NEONATAL PULMONARY ISCHEMIA

J.C., Departments of Pediatrics, Western Reserve University School of Medicine and Mt. Sinai Hos-pital, Cleveland, Ohio.

J.A.C., Cardiovascular Research Institute and Department of Pediatrics, University of California Medi-cal Center, San Francisco; Career Investigator, American Heart Association.

E.K.C., Department of Pediatrics, University of Colorado Medical School, Denver, Colorado.

M.H.K., Department of Pediatrics, \Vestern Reserve University School of Medicine, Cleveland, Ohio. A.Y.S., Departments of Pediatrics, Western Reserve University School of Medicine and Mctropolitan General Hospital, Cleveland, Ohio.

W.H.T., Cardiovascular Research Institute and Department of Pediatrics, University of California Medical Center, San Francisco, California; John and Mary Markie Scholar in Academic Medicine.

B.L.B. and L.C.B., Cardiovascular Research Institute, University of California Medical Center, San

Francisco, California.

Work supported in part by U.S. Public Health Service Grants HE-06285, HE-09504-01, and

HE-01464-02, and the University of California International Center for Medical Research and Training with Research Grant GM-i 1329 from the Office of International Research, NIH.

ADDRESS FOR REPRINTS: Editor, Cardiovascular Research Institute, University of California Medical

Center, San Francisco, California.

PEDIATRICS, Vol. 40, No. 4, Part II, October 1967

709

one

NEONATAL

PULMONARY

ISCHEMIA

Part I: Clinical

and Physiological

Studies

J. Chu, M.D., J. A. Clements, M.D., E. K. Cotton, M.D., M. H. Klaus, M.D., A. Y. Sweet, M.D., and W. H. Tooley, M.D., with the assistance of

B. 1. Bradley, B.A., and L. C. Brandorif, B.A., R.N.

I

flow is one of the crucial adjustments to

extrauterine life that the newborn infant

must make. With the cessation of umbilical

circulation the lungs become the only organs

of oxygen gain and carbon dioxide loss, and

adequate pulmonary blood flow is essential

for these processes. It is hardly surprising,

therefore, that failure to accomplish this

ad-justment smoothly constitutes one of the

chief hazards to life in the neonatal period

and that it presents itself as pulmonary

failure.

If pulmonary ischemia is sufficiently

pro-found and prolonged, degenerative changes

are to be expected in the structure and

corn-position of the parenchyma, and these

changes may concern the observer more than

any other feature of circulatory

dysadapta-tion. It is our view that idiopathic

respira-tory distress of the newborn, or hyaline

membrane disease, results from and

primar-ily involves pulmonary ischemia and that

secondary changes in structure, composition,

and physical properties of the lungs have

tended to divert attention from it. We have

already presented this view in a preliminary

report.’ Our purpose in this paper is to set

down in greater (letail the reasoning and

evidence which support our conclusions. The

substance of this paper derives mainly from

clinical and physiological studies on infants

with idiopathic respiratory distress. In a

later paper we intend to give in detail the

re-sults of correlated postmortem physical,

chemical, and morphological studies on this

disease.2

DEFINITION AND ETIOLOGY

Neonatal pulmonary ischernia is

charac-terized by respiratory distress3 varying from

mild and transient difficulty after birth to

severe, progressive distress and cyanosis.

Breathing is labored, with expiratory

grunt-ing and inspiratory retractions. Tachypnea

may occur. Breath sounds are often

dimin-ished or inaudible. The chest film4 shows

diffuse densities and helps to rule out other

causes of respiratory difficulty. Visceral

ac-tivities may be decreased as judged by

ab-sence of bowel sounds and delayed diuresis

710 NEONATAL PULMONARY ISCHEMIA

often marked. Heart rate may be elevated

and fixed until the infants are terminal;6

sys-temic blood pressure is reduced in iuost cases

even before the agonal fall.7 Body

tempera-ture tends to (Irop, especially in the hypoxic

infant.8 The miiain functional changes are

diminished lung volume9 and greatly reduced

compliance,’0” arterial oxygen

desatura-tion’2 and carbon (lioxide accumulation,’3

large differences between alveolar and

ar-terial oxygen and carbon dioxide

ten-sions,’4”5 metabolic acidosis,’3 and

hyper-kalemia 16 Large right-to-left shunts’4 may

occur, especially when the infants are

se-verely ill. Recovery or death commonly

occurs wit hin 3 (limys.

At autopsy there are usually widespread

evidences of deep asphyxia. Pathognornonic

lesions are confined, however, to tile lungs.

These are collapsed, firm, and dark red when

the chest is opened. The lungs expand only

to one third to one half of the normal volume

and tend to collapse completely on

defla-tion .‘‘‘ histologic examination shows

ex-tensive alveolar collapse, (hilatation of

alveo-lar ducts and respiratory bronchioles, and

tile well-known hyaline nlembranes.’8’20’2’

Electron microscopic studies have shown

de-generative changes in epithelial an(1

endo-thelial cells of the alveolar menibranes and

dehiscences in the basement membrane.22

Probably as a result of such

degenera-tion, blood constituents2’ 23,24 and epithehial

cells21’22’25 and fragments appear in tile

air-spaces and, together with substances

nor-mally containe(I therein, are compacted into

hyaline membranes. No doubt many

reac-tions occur when such normally separated

substances are mmlixe(1. Some possible

inter-actions of proteins in the plasma clotting

sys-temn with surface-active lipoproteins have

already been described.26 On chemical

frac-tionation the lung tissue yields decreased

amounts of neutral lipids, phospholipids, and

surface-active lipoprotein.”2’27’28 Again, these changes may reflect deterioration of alveolar

cells from which surface-active material is

thought to originate.29’30 Saline extracts of

the lungs show abnormally high surface

ten-sion when examined by traditional

meth-ods,3’ and the stability of bubbles removed

from the lung is reduced.32 These facts have

been related to tile striking tendency of the

lungs to collapse after inflation.31-’33

Though the etiology of the syndrome is not

clear, we postulate that it is usually the

re-sult of fetal distress (e.g., intra-uterine

as-p1i’xia) or hypovolernia leading to

pulmo-nary vasoconstriction and ischemia. The

predilection of the syndrome for premature

infants is probably related to tile high

in-cidence of complications of pregnancy, labor,

an(l delivery in these cases, especially

ma-ternal bleeding and placenta previa.’7’2”34’3’ In a(l(hition, the lungs, like other organs,

con-tinue to develop structurally, chemically,

and functionally throughout gestation. A

given stress may therefore do greater damage

when it falls upon the tissues of the

prema-ture infant than it would later.

Infants born to mothers with overt or

latent diabetes are at high risk, regardless of

gestational age.3#{176}The recent denlonstrationtm7

that these infants have an abnormally large

mass of pulmonary arteriolar smooth muscle

may mean that they are especially subject to

pulmonary ischemia inder stress. The reason

for this hypertrophy is not clear. Perhaps it

reflects tile repeated sympathetic activation

which accompanies abnormally large daily

oscillations in blood glucose levels that may

occur even in well-controlled diabetics.38

BASIS AND PLAN OF INVESTIGATION

Though the best efforts of many

investiga-tors have failed to reveal the ultimate causes

of the syndrome, they have greatly refined

the description of its manifestations. When

we began the studies to be described in this

paper, we felt that certain characteristics

were established beyond reasonable doubt,

at least in the severe, untreated, fully

de-veloped syndrome, and that these have vital

functional significance. These characteris-tics are:

1.the lining of the pulmonary airspaces is

altered so that the lungs tend to collapse and

2. exchange of oxygen and carbon dioxide

is so grossly impeded that severe hypoxemia

and hypercarbia occur,

3. anaerobic metabolism occurs and

or-ganic acids accumulate.

In addition to these phenomena, we

postu-lated that severe hypoxemia and acidemia

would stimulate pulmonary

vasoconstric-tion, as they have been shown to (10 in other

circumstances,39’47 leading to pulmonary

ischemia, deterioration of alveolar tissue, and further interference with tile alveolar lining.

The resulting extension of atelectasis would

further intensify asphyxia and its

conse-quences. We were encouraged in making this

postulate by the similarity of pulmonary

changes which occur in hvaline membrane

disease and in experimental I)ulmllonar’

ar-terial occlusion.48 We reasoned that if we

could halt or reverse the progress of atelecta-sis an(I so interrupt tile circle of j)athological

events, we might ameliorate tile syndrome.

We chose to attempt this by supplying a

synthetic surfactant, L-alpha-dipalmitoyl

lecithin, whose properties as a surface film

closely resemble those of pulmonary

surfac-tant,49”#{176} to replace or reinforce tile natural

alveolar lining. Success with this therapy

would be measured by increase in lung

vol-mime and compliance and by iniprovemnent in

alveolar-capillary gas exchange. A similar

trial had already been reported,” and,

though it was apparently successful, no

con-trols were mentione(1 and physiological

docu-mentation of the response to treatment was

not given.

After extensive studies to establish tile

safety of the surfactant as a drug, we

evalu-ated its effect on 18 infants with respiratory

distress. In most of these infants lung

comn-pliance increased. In some, however, in spite

of increasing conipliance and adequate

ven-tilation, the arterial desaturation, carbon

dioxide retention, and alveolar-arterial gas

tension gradients increased, and the clinical

condition worsened. In these cases extension

of atelectasis did not seem a reasonable

ex-planation for the (leterioration in gas

ex-change, and we suspected mounting

pulmiio-nary ischemuia. An elementary consideration

of gas diffusion in the lumigs as modified by

hvaline membrane disease (Appendix I)

mdi-cated that only a small flow of blood coul(1

be passing in reasonable proximity to

venti-late(I airspaces. Since ventilated a irspaces are rather uniformly distributed throughout

the tissue (even in severe hyaline membrane

disease) and much of the parenchiyma should

be within “diffusing distance,” the lung as a

whole was probably receiving greatly

re-duced pulmonary flow. If so, the itiost likely

explanation would be rnlm1lonary arterial

constriction with large right-to-left shunting

through extra-pulmonary channels.’4 ,5255 We

therefore (levelope(l miethods for calculating

and measuring effective pulmonary blood

flow in these infants and found it to be lower

than that in normal subjects. Surfactant

therapy di(1 not improve it substantially, and

we decide(1 that a more (hrect approach to

pulmonary vasodilatation should be

at-tempted.

We knew from thc work of Dawes’6 and

Rudolph43 an(I their co-workers that

acetyl-choline is a powerful pulmonary arterial

re-laxant in fetal and newborn aflinlals. If

pulmonary ischemia in our patients was due

to vasoconstriction, administration of this

drug might increase effective flow amid

im-Irove gas transfer. Acetylciiohine usually, but

not invariably, pro(luce(l responses

consis-tent withi pulmonary vasodilatation and

in-creased flow. Since the puliiionary arterial

and left atrial pressures are normal or nearly

normal in such infants,’4 these responses len(l

support to the notion that pulmonary

isch-emia results to a significant extent frommi

in-crease(l smooth mimuscle tone in the vessels of

the lung.

METHODS’

Umbilical Catheterization and Temporal Artery Puncture

We cut feeding tubes* with an internal

diameter of 1.5 mmsmn inches from the flanged

aSymbols are defined in glossary (Appendix II).

* Argyle, Aloe Medical, 1831 Olive St., St. Louis,

700

-OXYGEN ELECTRODE

600 - READING

mmH9

500

-/

-200

-100

712 NEONATAL PULMONARY ISCHEMIA

#{149}ELECTRODE SET WITH /0% 02

o ELECTRODE SET WITH

98% 02

(AVERAGE G 5 READINGS FOR EACH POINT)

I I I I

0 100 200 300 400 500 600 700

P02 (FROM P3 E. CALIBRATING GAS)

Fic. 1. Calibration of the oxygen electrode. When

cali-brated with 98% oxygen, the standard deviation of each point varied from 0 mm hg at the high range to 3.0 mm

Hg at 146 mm Hg. When calibrated with 10% oxygen, the standard (leviation of each point varied from 0.3

mm Hg at 146 mm Hg to 9.5 mm Hg at 685 mm Hg.

end and fitted a luer-lock, 20-gauge blunt

needle attached to a two-way stopcock into

the cut end. These were then filled with 0.9%

sodium chloride saline containing 5 USP

units of heparin per milliliter and inserted

into one umbilical artery and the umbilical

vein. We x-rayed the abdomen, after

ad-vancing the umbilical artery catheter 8 to 10

cm, and in every instance the catheter was in

the abdominal aorta. We mneasured pressure

continuously as we attempted to place the

umbilical venous catheter in the inferior

vena cava above the diaphragm, right

atrium, or right ventricle. When pressure

tracings indicated the proper location, we

checked the position by x-ray.

We cannulated the temporal artery with a

23- or 24-gauge needle attached to a winged

scalp infusion sett as described by

Thom-sen.57 We used blood from the temporal

ar-tery for pH and blood gas analyses in those

instances where umbilical artery

catheteriza-tion was not possible and during follow-up

studies of infants recovering from respiratory

distress. These values are indicated in the

f Abbott Laboratories, North Chicago, Illinois 60064.

tables by a superscript (TA). All values not

otherwise identified are froni blood taken via

the umbilical artery from the abdominal

aorta.

Blood Pressures

We used strain gauges for measuring

sys-temic pressures. They were placed at the

level of the heart. We recorded aortic blood

pressure continuously for as long as 6 days,

central venous pressure for as long as 3 days,

and on three occasions right ventricular

pres-sures for periods of 10 minutes to 1 hour. The

system was calibrated twice a day with a

mer-cury mnanometer and was extremely stable,

varying less than 5% during any 24-hour

period. The frequency response of the system

was linear to 25 cycles per second.

Blood pH, HC03 and Gas Tensions

We measured pH with a glass micro

elec-trode at 38#{176}C,bracketing each experimental

determination with readings of a standard

buffer solution. After adjusting the value for

change in calibration, we added a correction

to compensate for the difference between

38#{176}Cand the infant’s rectal temperature.58

We used an oxygen electrode of the Clark

type at 38#{176}Cwith a 40 microliter volume for

measuring oxygen tension (Po2). It was

cali-brated with room air saturated with water

vapor before and after each determination.

The meter was set to 0.5% daily with 99.5%

nitrogen. Since gas samples give a higher

reading than blood samples having identical

tensions, we multiplied the blood sample

readings by an appropriate factor (1.040).

The electrode was very stable. Fifty pairs of

duplicate samples with tensions from 20 to

100 mm Hg had a standard error of 0.5 mm

Hg, and 50 pairs of duplicate samples with

tensions from 100 to 600 mm Hg had a

stan-dard error of 2 mum Hg when the electrode

was calibrated with room air. The calibration

of the oxygen electrode using gas mixtures

analyzed with Scholander apparatus is given

Statham Medical Instruments Co., 1401 W. Olym-pic Blvd., Los Angeles, California 90064.

in Figure 1. We corrected the oxygen tension of blood samples for the baby’s temperature

using the nornogram constructed by

Sever-inghaus.’9

We estimated carbon dioxide tensions

(Pco2) using the Astrup technique as

mnodi-fled by Siggaard-Andersen, el at.,6#{176}applying a

correction factor, if necessary, for oxygen

unsaturation. One hundred samples were

measured by both the Astrup technique and

a Severinghaus electrode6’ with a 300

micro-liter volume. The indirect estimates averaged

0.7 mm Hg (S.D. 0.6) lower than the direct.

All values given elsewhere in this paper were

determined by the Astrup method.

Samples were taken directly from the

pa-tient and analyzed within 5 minutes on the

pH, oxygen, and carbon dioxide electroles

and the Astrup apparatus, which were in the

same room. Oxygen tension was always

measured first, usually within 1 minute, and

a small correction for change in pH was muade

according to the elapsed time.62 All

measure-ments of oxygen and carbon dioxide tensions

and pH were performed in duplicate.

Hemoglobin and Hematocrit

We determnined the hemnatocrit by spinning

blood in heparinized capillary tubes at 7,500

RPM for 10 mninutes and measured

hemo-globin by Drabkin’s cyanomethemoglobin

method 63

Oxygen Saturation and Shunt Calculation

We calculated the oxygen saturation by

taking the pH and the Po2 of the blood at

body temperature, correcting the Po2 to 1)11

of 7.40 and 37#{176}C, using the line charts of

Severinghaus.’9 We then read the saturation

from the oxygen dissociation curve for fetal

blood.64

Blood samples were withdrawn after

in-spired oxygen concentration (Fio2) was

con-stant for 10 minutes. Although we drew most

of the samples while the patients breathed

97 to 98% oxygen (the oxygen used in these

studies contained 2 to 3% of inert gas), we

took some samples with the patients

breath-ing lower oxygen concentrations. In Table IX

we report the actual arterial oxygen tension

measurements (Pao2) before therapy, but the

remainder of the oxygen values are expressed

in termus of shunt in order to allow

compari-son between values obtained while breathing

various oxygen concentrations.

We ulSe(1 Berggren’s equation6’ as described

by Nelson and co-workers” to calculate

right-to-left shunt:

Equation 1

QS/QT (Cao - Co2)/(Co, - Ceo2) where:

= fraction of cardiac input shunted

right to left.

Cao2 mill 02 in 100 miii arterial blood.

Ceo,=ml 02 in 100 ml end-pulmonary

capillary blood.

Cv02= ml 02 in 100 ml mixed venous

blood.

To solve equatiomi 1 we misade the following assuml)tions:

1. That the mixed venous saturation is

less than aortic saturation by a constant

amuount. In the infants with muoderately

severe an(i severe respiratory distress

re-ported by Rudolph and his co-workers,’4

there was a mnean difference of 15% between

the saturations of abdominal aortic and right

ventricular blood. We subtracted 15% from

the saturation of aortic blood and multiplied

this by the capacity of whole blood for

oxy-gen to derive the (Vo2.

2. That the capacity of blood for oxygen is

equal to 1.34 timiies the numiibers of grams of

hemoglobin in 100 mid of blood. In 20 infants

with respiratory distress, the oxygen

capac-ity of whole blood measured with Van

Slyke’s manometric apparatus was 1.34

ml/gmu of hemoglobin (S.D. 0.02).

3. That for each mmii hg Po2, 0.003 ml

oxygen is dissolved in the blood.

4. That after 10 mninutes of breathimig a

mixture containing any concentration of

oxygen, the oxygen is uniformly distributed

thirough the lung. This appears reasonable

since thie distribution of ventilation imi

a-tients with, respiratory distress is uniform as

reported by Nelson and co-workers” and

20r

I

714 NEONATAL PULMONARY ISCHEMIA

I).

N2rN2fl

VT

(ml)

CASE 25

AGE I37t iS,.,

E,

MINUTES

2

F,o. ‘2. I)istribution of ventilation and determination of lung volume in respiratory

distress. Tue lower panel shows recordings of tidal volume (VT) and nitrogen con-centration. The upper panel gives plots of the difference oii a logarithmic scale be-tweeti the end-expired nitrogen concentration in each breath (N;,) and the nitrogen

concentration when nitrogen washin is complete (N2f). The two successive lung

vol-umes derived by equilibration (VL) are identical. Somewhat higher lung volumes

[Vm,(W)l were obtained from analyses of the nitrogen washin subsequent to rebreathing.

5. That alveolar CO2 tension is, for this

calculation, not different from arterial CO,

tension. As discussed below, this assumiiption

is erroneous, but the error in calculating

shunt caused by the apparently large

ar-terial-alveolar CO2 tension difference is

small.

6. That end pulmonary capillary and

alveolar oxygen tensions are equal. This

as-sumnption defines S/QT so as to include both

anatomical and physiological shunt flow.

The most important source of error is in

the calculation of mixed venous oxygen

con-tent. However, in three instances we

ob-tained simultaneous samples from the right

ventricle and abdominal aorta, and these

were consistent with our assumption (Table

Nasal Airway

We comistructed a nasal airway of

poly-ethylene tubing (Fig. 3) simnilar to that

de-scribed by Golinko and Rudolph,66 closed at

one end and connected at the other to the

pneumotachygraph. This niade a tight seal in

the nostrils and provided a pathway having

low flow resistance (<5 mum H,O

peak-to-peak pressure oscillation during quiet

breath-ing) and small dead space (<0.5 ml) to the

pneumotachygraph and associated

equip-muent. A port opposite the nostrils admitted

the sampling catheter of the gas analyzers

into the airway. Because of its lightness this

adapter remained in place without further

support when inserted into the nostrils and

did not appear to distress the infants or

Sample

Caae Age F10, Source P0, jll PLO, So,

19 74 .98 UA 75 7.21 54 98%

RV 42 7.19 56 81%

24 94 .97 UA 85 7.18 56 99%

RV 45 7.13 61 85%

26 6l .98 UA 176 7.27 50 100%

ltV 43 7.21 55 84%

Symbols are defined in Appendix II.

SaO,-SRvO,

14%

16%

TUB/NG GUAI RUBBER 2mm. ID SEEVE5

_M

6nim.

POLYETNrLENE TUBES

/

FIG. 3. Nasal airway.

TABLE I

ARTERmOVENOTJS DmFFERENCE IN OXYGEN SATURATION (Sao,-Savo,) m ThREE INFANTS WITH RESPIRATORY DISTRESS

resj)ire(I gas concentrations were to be

rnoni-tored over long periods, the mualleable

sam-pling catheter was molded to fit the infant’s

face and taped in place so that the end lay in

one nostril. The infants with acute

respira-tory distress were usually inactive, so that

occasional movements of their hands did not

disturb the equipmuent, and muovements of

the head only occasionally dislodged the

samnpling catheter or nasal airway. Normal

infants and infants recovering from

respira-tory distress were loosely swaddled to

pre-vent interference with the sampling devices.

Pneumotachygraph

We constructed a flow meter of the kind

described by Fleisch67 froni polyethylene

tubing chosen to mate with the nasal

adapt-er. The resistance clement consisted of a

bundle of polyethylene catheters1 2.5 cmii in

length forced into the flow meter tubing.

PE 160 (Clay Adams, Inc., 141 E. 25tl Street, New

York, New York 10010).

5mm.

Piezo holes for mneasuremnent of lrcssure

(lif-ference across the elemuent were placed in the

wall of the tubing 2 mnmii from the ends of the

element and connected by flexible polyvimiyl

tubing to a differential pressure trans(lucer.

#{182}

Rejection of “zero-flow” pressure signals was

optimized by adjusting the resistance of the

tubing. Response to a step-change in flow

was 95% comnplete in 0.02 secon(ls.

Calibra-tions were done with air an(1 oxygen and

gave linear plots of flow against pen

deflec-tion on the polygraph.# The resistance of the

flow meter and nasal adapter together gave

peak-to-peak pressure oscillations of less

than 1 cm H20 during breathing, and total

volume was less than 1.5 ml. Because the

adapter and flow meter were used inside a

heated incubator and because of their plastic

composition, condensed water did not

ac-1 PMac-15TC (Statham Medical Instruments (‘o., 12401 W. Olympic Blvd., Los Angeles, California

90064).

# Model 6 (Grass Instrument Co., 101 Old Colony

Ave., Quincy, Massachusetts 02169).

3-6 V AC

MALLEABLE CAT/,’ETER

NEEDLE VALVE

CARBON D/OX/DE

ANALYZER

MICRO CATHETER

CELL

NEONATAL PULMONARY ISCHEMIA

MEC/1AN/C.4

kZCC/(/M PC/Mg#{176}

FIG. 4. Arrangement of sampling catheter and gas analyzers.

N/7’IQOGEN

ANAYZEIQ

cumulate in them and heating elements were

not needed.

The signal fromn the flow meter was

in-tegrate(i electrically to obtain a display of

tidal volume. Calibratiomi by pumping was

linear withiimi 5% with stroke volumes of 5 to

30 ml and varied less than 5% with respect

to frequency over the range 20 to 120 per

minute. Most measurements of tidal volume

were made at frequencies between 30 and 90

per mninute. Tidal volumes were usually

be-tween 5 an(1 15 ml, and minute volume rarely

exceeded 1,000 nil during recording of

respi-ration. Interim calibrations were done at tidal

volumes and frequencies roughly matching

those of the Patient.

lntraesophageal Pressure

We used an air-filled balloon, catheter, and

strain gauge** to record pressure in the middle

third of the esophagus. The catheter was a

30 cm long, French No. 5 polyethylene infant

feeding timbe, and the balloon was made

ac-cording to the niethod described by Mead

and co-workers.68 It was 3 cm long and .its

volumue, attached to the catheter, was 0.6 ml.

1)uring the registration of intraesophageal

pressure, the volume was set at 0.2 ml. The

speed of response to pressure change was at

the limit of the polygraph. Gas Analysis

Accimrate continuous recording of CO2 and

N2 concemitrations in the breath of small

pre-** PMI3ITC (Statham Medical Instruments Co.,

12401 W. Olympic Blvd., Los Angeles, California 90064).

miiature infants in respiratory distress, whose

minute ventilation was as sniahl as 200 ml/

minute and mid-expiratory flow as slow as

0.5 I/minute, required mnodification of

stan-dard techniques in order to achieve adequate

dynamic response. To minimnize sample flow

the CO2tt and N2 analyzers were arranged

in tandemii (Fig. 4). To maximize speed of

response, the CO2 analyzer was operated

with unusually low pressure in the

micro-catheter cell and a malleable, heated,

sam-pling catheter was constructed in which gas

volume was small and resistance to gas flow

was high. Tb needle valve of the N2

ana-lyzer was inserted directly into the outlet

port of the CO2 microcatheter cell. A

me-chanical vacuum pump drew gas from the

airway via the malleable catheter to the CO2

analyzer and thence to the N2 analyzer.

Sampling Catheter

Because the malleable catheter was critical

to the operation of our analytical system,

be-cause it is convenient to use, and because it

has not so far as we know been previously

described, sonic details of its construction

will be given here (Fig. 5). A 77 cmii length of

bare nichrome wire (S & W gauge No. 28)

was threaded through 75 cm of polyethylene

tt Model LB-i with microcatheter cell (Beckman

Instrument Co., 2500 harbor Blvd., Fullerton, Call.

fornia 92634).

4 Model 105 (Custom Engineering and Development

Co.; Med-Science Corporation, 2647 Locust St., St

Louis, Missouri).

§ 1)uo Seal, Cat. No. 14(5) (Welch Scientific

SO-. NO. 2/

BLUNT NEEOLE

TRANSFORMER

P01 YETHYLENE

TUB/NG, PE /90

/

CROSS-SECTION

FIG. 5. Malleable sampling catheter.

tubing

ii

at each end. The leading end was soldered

neatly to 150 cm of enameled copper wire

(S & W gauge No. 36) and bent back flat

against the outside of the PE 50 tubing. The

copper wire was brought along the outside of

tubing to the trailing end in a spiral of two

or three turns. This assemubly was then

threaded (copper wire first) into a 73 cm long

sleeve of polyethylene tubing,f{ so that the

sleeve j)rojected about 1 mm beyond the

leading end of the inner tubing and wire. At

the trailing end of the sleeve the two tubes

were fixed together by a wrapping of

ad-hesive tape 1 cm wide. The trailing end of the

nichrome wire was then wrinkled slightly and

forced into the lumen of a blunt, 21-gauge

hypoderniic needle as the needle was screwed

into the lumen of the PE 50 tubing. The

needle hub was placed firmly on the male

adapter of the inlet tube of the CO2

micro-catheter cell. About 60 cm of the excess

copper wire was cut off. Connections were

made from the needle and the copper wire to

the secondary winding of a stepdown and

isolation transformer, so that alternating

cur-rent at 3 to 6 volts could be applied to the

heating wire. The voltage was set

(approxi-PESO (Clay Adams, Inc., 141 E. 25th St., New York,

New York 10010).

190 (Clay Adams, Inc., 141 E. 25th St., New York,

New York 10010).

mnately 4.5 volts) so that the sleeve was

warm to the touch; this amoumit of power

dissipation was sufficient to prevent

conden-sation of vapor as the sampled gas expanded

along the cathieter.

The use of nichrome heating wire within

thie sample catheter accomiiphislied the follow-ing:

1. it prevented condensation of vapor in

the line;

2. it provided a malleable assembly which

could be shaped to the patient’s face, taped

in place, and left for long periods without

re-quiring muuch attention and without causimig

discomfort to the patient;

3. the wire occupied mnost of tue lumnen,

creating a long capillary path of low volume

and high resistance-as a result, variations

in airway pressure had little effect on the

calibrations of the analyzers;

4. since a large pressure drop occurred

along the catheter leading to a high linear

velocity in the gas stream amid rapid flushing

of the CO2 muicrocatheter cell, only a smuall

samiiple flow was needed despite

tue

N, and CO2 Analyzers

Under typical comiditions, the samiiple flow

was 40 mul/minute. (1)tiring sinusoi(lal

breath-ing at 60/miiinute withi a tidal volume of 10

718 NEONATAL PULMONARY ISCHEMIA

mi/minute so that the sampling rate was less

than 4% of the mean expiratory flow rate.)

Following a step change in concentration,

transit time from catheter tip to CO2

ana-lyzer was 0.18 second, and the rise time was

0.16 second for 95% response. Transit to the

N2 analyzer was slightly longer, 0.19 second,

and rise time was 0.16 second. Sample flow

rate was set by adjusting the needle valve of

the N2 analyzer and nieasured by timing the

passage of a soap film between marks in a

syringe barrel connected to the catheter.

Whien flow rate was adjusted to a given value

(within the accuracy of this flow

measure-ment), the dynamic response characteristics

of the system were reproducible with a

pre-cision better than 10%, i.e., precision was at

the limit of the polygraph. Six malleable

catheters constructed as described above

were interchangeable in respect to dynamic

characteristics of the system. Only minor

adjustment of the needle valve was required

to obtain nearly identical sensitivity and

dynamic calibrations.

In this configuration the CO2 analyzer was

operated at high gain, and frequent

calibra-tions were essential. Calibration curves with

six gas mixtures were done at least twice

daily. These showed little variation from day

to day and required little adjustment of

sensitivity. Calibration curves for N2 and

CO2 were linear when plotted on log-log

graph paper; and even when sensitivity

changed somewhat, the slopes of the lines

were unchanged. Frequent interim

deter-muinations of the position of the calibration

lines could therefore be made with a single

gas mixture (against a baseline with tank

02).

Calibrating gas mixtures were stored in E

cylinders. Their composition was determined

by Scholander’s method.69 Triplicate

analy-ses agreed within 0.05% for 02, CO2, and

nonabsorbed gases.

Because the infants breathed gas saturated

(or nearly saturated) with water vapor in

incubators set at 33 to 36#{176}Cand because

condensation in the external airway and

sampling line was avoided, the continuous

analyzers worked on gas containing about

6% water vapor. Calibrations were done,

therefore, with mixtures saturated with water

vapor at 26#{176}and 37#{176}Cby bubbling through

two warmed washing towers in tandeni, the

sampling catheter being inserted directly

into the gas space in the second tower. Since

the difference between calibrations at 26#{176}

and 37#{176}Cwas negligible, routine calibrations

were done with gas muixtures saturated with

water at room temperature. Using the

com-positions of the dry calibrating mixtures and

measured barometric pressure and assuniing

that the partial pressure of water vapor was

47 mm Hg, we expressed the polygraph

de-flections as partial pressures of CO2 and N2.

Partial pressure of 02 was calculated by

subtraction. (The error due to the effect of

argon on the N2 analyzer was considered

negligible.) Freon Analyzer

An analyzer for continuous recording of

freon concentration in the breath was

con-structed according to the principle described by Mead and Collier.70 Because the

viscosity-density-heat capacity parameter of freon is

very different from those of air, alveolar gas,

and 02, freon can be determined in these

gases by a pressure measurement.

The apparatus (Fig. 6) consisted of the

malleable heated catheter, serving as a

capil-lary resistance, a T-tube connected to a

gauge## for measuremuent of pressure drop

through the catheter, a critical orifice, and a

mechanical vacuum pump.*** The critical

orifice was made as a pinhole in a diaphragm

of 0.002 inch thick phosphor-bronze, and the

size was adjusted empirically with a needle

to give a sampling rate through the catheter

of about 30 ml of air per minute. The ne&lle

hub of the malleable catheter, the T-tube,

and the adapter bearing the critical orifice

were wound with 70 cm of No. 28 insulated

nichrome wire heated with alternating

cur-rent at 3 to 6 volts to prevent condensation of vapors.

## P23dc (Statham Medical Instruments Co., 12401

W. Olympic Blvd., Los Angeles, California 90064).

*** Duo Seal, Cat. No. 1400 (Welch Scientific

L(/EiQLOC/( T-T(IBE

MALLEABLE SAMPLING CATHETER

(AS CAPILLARY

RESISTANCE)

PAESS(/RE G4(/GE

FIG. 6. Freon analyzer.

20

0 20 40

DEFLECTION (mm)

Values are given ill IIfl Hg. FIG. 7. Calibration of the freon analyzer.

__ TO MECHANICAL

VAC(JC/M P(/MP

002” THICK PHOSPHOR -BRONZE

D,’APHRAG/vf PERFORA TED

BY PINHOLE

(As CRITICAL oRIFIcE)

The capillary resistance in our modified

analyzer was very much higher than that in

Mead and Collier’s.70 This had the

disad-vantage that pressure signals due to change

in gas composition were detected against a

large background signal (about 670 mm Hg),

which was balanced out electrically. As a

result, there was annoying but not disabling

instability in the recorded baseline. The

ad-vantage of this design was that the analyzer

responded rapidly. Following a step-change

in gas composition at the tip of the catheter,

response began in 0.10 second and rose to

95% of final response in 0.15 second. Table

II shows pressure differences through thie

catheter measured with several gases. It can

be seen that the pressure changed 2 mm Hg

or less between air, 02, and alveolar gas, but

fell by 85 mumu Hg withi freon 21. Calibration

was linear (Fig. 7) between pen deflection

amid volume fraction of freon over the range

of concentrations used in our studies. When

freon was determined in the rebreathing

sys-tem, a control run was also done without

freon to show the effect, if any, of 02

absorp-tion and CO2 accumulation on the freomi

TABLE II

SENSITIVITY OF FREON ANALYZER TO FIVE (;AS

4ir 02

Alveolar

Gas

670 672 672

analyzer during a comparable period of

re-breathing. The effect was smiiall an(l it was

usually necessary to apply a siiiall correction to the indicated freon concentrations.

Rebreathing Apparatus

Our miiethods for miieasuremnent of lung

volume and effective pulmonary blood flow

each required rebreathiing. The apparatus is

shown schematically in Figure 8. A

thin-walled (0.0035 in.) polyethylene sac

(ap-proximately 3 cm in diamneter and 15 cm in

length) was mounted on a No. 5 one-hole

rubber stopper cut to a length of 1.5 cm and

containing a 2 cmii length of plastic tubing of

the same size as the pneumotachygraph. A 3

GC/M

T(./BING

ADAPTER

ANAL YZER

POLYETHYLENE SAC

HEMOSTAT

720 NEONATAL PULMONARY ISCHEMIA

FIG. 8. A rebrcathing apparatus for measurement of lung volume and effective pulmonary blood flow.

cm length of guni rubber tubing connected

the plastic tubing to a 1 cm length of plastic

tubing tapere(I to connect smoothly to the

pneumotachygraph. 1)ead space in this

(he-vice was 1.1 ml. The sac was rinsed three

tunes with the gas Inixture to be rebreathed,

and the gas was then aspirated to collapse the

sac completely. A known volume of the gas

mixture (up to 100 mnl) was introduced into

the sac imnnie(hiately before use, and the

rub-ber tubing was clamiiped with a hemostat,

which also served as a handle for the device.

With j)ractice, the rebreathing sac could be

deftly connected to the pneumotachygraph

at end-expiration and the hemuostat could be

simmmultaneously opened so a leak-free

connec-tion could be made a functional residual

vol-ume without obstructing the airway or

dis-turbing the patient. At the end of the

re-breathing interval the sac was remuoved

smoothly, again without disturbing the

pa-tient.

Apparatus for Mixing Expired Gas

A non-rebreathing apparatus (Fig. 9) was

constructed for the determninat ion of mixed

expired gas concemitrat ions. This consisted

of a T-tuhe, inspiratory an(l expiratory check

valves, and an expiratory mixing tube. The

T-tube was of polyethylene and had a side

tube tapered to niate with the

pneumotachy-graj)h. The check valves were 6 cm lengths of

in. glass tubing which was ground to a 45#{176}

bevel, closed with a flap of thin teflon glued

on at the upstream end of the bevel, and

enclosed in in. glass tubing. Mixing of

cx-pired gas was completed in a 30 cm length of

inch gum rubber tubing beyond the

ex-piratory valve. In use this apparatus

in-creased the oscillations in airway pressure at

the nasal adapter to at most 1.5 cm water

peak-to-peak, and added less thian 1% CO2

to the inspired gas. To make mneasurements

of Inixed exl)ired gas concentrations, the

nialleable catheter was removed from its

port in the nasal adapter, the port was

plugged with a short length of sealed

cathe-ter, an(I the sampling catheter was

intro-duced about 10 cm into the expiratory

tub-ing. Typical tracimigs are shown in Figure 10

together with recordings of tidal volume and

airway pressure. For the calculation of

ap-parent physiological dead sj)ace, inspired

CO2 was deterlnined by replacing the

malle-able catheter into the port of the nasal

adapter before the rebreathing device was

re-moved. This value was then subtracted from

VALVES

NASAL ADAPTER FLOWMETER

TO ANALYZERS

FIG. 9. A non-rebreathing device for mixing expired gases.

CASE /7 AGE 98 ,r.

+10 AI R (cmH2O) 0

-10

)

Co2

0/ 4

1 MINUTE

FIG. 10. Recordings of airway pressure, tidal volume,

and mixed expired CO, concentration.

of simultaneously drawn systemim ic arterial

blood or of emid-expiratory gas.

Procedures for Physiological Measurements

Because of the nature of the experimental

subjects and of their affliction, it was not

generally possible to niake physiological

muea-surements umider ‘steady state conditions.”

We were alert to this shortconiing in our

studies and have rejected those in which

sig-nificant variations were recognized. The

fol-lowing determinations were made with this

limitation in mind.

END-EXPIRATORY CO2 TENSION was

Inca-sured fromii the continuous tracing of respired

CO2 concentration. It was required that the

tidal volumime be sufficiently large to clear the

anatomical amid instrumnental dead space and

that the expiratory flow rate be at least 10

times the samnple flow rate. Values were not

tabulated unless CO2 rose less than 10% in

the last of the tidal volume.

MIXED-EXPIRED CO2 TENSION was

deter-mined with the apparatus already described,

or by longhand calculation from

imieumiio-tachygraphi and continuous CO, tracings

(Fig. 11). In the latter the CO2 concentration

in expired gas was measured at the niidpoint

of each 1 or 2 ml incremnent of expired

vol-umime. Each of these concentrations was

con-sidered to he the average for the interval.

They were sullimed and divided by the

ntzm-ber of incremnents to derive the

mnixed-ex-pired CO2. In 30 instances, the shape of the

CO2 tracing was redrawn to correct for thie

lag in response of the CO2 analyzer. A

coni-parison between the miiixed-expired CO2

con-centrations calculated from corrected and

uncorrected CO2 tracings showed a difference

of less than 5%. Therefore, this correction

has not been applied. In either method of

ventila-+10

CASE 22

AGE 48hrs.

0

E5 -10

(cmH2O) -20

VT

(ml)

20

10

0

80

AV(mI) 2 2 2 2 2 2

Co2 / 0/

‘ /0

________ Fco2

0.1 1.0 2.8 4.3

5.4

5.8

ii#{247} 6: FECO2: 3

2

..L 3 SECONDS

NEONATAL PULMONARY ISCHEMIA

N2 /0/ \

I0/ 40

0

FIG. 11. Calculations of mixed expired CO, concentratioti aIld lung compliance from tracings of tidal volume, CO2

concentration, and intraesophageal pressure. CO, and N, tracings have been aligned with the volume tracing to

correct for delay in gas sampling. The lower set of vertical lines was erected at the midpoints of seven equal

incre-ments of tidal volume. The upper two vertical lines were drawn through maximum and minimum volumes. For

de-tails of calculations see text.

tion be steady for at least 5 muinutes before

the measurement an(I throughiout the

inter-val of recording. We mneasured

mixed-ex-pired CO, concentrations by both techniques

on 20 occasions in six sick infants. Time mean

difference between the methods was 0.08%

(S.D. 0.04%), which was not significant.

Therefore, the methods were used

inter-changeably and values (lerived by one or the

other are not separately i(lentifie(I. The CO2

concentrations were converted to tensions as

described under calibrations of the gas

ana-lyzers.

TIDAL AND MINUTE VOLUMES were

re-cor(led continuously for periods of from 10

minutes to 3 hours. Tidal volume varied in

relation to grunting, but it was fairly uniform

during periods of rapid respiration between

grunts. Minute ventilation was obtained by

adding tidal volunies. The values given in the

tables and graphs are the mean tidal and

miiinute volumnes for 10- to 30-minute

inter-vals when ventilation was relatively

con-stant. We obtained blood samples and

calcu-lated a-Aco2 differences, apparent

physio-logic dead space, apparent alveolar

ventila-tion, and CO2 elimnination (luring such

inter-vals.

CO2 ELIMINATION: 1Iean expired CO2

concentration by either of the foregoing

methods and minute ventilation were

mul-tiplied together and the products were

re-duced to standard temperature and pressure

for the estimation of CO2 elimination.

Cor-rection was made if necessary for inspired

ARTERIAL-ALVEOLAR CO2 TENSION

GRA-DIENT: End-expiratory CO2 tension was

re-corded during steady breathing while a

samii-plc of systemic arterial blood (either

teni-poral or abdominal aorta) was drawn for

analysis, as described above.

APPARENT PHYSIOLOGICAL DEAD SPACE

(VD(app)): Thie fraction of thie tidal volume

which was apparently wasted VD(app),/VT

was calculated from the estimated alveolar

CO2 tension (using tue CO2 tension of

sys-temic arterial blood or end-expiratory gas)

and in mixed-expired gas by the formula:

VD(5PP)/VT 1

where:

Equation

mixed-expired CO2 tension

estimated alveolar CO2 tensiomi

VD(app) = apparemit physiological dead space

VT = tidal volume

If mmieasurable, inspired CO, tensiomi was

subtracted from alveolar and mixed-expired

CO2 tensions in this formula.

We use the term “apparent physiological

dead space” because of the ambiguity in

(he-fining wasted ventilation when there are

pulmonary ischemia and large right-to-left

shunts. The denomuinator in Equation 2 is

difficult to estimate. If the lung is uniformuly

ventilated in space and time with an

ade-quate tidal volume, time en(l-expiratory CO2

tension is a good approximation of the mean

alveolar CO2 tension and it is time proper

fac-tor for inclusion in time formula. If the tidal volumes are too small to clear the anatomical

dead space, end-expiratory CO2 tension is

lower than alveolar tension, dead space is

underestimated, and an arterial CO2 tension

measurement is preferable. If there is

non-uniformity of either ventilation or blood flow,

an arterial CO2 tension measurement is

prob-ably preferable. Since there are often large

right-to-left shunts (see below), the arterial

CO2 tensions are higher than the

end-pul-monary capillary and alveolar CO2 tensions

because of admixture of venous blood, and

(lead space is overestimnated. The use of

blood frommi the ascendilig aorta (temiiporal

artery) has the advantage that it (hoes not

contain venous blood shimnted through a

pa-tent ductus arteriosus and the overestimate of dead space is not as great as with

abdonmi-nal aortic blood. Apparent physiological (lead

space has been calculated using end-expired

(VD(acp)E), abdoniinal aortic (VD(app)UA) trid

temporal-arterial (VD(,I,I,) TA) carbomi dioxide

tensions in an attempt to demonstrate the

effect of right-to-left shunting.

APPARENT ALVEOLAR VENTIlATION (VA(app))

was computed from time formula VA(u1)

V

in-stances more thian one alveolar ventilation

was calculated iTA app)E. VA (npp) and

VA(app)TA, depending on time value used for alveolar CO2.

ALVEOLAR-ARTERIAL 02 TENSION

GRADI-ENT: Alveolar 02 tension was determined

from end-expired N2 and end-expired or

ar-terial CO2 analyses by subtracting the suni

of their partial pressures and that of water

vapor at body temperature from barometric

pressure. 02 tension in arterial blood was

determined as described above and

sub-tracted fromu alveolar 02 tension to give the

gradient.

LUNG VOLUME (V mj was estimated by

di-lution of N271 during rebreathiing in the

ap-paratus already described (Fig. 8). Because

the rebreathming interval was brief, no

correc-tion was mnade for 02 and CO2 exchange. The

rebreathing sac was filled to a volummie judge(1

to equal time patient’s lung volunie and

con-necte(1 to the pneumotachygraph at

end-expiration. If the I)atient was breathing an

oxygen-rich niixture, time sac was filled with

air; if he was breathing a mixture with less

than 50% 02, the sac was filled with 02. The

fine rubber pressure tubing leading into thie

N2 analyzer was clamped to stop sample flow

at time beginning of the rebreathiing

nianeu-ver; after 10 to 20 breaths time clamp was

removed from time saniple line in or(ler to

re-cord N2 and CO2 concentrations. If

equilibra-tion was inadequate or ventilation was very

unsteady, time determimination was not

calcu-lated. W’hemm two or three such trials agreed

724 NEONATAL PULMONARY ISCHEMIA

t tf A mixture of 40% dichloromonofluoromethane

and 60% difluoromonochloromethane.

single estimate of lung volume. Figure 2

shows a tracing from two successive

equili-brations.

Lung volume was calculated from the

formula:

where:

VL = VB(’-_- FNB)

\FNE -

uN

Equation 3

= initial volume in the sac,

milliliters-= nitrogen concentration at equilib.

rium.

= initial nitrogen concentration in the

sac.

FNE = initial en(1-expired nitrogen concen-tration.

Because time tillie for equilibration was

brief, we ignored the quantity of nitrogen

added to or from time tissues. VL was corrected

to body temperature and saturation with

water vapor. In 19 sick infants, VL was

simnul-taneously calculated by analyzing the change

in concentration of end-expired nitrogen when

the inspired gas mixture was changed (see

below). Lung volumnes obtained by these two

methods are in close agreement (Table III).

ANATOMICAL DEAD SPACE AND THE

DIS-TRIBUTION OF VENTILATION: The

determuina-tion of lung volumne by rebreathing afforded

large changes in expired nitrogen

concentra-tion, which we used for the calculation of

anatomical dead space and the distribution

of ventilation. We calculated anatomimical

dead space using the graphic techmnique of

Fowler.72 On 19 occasions tidal volunme was

sufficiently constant to allow an analysis of

the distribution of ventilation. The

loga-rithm of the end-expiratory nitrogen

con-centration was plotted against the numnber of

breaths after changing the inspired gas

con-centration. In 13 instances the plot was

linear, indicating that the distribution of

ventilation was uniform. In six, distribution

was not completely uniform; however, the

change in nitrogen concentration could be

ex-pressed as two exponentials which

repre-sented the major rates of alveolar ventilation.

We examined the slopes and intercepts of

these two exponentials using time template

described by Finley73 and an analysis similar

to that described by Fowler, Cornish, and

Kety74 as shown in Figure 2. This yielded time

size of the two regions receiving ventilation

at the two different rates. Time sumu of the

volumes of these two regions was taken as

time lung volunme (VL(w)) (Table III).

EFFECTIVE PULMONARY BLOOD FLOW: The

volume of blood flowing through the lungs in

sufficient proxiniity to ventilated airspaces so

that significant gas exchange could occur

was estimmiated by uptake of the soluble gas,

freon,tft from the rebreathing apparatus

al-ready described. The method is a

modifica-tion of Krogh and Lindhard’s technique,75

with rebreathing substituted for

breathhold-ing. The rebreathing sac was filled with a

volume of the incubator gas, approximately

equal to lung volume just previously

deter-ruined, and freon was added to obtain a

con-centration of 10% by volume. As in the

mea-surement of lung volume, the rebreathing sac

was connected to the pneumotachygraph at

end-expiration, and respiration muixed the

lung and sac gases. Freon was carried away

from time lungs by blood flow, and its

concen-tration in the lungs and rebreathing sac fell

at a rate depending upon the rate of blood

flow. Figure 12 illustrates time respiratory

patterns and freon concentrations in two

infants with high and low effective

pulmo-nary blood flows.

Effective pulmonary blood flow was

calcu-lated frommi the sum of lung volumime and sac

volumne and time recorded freon concentration

in one of two ways, depending upon time error

introduced by assuming that volumne was

constant. When absorption of freon was

rapid and the recording interval was 20 to 30

seconds, the volume change due to

with-drawal of gas for analysis was proportionally

small (e.g., 10 to 15 ml froni 200 nil) and was

ignored. The volume change, due to unequal

gain of CO2 and loss of 02 in the gas space

during this period, was small (less than 1 ml)

C1 and

C2

oscil-lation of concentration. C1 was not read until

after time initial mixing had occurred, i.e.,

alveolar concentration hma(I begun falling,

Equation 4 and the amplitude of oscillation was less tiian

Qef = 2.3O3VL+BaBt1,2 logio (C,/C) a for the freon in neonatal blood at 37#{176}Cwas

kindly determined by E. Eger and R. Shargel. arm O.74

± 0.015 vol/vol/atm.

where:

TABLE III

LUNG VOLUMES IN 19 SIcK INFANTS

Case Age (hr) Vr/kg VD(an) kg ID(an) -VT JD(opp)E kg VD(app)(A -kg VD(app)E VT 1’I)(cpp)UA VT VL() kg JL -kg 2 S 7 8 10 12 14 15 16 17 19 20 21 22 23 24 25 26 27 124 7 Sf 2 7 13f If 24 22 4 7 34 3f 24 6 Sf 84 6f 44 5.2 5.7 4.3 5.9 3.9 6.1 5.2 5.6 6.6 5.4 4.6 6.6 4.6 3.6 4.3 3.9 4.4 4.7 4.1 2.1 2.3 1.8 2.5 1.5 2.4 2.0 2.2 3.1 2.3 2.1 3.0 2.1 1.5 2.0 1.7 1.9 2.1 1.7 .40 .40 .42 .42 .38 .39 .38 .39 .47 .42 .46 .45 .46 .42 .46 .44 .43 .45 .41 3.8 3.8 3.1 4.2 2.4 4.7 3.2 4.4 3.9 4.1 2.8 4.7 2.2 2.7 3.1 1.8 2.8 3.0 2.9 4.3 4.0 3.2 4.5 2.6 4.8 3.6 4.9 4.8 4.4 3.6 5.1 3.6 2.8 3.3 -2.9 3.3 3.1 .72 .67 .72 .71 .63 .78 .62 .77 .60 .76 .62 .71 .49 .74 .72 .46 .63 .64 .71 .83 .70 .74 .76 .67 .79 .69 .88 .73 .81 .78 .77 .78 .78 .77 .66 .70 .76 17 24 30 34 23 19 26 24 21 26 14 20 30 14 20 19 16 22 24 26 23 So 39 24 25 42 24 16 25 19 31 35 17 28 17 20 25 28 n Mean S.D. 19 5.0 .92 19 2.1 .43 19 .42 .03 19 3.3 .85 18 3.8 .80 19 .67 .09 18 .76 .06 19 22 5.4 19 26 7.2

Probability <.01 .005<P< .01 .05 <P< .1

Anatomical dead space is compared with apparent physiological dead space calculated from end-expired and

aortic CO, tensions. Lung volumes derived from nitrogen equilibration are compared with lung volumes calculated

from analyses of nitrogen washin or washout. Vn() = anatomical dead space; VD(app)E= apparent physiological

dead space using end-expired CO,; VD()uA= apparent physiological dead space using the CO, tension of

abdomi-nal aortic blood; VL() = lung volume from analysis of N, washin or washout; VL= lung volume from equilibration

with O or room air. The statistical significance between the means for VD(PI)UA and VI)(ftpp)E, VD(ap1UA/VT

and VD(app)E/VT, and VL() and VL are shown. The difference between mean VD()/kg and either VD(app)Efk, or

VD()uA/kg is significant (P < .001) as is the difference between mean VD(),V.rand either VD(ftP,IVTorVDftPP)uAIVT

(P<.001).

was set at 10% in the sac and initially fell to

about 5% by dilution with gas in time lungs.

Absorption of freon, therefore, reduced the

total gas volume by less than 5%, and this

change was ignored. Under these

assumnp-tions volume was treated as constant, and

the equation relating effective pulmonary

blood flow (Qeff) to freon concentration (C)

was (see Appendix III):

VL+B = sunm of lung and sac volume

ams =solubility of freon in blood14 time interval betweemi two

observa-tions,

C1

C2,

FREON

%

+10 PAIR (cmH2O) -0

40

(ml)VT

L _.1

1 MINUTE

5r

0I.

-5

AI R _______

(cm H20)

VT

(ml)

2

MIN LIT ES

Fin. 1. Tracings from top to bottom of freon

concen-tration at the nasal airway, pressure at the nasal airway, .111(1 tidal volume. In a tidal volume and freon concentra-tion show some irregularity during the initial equilibra-ion but thereafter, freon concentration falls quickly

because of rapid effective pulmonary blood flow

(Q11= 202 mI/minute/kg). In b the freon concentration

drops slowly because effective pulmonary blood flow is snmall (Qeff 64 mI/minute/kg).

20% of time average concentration. (C2 was

read before recirculation of freon, if evidence

of recirculation appeared in the recording.) Only about one half of time trials yielded data

that nmet tlmese criteria, and only those were

used for conmputation of Qeff. Trials were not

repeated until freon was undetectible in the

breath.

When freon absorption was slow, it was

necessary to continue rebreathing longer to

obtain a significant fall in its concentration.

726 NEONATAL PULMONARY ISCHEMIA

We did not find it feasible to sample the gas

a nmixture internmittently because of artifacts

produced in the recording of concentration,

amid we had to accept continuous sampling

an(I the significant change in gas volume that

it caused. However, since the sampling rate

was known with good accuracy, the change

in volume could be taken into account.

Under this condition, the equation relating

effective pulmonary blood flow and freon

concentration was (see Appendix III):

Equation 5

(armQeff/k,) .log1o [(VL+B - ks/tl,2)/VL+mm]

= log10 (C2/C1) in which aB, Qeff, VL+B, C1, C2, and zt1,, have

,,,- the same meaning as above, and k8 stands

b for the volunme sampling rate of the freon

analyzer. Time quantity (VL+B - k8t1,2)

could be calculated for any elapsed tinme of

______ sampling and uptake, since VL+B, k,, and

ti,2 were all known with acceptable

accur-acy. A plot of this quantity against C2 on full

logarithmic graph paper yielded a straight

line. If its slope is designated by m, Qeff

= k,m/aB, and effective pulmonary blood

flow can be calculated. Data for this

com-putation were accepted according to time

criteria alrea(ly given.

We rejected the widely used

plethysnmo-graphic method76 because we felt that it

in-terfered unduly with the clinical care of the

seriously ill infant and imnposed on himn

an unacceptable stress. The rebreathing

mimetimod, as we used it, did not interfere

sig-nificantly witim care of the patient and (lid

not cause hmimn (listress; it was carried out

within the incubator, and we thereby

avoided time handling, cooling, and

temmm-omuy reduction of anmbient oxygen

concen-tration and humidity that the

plethysnmo-graphic method entailed. The technical and

theoretical shortcomings of the freon mmmethod

did not prove disabling, because a high

de-gree of precision was not necessary in

dis-tinguishing the large differences in effective

pulmonary blood flow between healthy

in-fants and those with severe respiratory

dis-tress or the substantial changes sometimes

SUPPLEMENT

Several difficulties plague the use of soluble

gas for the nmeasurement of effective

pulmo-nary blood flow,77 such as, (1) inequality of

gas concentrations between the sac and the

lungs, as well as within the lungs; (2)

in-equality of oxygen uptake frommm and carbon

dioxide elimination into the sac-lung gas

space; (3) recirculation of the indicator gas

in the blood; (4) solution of gas in the lung

tissue; (5) changes in the volunme of the gas

space due to sampling for analysis; and (6)

pharmacologic effects of the indicator gas

and CO2 accumulation. These difficulties,

and the fact that our methmod is not

stan-dard, require justification of its use.

1. In practice, mixing of gas within time

lungs and rebreathing sac was usually

ade-quate, as judged by the recording of freon

concentration (Fig. 12). When breathing was

sufficiently shallow or irregular to disturb

the recording, the trial was discarded. Other

workers55 have shown that intrapuinmonary

gas mixing is excellent in infants with

respira-tory distress, and our observations are in

ac-cord. Fortunately for our study, the effect of

unevenness of ventilation of the lungs on gas

uptake was small (i.e., that part of the lung

that was detectably ventilated was uniformnly

ventilated), and we were spared one of the

chief disadvantages of this kind of method as

applied to patients with other pulmonary

diseases. In addition, rebreathing tended to

mininiize regional differences in gas concen-trations.

2. The effect of unequal CO2 and 02

ex-change on gas volunme and freon

concemitra-tion was small, and we have neglected it.

Wimen rebreathing was prolonged, however,

CO2 concentration rose sufficiently to affect

the freon recording. In such circumnstances, a

control rebreathing without freon was done,

and a signal due to CO2 at any nmoment was

subtracted. This correction increased

calcu-lated Qff. Since it was relatively greater

when freon uptake was show, application of

the correction tended to decrease the

differ-ence between measurements of effective

pul-monary blood flow in normal and distressed

infants.

3. Recirculation of freon in the blood

de-creased the rate of uptake and could

some-times be seen as an inflectiomm imi the

concen-tration recording. If ignored, the effect

tended to decrease calculated Qff. Freon is

soluble in the tissues, imowever, and is readily

(liffusible. Rebreatiming by normal infants

denmonstrated that time comicentration of

freon in systemic blood returning to the lungs

was negligible, since time gas phase

concen-tration rapidly became undetectable. Healthy

infants and those recovering from respiratory

distress might imave simunting of blood

through the ductus arteriosus. This blood

would carry a high freon concentration, and

its re-entry into the pulmonary vessels would

decrease time rate of uptake and calculated

Qff. As shown elsewhere in thus paper,

imow-ever, infants with severe respiratory distress

have net right-to-left shunting and

sig-nificant freon recirculation is precluded in

timese circummistances. At time same tinme, blood

equilibrated with freon in the lummgs is diluted as much as four tinmes because of rigimt-to-left shunts before being sent to the tissues, whicim readily extract it. In timose infants who re-quired prolonged rebreatlming periods for time

mumeasurement, re-emmtry of freon into) time

lungs was negligible, and we imave ignored it.

Therefore, the difference in functional states

of the subjects and our handling of time data

again combine to mimmimize the difference in estinmates of Qeff between nornmal infants and

timose with respiratory distress.

4. Freon (hssolves imm time lung tissue, amid

this process appears at the beginnimmg of

re-breathing as part of time mmiixing anol dilution

of freon. The tissue acts as amm additional

reservoir of freon (luring absorptiomm into time

flowing blood and slows time fall in

concentra-tion. This tends to nmake the calculation of

effective pulmonary blood flow too low.

In-spection of Equation 4 shows that Q.u is

proportional to \L+B. Qeff is too low in time

ratio VmB/(VmB+atj, V115), where a1, is

the solubihity of freon in lung tissue and V11,

is time amount of lung tissue accessible to

freon. Assunming that the solubility of frcomm

is approxinmately the sanme in lumig tissue and

in blood, ap)roximate values of this ratio are

0.89 for healthy infants and 0.86 for those

with severe respiratory distress. In view of