIRATION AND EXPIRATION 7. Bjurstedt, H., and Hesser, C. M., Effects of lung AT NORMAL AND SLOW RATES inflation on the in anesthe- RH = right heart (including pulmonary ); tized dogs. Acta physiol. Scandinav., 1953, 29, 180. PCB = pulmonary capillary bed; LH = left heart (includ- 8. Lee, G. de J., Matthews, M. B., and Sharpey-Schafer, ing pulmonary veins). The change of blood flow is indi- E. P., The effect of the Valsalva manoeuvre on the cated by + (increase), - (decrease), and (no change). systemic and pulmonary arterial pressure in man. Brit. Heart J., 1954, 16, 311. pulmonary artery pressure which occurs during 9. Baxter, I. B., and Pearce, J. W., Simultaneous meas- inspiration is probably due partly to an increased urement of pulmonary arterial flow and pressure output of the right side of the heart and partly to using condensor manometers. J. Physiol., 1951, 115, 410. an increased resistance to pulmonary blood flow; 10. Daly, I. de B., The resistance of the pulmonary vas- as a result, the flow into the capillaries is constant. cular bed. J. Physiol., 1930, 69, 238. The reduction of the output of the left heart which 11. Edwards, W. S., The effects of lung inflation and occurs a beat or two later can only be explained epinephrine on pulmonary vascular resistance. on the basis of an increased capacity of the pul- Am. J. Physiol., 1951, 167, 756. 12. Heinbecker, P., The mechanism of the monary capillaries or veins but the exact location respiratory waves in systemic arterial blood pressure. Am. J. of this increased capacity and its mechanism are Physiol., 1927, 81, 170. not understood. 13. Ramos, J. G., On the dynamics of the lung's capil- When the breathing is slower and deeper it is lary circulation. I. The mechanical factors. Am. probable that the increased cardiac output, due to Rev. Tuberc., 1955, 71, 822. 14. D. I. and an increased venous return, is greater than can be Cahoon, H., Michael, E., Johnson, V., Respiratory modification of the cardiac output. accommodated by distension of the pulmonary ar- Am. J. Physiol., 1941, 133, 642. terial system and the balance between cardiac out- 15. Osgood, H., Blood pressure fluctuations in respira- put and pulmonary vascular resistance is upset, re- tory obstruction; experimental observations. J. sulting in an increase in pulmonary capillary blood Lab. & Clin. Med., 1942, 27, 1536. flow towards the end of inspiration. The increased 16. Shuler, R. H., Ensor, C., Gunning, R. E., Moss, W. G., and Johnson, V., Differential effects of res- cardiac output is due mainly to increase in stroke piration on the left and right ventricles. Am. J. volume since the effect is not abolished when the Physiol., 1942, 137, 620. sinus arrhythmia is prevented with atropine. 17. Trimby, R. H., and Nicholson, H. C., Some obser- Figure 4 is a schematic diagram which attempts to vations on the nature of the respiratory waves in Am. summarize the findings reported in this paper, and arterial blood pressure. J. Physiol., 1940, 129, 289. their relationship to the work discussed in the 18. Boyd, T. E., and Patras, M. C., Variations in filling preceding paragraphs. and output of the ventricles with the phases of respiration. Am. J. Physiol., 1941, 134, 74. REFERENCES 19. Dupee, C., and Johnson, V., Respiratory changes in 1. Wiggers, C. J., The regulation of the pulmonary cir- pulmonary vascular capacity. Am. J. Physiol., culation. Physiol. Rev., 1921, 1, 239. 1943, 139, 95.