response patients failure cardiopulmonary disease...

Journal of Clinical InvestigationVol. 45, No. 10, 1966

The Response of Patients with Respiratory Failure andCardiopulmonary Disease to Different Levels of

Constant Volume Ventilation *

J. HEDLEY-WHYTE,t H. PONTOPPIDAN,ANDM. JOCELYNMORRIS

(From the Respiratory Unit and Anesthesia Laboratories of the Harvard Medical School atthe Massachusetts General Hospital, Boston, Mass.)

The purpose of this study was to determine theeffect of increasing the tidal volume on pulmonaryventilation-perfusion relations in patients withrespiratory failure caused by cardiopulmonarydisease.

The frequent occurrence of an increased physio-logic dead space (2, 3) and of increased physio-logic shunting (3) in patients undergoing pro-longed artificial ventilation has previously been de-scribed. These changes in ventilation-perfusionratios mean that very large tidal volumes and highpercentages of inspired oxygen are often requiredto maintain life during prolonged intermittent posi-tive pressure ventilation. The aim of our studywas to measure the consequences of changing thetidal volume, but not the respiratory frequency,of patients with respiratory failure secondary toeither acute intrapulmonary infection or chronicpulmonary emphysema.

Methods

Selection of patients. At the time of the study none ofthe twelve patients had a total vital capacity above 400ml, and hence all were completely dependent on inter-mittent positive pressure ventilation. Eight of the pa-tients studied were selected because they had been freeof symptomatic pulmonary disease on admission to thehospital, but had later developed nonemphysematouscardiopulmonary disease and acute intrapulmonary in-fection that caused respiratory failure. The diverse

* Submitted for publication January 20, 1966; acceptedJune 16, 1966.

Supported by U. S. Public Health Service researchgrants HE 08558-03, HE 06848-05, and HE 09337-01.

Presented in part before the American Society ofAnesthesiologists, October 1965. A preliminary reportof this work has been published (1).

t Address requests for reprints to Dr. John Hedley-Whyte, Massachusetts General Hospital, Boston, Mass.02114.

nature of the diseases present in these eight patientsshould be noted (Table I). They have been grouped to-gether for the purpose of contrasting their response tolarge tidal volumes with the response of emphysematouspatients. The other four patients selected had severegeneralized pulmonary emphysema. The diagnosis ofemphysema (confirmed at autopsy) was made on the fol-lowing grounds: 1) at least a year's history of unremit-ting exertional dyspnea, 2) radiological diagnosis of gen-eralized pulmonary emphysema made independently by tworadiologists, and 3) a vital capacity between 1.5 and 3 Land a 1-second forced expiratory volume less than 700ml during tests made more than 6 months before the pres-ent studies. None of the patients studied appeared clini-cally to have intra-alveolar pulmonary edema, nor hadany of them had an attack of pulmonary edema in theprevious 6 months.

Technique. All patients were supine and horizontal;each had a cuffed tracheostomy tube with an airtight fitin place. Controlled positive pressure ventilation wasachieved with a volume constant sinusoid flow generator(Emerson postoperative ventilator) set at a frequencyof 20 breaths per minute, inspiration occupying 1 second.The frequency of ventilation was not changed at anytime, but tidal volume was changed approximately every30 minutes. Expiration was passive through a low re-

sistance outlet. Apparatus dead space was measured bywater displacement.' The valve system on each of thetwo respirators used for all studies was repeatedly checkedand found to be competent. For 30 minutes before andduring all studies, ventilation was with 100% oxygenhumidified by hot water bypass. Gas analysis and cir-culatory measurements were made 20 minutes after thechange of tidal volume.

Polyethylene catheters were placed percutaneously ineither a radial or femoral artery and in the superior venacava. These catheters were used for blood sampling andcontinuous pressure recording via a Sanborn 350 system.Continuous intratracheal pressure and the electrocardio-

1 The apparatus dead space, average volume 28 ml, ex-tended from the tip of the tracheostomy tube lying in thetrachea to the junction of the inspiratory and expiratorytubes of the ventilator, a distance of 25 cm; the internaldiameter of the tubing that comprised the apparatus deadspace was 1.2 cm.

1543

J. HEDLEY-WHYTE,H. PONTOPPIDAN,AND M. JOCELYNMORRIS

TABLE I

Clinical data

Hospital course

Duration of Death Deathartificial (days (chief cause

Patient ventilation Dis- after as determinedno. Age Sex Wt Diagnosis before study charged study) post-mortem)

years kg days1 44 M 59 Pulmonary emphysema. 4 17 Emphysema.2 49 F 42 Pulmonary emphysema. 7 25 Emphysema.

Diverticulitis coli.3 49 M 74 Pulmonary emphysema. 6 12 Emphysema.4 72 M 81 Pulmonary emphysema. 3 98 Myocardial

Postoperative repair infarction.perforated duodenal ulcer. Emphysema.

5* 50 M 72 Postoperative aortic 37 25 Partial unseat-mitral and tricuspid ing tricuspidvalve replacements. valve prosthe-

sis (ventricu-lar fibrilla-tion).

6* 57 F 65 Postoperative partial 5 10 Cerebralgastrectomy. hemorrhage.Bronchopneumonia. Bronchopneu-

monia.7* 60 F 61 Viral pneumonia. 2 12 Influenzal

pneumonia.

8* 67 M 62 Postoperative aortic and 2 19 Myocardialmitral valve replacements. rupture.Bronchopneumonia.

9 50 M 85 Multiple injuries with 20 +flail chest. Broncho-pneumonia and aspirationpneumonitis.

10 17 F 59 Multiple sclerosis. 2 +Bronchopneumonia.

11* 70 F 63 Postoperative aortic and 16 17 Hepatic failure.mitral valve replacements.Bronchopneumonia.

12 31 F 45 Postoperative aortic and 2 +mitral valve replacements.Bronchopneumonia.

* No morphologic evidence of pulmonary emphysema was seen on postmortem examination of Patients 5, 6, 7, 8, or 11(autopsy no. 28,969, 28,582, 28,595, 28,835, 28,894).

gram (lead 2) were also recorded by this system. Meanpressures were obtained by electrical integration. Im-mediately before and after arterial sampling, cardiac out-put was determined by analysis of dye dilution curves witha Gilford 103 1R densitometer. Gas was collected in a

60-L Douglas bag over a period of 3 minutes. Gas volumewas measured in a Tissot spirometer, and tidal volume(VT) and minute volume (VE) were calculated. The mixedexpired carbon dioxide concentration, FEco2, and mixedexpired oxygen concentration, FEO2, were measured witha Beckman model LB-1 infrared carbon dioxide analyzerand a Beckman model E 2 oxygen analyzer, respectively.During the period of gas collection, the arterial and supe-

rior vena caval blood samples were slowly withdrawn into10-ml heparinized glass syringes. Blood carbon dioxidetension was measured with a Severinghaus electrode, pH

by a Radiometer glass electrode, and oxygen tension by amodified Clark electrode with a Sanborn blood gas analysisadapter (model 416-215) and null meter. Blood oxygencontent of arterial and superior vena caval blood wasmeasured in duplicate by the techniques of either VanSlyke and Neill or Laver, Murphy, Seifen, and Radford(4). All measurements were required to agree to withini 0.2 vol per 100 ml for any particular sample. Oxygencapacity at Po2 = 150 mmHg, temperature 380 C (cap),was determined by equilibrating the blood at 380 C with aknown oxygen tension of between 140 mmHg and 160 mmHg and then measuring the blood oxygen content. Allblood gas electrodes were maintained at 380 C. For pa-tients whose temperature differed from 38° C, standardblood gas temperature correction factors were applied(5-8).

1544

PHYSIOLOGIC SHUNTDEADSPACEAND CARDIAC OUTPUTIN RESPIRATORYFAILURE 1545

The physiologic dead space to tidal volume ratio(VD/VT) was calculated2 as follows:

Paco2 - PEC02VD/VT Paco2 [1]

where PECo2 is mixed expired carbon dioxide tension andPaco2 is arterial carbon dioxide tension.

The physiologic shunt3 Qs/Q was calculated by thestandard physiologic shunt equation (11):

Qs/Q = Cco2 - Gao2 ECco2 - Cv02' [2]

where Cco2 is the oxygen content that the patient'sarterial blood would have had if equilibrated with meanalveolar gas, CaO2 is arterial oxygen content, and Cvo2 isthe oxygen content of mixed venous blood. (In this studysuperior vena caval blood oxygen content substituted forpulmonary arterial blood oxygen content.)

To determine Cco2, we took advantage of the fact thatat oxygen tensions of above 150 mmHg hemoglobin isfully saturated (13). Therefore, Cco2 was determined byfirst multiplying the Bunsen solubility coefficient for oxygenin blood by the difference between the oxygen tensions ofmean alveolar gas (PAo2) and arterial blood (Pao2).This multiple was then added to CaO2. (If Pao2 wasbelow 150 mmHg, the difference between PAO2 and 150was multiplied by the Bunsen coefficient and added to theoxygen capacity.)

CCO2 = CaO2 + (PAo2 - PaO2) X 0.0031, [3]

or if Pao2 was below 150 mmHg

Cco2 = cap + (PAo2 - 150) X 0.0031. C4]

PA02 was calculated from the simplified alveolar gasequation applicable when nearly pure oxygen has beenbreathed long enough to allow effective denitrogenation,

PAo2 = PB - PH20T - PaCo2, [5]

where PB is barometric pressure and PH2oT is saturatedwater vapor pressure at the patient's body temperature.4

Limitations of method. A detailed estimation of theerrors inherent in these methods of calculating the physio-logic shunt has recently been presented (14). The use of

2 This equation for VD/VT represents the Enghoff modi-fication of the Bohr equation (9, 10). Physiologic deadspace as measured by this equation is sometimes called"functional" dead space (10).

3The "physiologic shunt" during pure oxygen breathingmeasures that proportion of the cardiac output which by-passes functioning alveoli (11). Under these circumstancesthe physiologic shunt has been called the "true," "pure,"or "anatomical" shunt, or the "direct" venous admixturecomponent (12).

4 In the first measurement in Patient 3 and in the firstfour measurements in Patient 11 (Table III) more than 2%nitrogen was present in mixed expired gas (due to entrain-ment of air into the inspired 100% oxygen), and PAo2 wasassumed to equal PEO2 + PFCo2-

superior vena caval samples to estimate mixed venousblood oxygen content is a compromise dictated by thepracticalities of clinical care. In resting normal man,superior vena caval oxygen levels are lower than those ofmixed venous blood (15); in anesthetized manduring inter-mittent positive pressure ventilation the average superiorvena caval blood oxygen content is 0.25 vol per 100 mlhigher than the average mixed venous blood oxygen con-tent (16). In five conscious patients on intermittent posi-tive pressure ventilation after open heart surgery, with peakintratracheal pressures up to levels of 60 cm H20, we foundthe average superior vena caval blood oxygen content tobe 0.3 vol per 100 ml higher than mixed venous bloodoxygen content (difference range -0.1 to +0.7 vol per100 ml) (17). Thus, in this study, in which intermittentpositive pressure ventilation was used, the average errorintroduced into the calculation of physiologic shunt byusing superior vena caval blood samples can be expectedto result in an overestimation by 0.5% of the cardiac out-put, e.g., a 12%shunt will be estimated as a 12.5% shunt.

Statistical methods. In this study a heterogeneous col-lection of patients was studied. Under these circum-stances it is most useful to analyze the results of changingtidal volume by computing the variance in each group ofresults obtained from each patient being considered andthen summing these variances (the numerator of the right-hand side of Equation 6 below is these summed variances)(18). These summed variances are then used to get anover-all view of the strength of any relationship in thepatients being considered. The within group correlationcoefficient (rw) expresses the strength of this over-all view.Hereafter in this study rw is known as the within patientcorrelation coefficient, as each "group" of measurements isfrom one patient. Like the total correlation coefficient(rt), rw can range only from +1, perfect positive correla-tion, to -1, perfect negative correlation. rw was calcu-lated in the following manner:

2: 2: (Xi - 1O) ( Yiv - fS)g

Z2 (Xig - I)2 2; ( Yig - )2-i u i g

[6]

The total correlation coefficients used to compare datapooled from all patients were calculated as follows:

rt =

2 2 (X£, -X) ( Yig - F)i g

41 2z (Xg -X)2 2zz ( Yg - Y)2. g i g

E7]

In both Equations 6 and 7 the subscript i refers to anymeasurement (the ith) made in the gth patient; thus X0 isthe mean measurement in the gth patient. Significancelevels (p) for rw were determined taking n to equal N - G- 1, and for rt taking n to equal N - 2 in the tables ofFisher and Yates (19) (N is the total number of observa-tions being considered, and G is the number of patientsfrom whom those observations came).

ResultsEffect of changes in tidal volume on the dead

space to tidal volume ratio. The VD/VT of pa-

rw =

J. HEDLEY-WHYTE, H. PONTOPPIDAN,AND M. JOCELYNMORRIS

tients with emphysema ranged from 0.57 to 0.79;the VD/VT of the remaining patients ranged from0.38 to 0.75. In all patients VD/VT was almostunaltered by large changes in tidal volume (Figure1) and cardiac index (Tables II, III). Conse-quently, since respiratory frequency was constant,physiologic dead space and alveolar ventilationboth increased as tidal volume was increased (Fig-ure 1 and Table IV).

Effect of changes in tidal volume on cardiac out-put. In patients with emphysema increasing the

16k

.ltN.QC.C4

z:1

12k

u

II10 20

yr//Kg BODYW7FIG. 1. THE RELATION BETWEENTIDAL VOLUMEAND

ALVEOLAR VENTILATION. With large increases in tidalvolume (VT) there was little consistent change in physio-logic dead space (VD) to tidal volume ratios. All mea-

surements were made at a respiratory frequency of 20 per

minute, inspiration occupying 1 second. Consequentlyalveolar ventilation (VA) increased in proportion totidal volume, and most of the plots fall along the VD/VTisopleth characteristic of this patient's lung function.Open circles represent measurements in patients withcardiopulmonary disease but without pulmonary emphy-

sema. Solid circles represent measurements from pa-

tients with emphysema.

4.0k

3.5

c,)C 3.0

.. 2.5

tU 2.0

Q 1.5

Q I.c

0.5

5 10 15 20 25

Vr / Kg Body Wt.30 35 ml

FIG. 2. TIDAL VOLUMEAND CARDIAC INDEX IN EMPHY-SEMA. Increased tidal volumes (VT), with respiratoryfrequency kept constant at 20 per minute, decreasedcardiac index in each of four patients with pulmonaryemphysema (rw = - 0.617, p <0.01). Linear regressionlines are shown for each patient and numbered so thateach patient can be identified from Tables I, II, or III.[In patients with nonemphysematous cardiopulmonary dis-ease (not shown), increased tidal volumes did not sig-nificantly decrease cardiac output (rw = - 0.061, TableIV)]. rw is the within patient correlation coefficient.

tidal volume decreased the cardiac output (Figure2) and stroke index (Table IV); however, bycontrast, in those patients without emphysema evenlarge increases in tidal volume generally had littleeffect on the size of the cardiac output or on strokeindexes (Tables II-IV).

Factors affecting the physiologic shunt. TheQs/Q measured during almost pure oxygenbreathing ranged froni 6 to 79%o of the cardiacoutput in the patients without emphysema (mean22.4%o ). Physiologic shunts above 30%o werealways associated with dead space to tidal volumeratios of over 0.65 (Figure 3). In the patientswith emphysema the mean physiologic shunt dur-ing almost pure oxygen breathing was 9.1%o(range 3 to 26%o).

High percentage physiologic shunts occurred attimes when cardiac indexes were increased. Ineach patient there was a positive correlation betweencardiac index and the percentage of the cardiac

5_

_

\ -1, 0)

£

a 4,,3,0

2.)

l l l

ml

/

Vo /VT =0.4/

8k

4kI VD/V=0.8

/

ml

1546

_

i/ -I

,(I .-I


U) 00o_ N_ N N,

aq ei Il _ )

- U)

'i00-4 0--V.-o00 C'--

5-0- c -

co

04-4-0-4-4

N ._% 00_C'0_.-¢Xoc4-

N

0 00 Uo U)

0 00 f) 04 U)

0 -0- 0 0.Nz NI~ N Nl N,0 U)00OU)04 i 0% 0 0%

_. _4 -

t) 0 0o) 0ot0 00 0--k- "

Nf N N N

.U4000-4 -40) o)o 0%

000t'-00'

oU) U)0 U) 042 t- o" 1) o

4 -4 " o4 _

O0O0OU00)C0 0

N

N) NU)

%Go _

C4NP', _. _ U) 0 -0 m * fU) U)

s'o

0 'o 4 "P "o _4 -* _4 + Cn m m inU " V- C4 m m "

C4 ei V 06 r:_

0co.00000c_____

0% 0 'o0 0'-

C4 WU U4

4N n U) >

C4 U) 'i It***

,* - - N t- O _ - -

) wd to 0 0 0 0N N 0C10 0

U) U)O U)0 U)OU U) U)

" m OOif)-'0U ) 0 0 MU)

ro - O O N0 0 0 O ) c0 0 0 0 N_ - NC N -4 0% 00 ot 0 '0c 0- 0N

_4 _4 _{ _4

in )0 %

0-4_ 00 '0 Ct 0-V.0 _ N t- N U) co00

oc0'0 C' 0'00 +--~o ~o NO I) o NO NO No t- \0 NO r- W) I- b

U, _ 0 r- 10, _i R U) li IR R _! xlb _il00-- t- tz U) t_ 0o h N4 ' in it) N4 O t- .o 0i-4 -4 C4C1N4

., 0 0U)'0 U)'0

N- 0- 0--C-C- t-C

b4

O N - 4 0 0

U0 i) 0-

O 0 so 0s 0~0% 04 NO')

t' 0% 0N

C C- N-

0%''_

U) 0% 0

0% 0% 0%

0z %OOso

_ Y) 0- 0\ U)

____

00

N _-4 N -

O t- N-

co t- *

0- 0 0O4 N00 0 if)U

a04

if)0 0 U)5

k'Cf en0

c;0

0U)

CC- U)

0 10 10 co NO

N 0-4 0c 04 0N4 04 U) U)

Oo ellm

04O0U) N-Ut) 0% t- 0% 0

04C04U74C V)

'0 000 0

-0N0 0-4 0f

*

0-n

;4

(--

x

.4

U1)

*t

'44

ce

%)

_4

P.%

pi

-Q

io%3

4)

T ).

C4

U

U0

C 4

U

x

UUC-

C1-0

0

*xl

80

0

C.

040W

CO

0 CoXAC g

X Cd

,0 0

W0

boo 04-C,,

0 C._00

8Cd>-@C

X .0

o o-.

nco

*? M.0

CX>dC, a006

0. S

,-4) )

N X

._,t .~

cd 4)

C-U C

_

u) -

c o

- wa CO

C P

CO .0

Ocd

t_ 0

>CO

'zoC

C0 4

06~

o > w C

4)-

4-CO

4i0 0

4)*'O

": 8

Cr 00;

Co >

CO-0

CO c

v 0 @

04CO

OC:o

C4

J. HEDLEY-WHYTE,H. PONTOPPIDAN, AND M. JOCELYN MORRIS

0011)oNoONCN0000091 CD")00

00o1U))U) 0000)00 --'o0 009100)0

00900 0I0 UU000000 0% C%0%, U) N091 01)01)09

o0'0 CI-'010900 0 90000omm

009000%00

-C)1)0) "

No NZ Nz N- NO

0W)1) '01 0% 00N4 N N. N N Nq

In) 1- 000 01) 11)-- '0 9090eq

'400 000

NO N N

000t t

01-1)-,1-1

0%01)10.4 )1m- i t)l1)09- t- N N 00 in d4Q0%U) ' 0%'-10%7 0009 00 t-0 0tn '4-4 N

00 m t- In m *. c 00 0 I-t mt-: (:. V: W; if; 06 cli t; el; (Ii e6

4 -4 -4 " -4 -4

It R R IR tll. IR 11"! I I"! -! -im - M 0 a, I- 00 r- 't U) 00

4 14 -4 I" " 1-4 " -4 I"

.0%a0 00%~--09C

1- -%1101

(0%0N- 0 0 to1)'009

0%1t-: -0I)0%0 0909

M0)- 'o "0 a%0901)

09'001)t: r-01)i r 1)0001)

0- 'q o00 t--1d t',a1 t'

t- -4 - 00

0 00 I- N '

1-- 01)1- 00 't

1-- -0

0001)- - co c

01 0 00 1- -ci e11fi003d;

00 t- 00 00 '0r--

oo -q00 09 '011)

0o00 00 000090

0 co't00m 't

'% 1-09 LO 00'0_;).4 .4 1.411_)

001-0

C49o0000 in

,-00 'o -0 0

11) - t- 00 09'0100 0% 00 00 0%1 0DI

11) 09 00 1- 09t tz00._;- C0

'009000%0% 000t-

m01)0%4

-09

0% 00co09

01)- 09

11)01in)00

0% -t 0%00

1-- 0%i V1)01 01)

'0 00 0-1If!00--

t%00-C09 o1 oo11)11

00 .- -

0 00 01 t1) 00'0 'o00 0000NO c c c'

It1 in 1- ' 0

OC;C4

0%in U) 09 '0 to)'0 In 0

C4 '40 C09 -4 000000t--'0 00 00 00 00000

U)00r t W00) *%1-.I00LIU0)-i~ .4 1ojC.4 t1) 01

0 r-

4

)Idc.4l't -:

M -4

01

0,00910 %t0 t

o01-I-

0~if

1-t It " 000%or

01)090- 0 00 00

0 10 00

0 %10 )o

to ON 0'in 0 10 U)0

U)00 m -

t-0%N0%0oo0ON0 00 00 00

10 00 00 01)00

OO;6 06 01 _;"

I 01 1 - 1 1 - 1-)-9- )-9-1 9-

U)j 00 0

1548

in'01 Ul)

JlN~N1109 U)

09 OR e

r-'rU

1U " 09 00 00'011) 01t-

to) 1) 'O00001)j 01)-'',OI 0 '40

C.)1

C.)

cU

CdI

Cd0

0

u

0Cdu

0

(Cd

0Cd

0

0

xda4

U) to 0

00 '001)

-4 - 0-

,ItN00

.N0U01

N

r- ~o0'0

010)40


TABLE IVThe effect of changes in tidal volume on respiratory function*

Patients with nonemphy-sematous cardio-

pulmonary disease Patients with emphysema All patients

Correlation Correlation CorrelationParameters coefficient Significance coefficient Significance coefficient Significance

Cardiac index -0.061 -0.617 p < 0.01 -0.251Stroke index -0.107 -0.548 p < 0.02 -0.282Physiologic shunt Qs/Q -0.275 -0.369 -0.274Physiologic dead space 0.942 p < 0.001 0.982 p < 0.001 0.957 p < 0.001Physiologic dead space to -0.278 -0.130 -0.198

tidal volume ratioMean central venous pressure 0.322 0.730 p < 0.001 0.496 p < 0.001Tidal volume/peak intra- 0.637 p < 0.001 0.689 p < 0.01 0.621 p < 0.001

tracheal pressureMean arterial blood pressure 0.541 p < 0.01 0.835 p < 0.001 0.669 p < 0.001

during inspiration minusmean arterial blood pressureduring expiration

* Within patient correlation between tidal volume and parameters concerned in pulmonary ventilation-perfusionrelations (respiratory frequency constant at 20 breaths per minute).

0.6[

0.4[

0.2-

0 20 40Os/O X /00

60 80

FIG. 3. PHYSIOLOGIC SHUNT AND PHYSIOLOGIC DEAD

SPACE. Physiologic shunts (Qs/Q) of over 30% of thecardiac output were always associated with dead spaceto tidal volume ratios (VD/VT) over 0.65. All measure-ments were made at a respiratory frequency of 20 per

minute. Open circles represent measurements in pa-tients with cardiopulmonary disease but without pulmo-nary emphysema. Solid circles represent measurementsfrom patients with emphysema. The mean physiologicshunt in patients with emphysema was 9.1% of the cardiacoutput; in patients with cardiopulmonary disease butwithout emphysema it was 22.4%. By contrast, the mean

physiologic dead space to tidal volume ratio was similar,0.673 in patients with emphysema and 0.617 in patientswithout emphysema.

output that was physiologic shunt, the over-allwithin patient correlation (rw) being 0.568 (p <0.001) (Figure 4).

No significant (p = 0.05) within patient corre-lation was found between the size of the tidal vol-ume and the percentage physiologic shunt.

Effect of changes in tidal volume on peak intra-tracheal pressure. Ratios of tidal volume to peakintratracheal pressure varied greatly from patientto patient (range 0.0104 to 0.0463 L per cm wa-ter). These ratios were influenced by the sizeof the tidal volume. The within patient correlation(rw) between these ratios and tidal volume was0.689 (p < 0.01) in emphysematous patients, andin patients without emphysema rw was 0.637 (p <0.001).

When all ratios of tidal volume to peak intra-tracheal pressure were plotted against VD/VT, thetotal correlation coefficient (rt) was - 0.257(p < 0.05). Another way of expressing this nega-tive relationship is to say that as tidal volume wasincreased, peak intratracheal pressure was less inpatients with the lower VD/VT ratios than it wasin patients with the higher VD/VT ratios. More-over, changes in VD/VT, although rarely of greatmagnitude, were reflected by corresponding changesin tidal volume to peak intratracheal pressure ra-tios (r, = - 0.547, p < 0.02 for emphysematouspatients; rw =-0.513, p < 0.01 for the otherpatients).

Table IV shows the within patient correlationcoefficients (rw) between tidal volume and the fol-

S

- j @O* °0@000~~~~~~0* 0 p

0

o

00000

I L

J. HEDLEY-WHYTE, H. PONTOPPIDAN,AND M. JOCELYN MORRIS

80k

70k

601

50k

40k

30k

20k

IF-

A. EMPHYSEMA

4a2~~~ ~ 3(o)

& 0

4(m~~~~~~~@

I0 I Z 3 4 5 6 7

CARD/AC INDEX

0 2 3

L/m2 BSA/min

4 5 6 7 8

FIG. 4. THE EFFECT OF CARDIAC INDEX ON PER CENT PHYSIOLOGIC SHUNT. The percentage physiologic shunt Qs/Qcorrelated with cardiac index both in patients with pulmonary emphysema (panel A: rw - 0.639, p < 0.01) and inpatients with cardiopulmonary disease but without emphysema (panel B: rw = 0.581, p <0.01). Linear regressionlines are shown for each patient and numbered so that each patient can be identified from Tables I, II, or III. Itshould be remembered that each point represents measurements made at different tidal volume (see Discussion) andthat the data in these panels are not adjusted for tidal volumes. After adjustments (see Appendix) the two corre-

lations quoted above were changed, r becoming 0.561 (p < 0.02) in panel A and 0.588 (p < 0.001) in panel B. It ap-pears, therefore, that the size of the cardiac output is a major determinant of the per cent physiologic shunt. All mea-

surements were made at a respiratory frequency of 20 breaths per minute.

lowing parameters: 1) cardiac index, 2) strokeindex, 3) physiologic shunt expressed as a per-

centage of the cardiac output, 4) physiologicdead space, 5) physiologic dead space to tidal vol-ume ratio, 6) mean central venous pressure, 7)tidal volume to peak intratracheal pressure ratio,and 8) per cent fall in mean arterial blood pressurecaused by inspiration.

Discussion

With respiratory rate constant, the ratio of deadspace ventilation to tidal ventilation (ratios rangedfrom 0.38 to 0.79) is almost unaffected by largechanges in tidal volume. Cardiac output is greatlydecreased by large tidal volumes in patients withemphysema, but generally unchanged in patientswithout emphysema. The amount of blood flow-ing through the lungs influences the percentagephysiologic shunt. These are the chief findings ofthis study, and they will be discussed in turn.

Physiologic dead space to tidal volume ratios.In patients with emphysema, and also in severe

bronchopneumonia, there is an abnormal distri-bution of ventilation to alveoli and poor mixing ofgases throughout the lung, so that alveolar gas

becomes heterogeneous in composition.Enghoff's modification of Bohr's equation was

proposed on the assumption that in normal man,

arterial carbon dioxide is in tension equilibriumwith the average alveolar carbon dioxide (9); inthese circumstances physiologic dead space is equalto anatomic dead space. When extreme uneven-

ness of pulmonary perfusion or ventilation causes

a gradient between the arterial carbon dioxide ten-sion and the average alveolar carbon dioxide ten-sion, the physiologic dead space computed bythe Enghoff equation will exceed the anatomicaldead space, and the difference (alveolar deadspace) becomes a measure of the ventilation ofrelatively poorly perfused alveoli (20).

lz

Ict

B.

aa

7(a~~~~8u

io"}

A a + 5(.)

x 12(s)

Il x

1550

94*1


The values we have found for physiologic deadspace and for the ratio of physiologic dead spaceto tidal volume are generally higher than otherworkers (21-24) have found in spontaneouslybreathing patients. For instance, in the emphy-sematous patients studied by Donald, Renzetti,Riley, and Cournand, physiologic dead space totidal volume ratios ranged from 0.29 to 0.59, andin the patients investigated with interstitial fibro-sis or pneumonitis physiologic dead space to tidalvolume ratios ranged from 0.21 to 0.67 (21).Similar values have been reported for patients withpoliomyelitis ventilated in a tank respirator (2).

In spontaneously breathing normal subjectswho hyperventilate, as during exercise, physio-logic dead space to tidal volume ratios almost in-variably fall (22-24), although total physiologic(but not anatomic) (23) dead space increases.The cause of the increase in the physiologic deadspace during voluntary hyperventilation in normalman is controversial. This increase has been ex-plained by Rossier, Biihlmann, and Wiesinger(10) in the following way: "Because of the in-creased intensity of gas exchange and because ofthe decreased time allowed for a respiratory cycle,homogeneous gas mixtures no longer exist in thealveoli. Therefore, a somewhat higher carbon di-oxide tension exists in the alveolus at the point ofgas exchange than is present in the anatomiccenter of the alveolus." This explanation is notaccepted by Bates and Christie (25), who feelthat it is unlikely that such an effect could occurin the very small alveoli of normal lungs. Thisobjection does not apply to patients with severelung disease. Increased heterogeneity of alveolargas composition within enlarged alveoli is onecause of enlarged physiologic dead space duringhyperventilation of patients with lung disease.Since respiratory frequency was constant through-out the study, the larger the tidal volume thehigher the inspiratory flow rate. The higher theinspiratory flow rate the greater the proportion oftidal volume distributed to alveoli served by air-ways with low flow resistances-and the less dis-tribution of ventilation depends on the elasticproperties of respiratory pathways (26). Thepreferential hyperinflation of some alveoli is moremarked the higher the tidal volume and will in-crease intra-alveolar gas heterogeneity and thuscalculated physiologic dead space. In emphysema

hyperinflation of some alveoli will be aggravatedby expiratory check valve mechanisms (27).

In this study, as in a previous study (3), everytime the physiologic shunt was in excess of 30%oof the cardiac output, physiologic dead space totidal volume ratios were in excess of 0.65. Theseincreases in physiologic dead space are too largeto be accounted for by increases in anatomic deadspace and must occur chiefly at the alveolar level(20). It should also be noted that apparatus deadspace (average 28 ml) was generally negligible bycomparison with physiologic dead space (range190 to 1,388 ml).

The effect of tidal volume on cardiac output.Cournand, Motley, Werko, and Richards in 1947(28) found that a pattern of ventilation, similarto the one used in this study, produced in humansubjects ventilated at, an average tidal volume of1.3 L a mean increase of 6%o in cardiac output. Inpatients with severe pneumonia and in three pa-tients with severe heart disease, we have found asimilar response to large tidal volumes (Table III)in spite of peak airway pressures being on occa-sion over 100 cm H20-five times higher than inthe study of Cournand and co-workers. Possiblythe presence of a large physiologic shunt lessensthe effect of high intrapulmonary pressure oncardiac output; a sympathetic nervous system re-sponse to extreme intrapulmonary distension aswell as the provision of normal passive expirationmay be added factors maintaining cardiac output inthese patients; different degrees of sympatheticresponse may also explain the great variability ofcirculatory responses to the start of intermittentpositive pressure ventilation.

The different circulatory response to large tidalvolumes delivered to patients with emphysema ata constant frequency has important practical im-plications. In patients with severe lung infectionsbut no emphysema, even extremely large tidalvolumes can be employed to maintain an acceptablelevel of alveolar ventilation. By contrast, in em-physema, if tidal and hence alveolar ventilation isincreased with respiratory frequency unaltered,cardiac output may fall to very low levels. If, onthe other hand, it is elected to maintain normaltidal volumes (as defined by ventilation nomo-grams) with high concentrations of oxygen, se-vere hypercapnia with eventual coma and deathmay result.

J. HEDLEY-WHYTE,H. PONTOPPIDAN,AND M. JOCELYNMORRIS

Factors affecting physiologic shunt. Said andBanerjee (12) found a mean physiologic shunt of1.7%o of the cardiac output in normal adults spon-taneously breathing nearly pure oxygen; by thesame methods the mean physiologic shunt inemphysematous patients was found to be 7.4%o(range 2 to 14%o) of the cardiac output. Theseresults are similar to the results we have obtainedduring the controlled ventilation of emphysematouspatients (Table II). In the patients withoutemphysema, however, the physiologic shunts weregenerally larger (up to 79%o of the cardiac output,mean 22.4%o). Postmortem findings, althoughoften obtained many days after these studies (Ta-ble I), suggest that these large physiologic shuntswere caused by perfusion of blood through almostairless lungs.

The amount of blood flowing through the lungs,measured as cardiac output, apparently influencedthe distribution of blood within the lungs becausethe greater the cardiac output the larger was thepercentage of blood flowing past unventilatedalveoli as physiologic shunt (Figure 4). Similarfindings have been reported in spontaneouslybreathing patients with mitral valvular diseasegiven either isoproterenol or norepinephrine (29).These findings suggest that either the shunt chan-nels in pneumonia, emphysema, or mitral lungdisease offer a lower resistance to the increasedflow than do the capillaries of ventilated alveoli,or alternatively, that with increasing pulmonaryblood flow the critical opening pressure of capil-laries in unventilated portions of the lung is sud-denly exceeded. A further possibility is that in-creases in the rate of flow of blood past thickenedalveolar membranes mean that insufficient time isavailable for full saturation of hemoglobin evenwhen nearly pure oxygen is breathed. Such dif-fusion/perfusion limitations are not evident innormal lungs when cardiac output is changed(30). Moreover, the physiologic shunt in patientswith normal lungs is too small (12) for reductionsin the percentage physiologic shunt to be easilymeasurable.

Large tidal volumes in this study did not con-sistently decrease the percentage physiologicshunt when cardiac output remained constant.This finding contrasts with previous studies (31,32) in which atelectasis of previously normallungs was produced by an unfavorable pattern of

ventilation and subsequently reversed by tidalhyperventilation.

This study, carried out with a ventilator set at aconstant frequency, has shown that the greatlyincreased ventilation requirements of some pa-tients with respiratory failure due to nonemphy-sematous cardiopulmonary disease can be met byincreasing the tidal volume to maintain normalalveolar ventilation. By contrast, in four patientswith advanced pulmonary emphysema, and littleor no pulmonary infection, large tidal volumesdrastically lowered cardiac output.

SummaryPhysiologic dead space to tidal volume ratios

from 0.38 to 0.79 and physiologic shunts from 5to 79% of the cardiac output were found in pa-tients on long term controlled ventilation. Tidalvolume changes at a constant frequency of 20breaths per minute did not appear to influence theratio of dead space ventilation to tidal ventilation.This ratio is thus a useful index of cardiopulmo-nary function during constant frequency con-trolled ventilation. Tidal hyperventilation de-creased the cardiac output in the patients withemphysema, but in the patients with cardiopulmo-nary disease without emphysema, cardiac outputwas essentially unaffected by the level of tidal ven-tilation. The percentage of blood flowing as physi-ologic shunt was proportional to the cardiac output;therefore, increases in cardiac output were as-sociated with increase in the proportion of thepulmonary blood apparently flowing past unven-tilated atelectatic, or consolidated, alveoli. In pa-tients with cardiopulmonary disease but withoutemphysema the level of tidal ventilation did notsignificantly affect the percentage physiologicshunt. When established lung disease has causedlarge physiologic shunts and dead space to tidalvolume ratios, the distribution of pulmonary bloodflow appears to be influenced more by cardiac out-put than by tidal ventilation and intratrachealpressure.

AppendixAs noted in the legend to Figure 4, besides within group

correlation another technique of variance analysis hasbeen used in this study-the determination of partial cor-relation coefficients. This technique allowed an assess-ment of the strength of the relationship between cardiacindex and percentage physiologic shunt, having "elimin-

1552


ated" the effect of the third variable, tidal volume. Sincewe were considering these three variables, cardiac index,per cent physiologic shunt, and tidal volume, we numberedthem 1, 2, and 3, respectively. There were three withinpatient correlations among them rwI2, rw,3, and rwa. Con-ceptually, the partial correlation coefficient we were con-sidering was the correlation between variables 1, cardiacindex, and 2, per cent physiologic shunt in a cross sectionof measurements all having the same value of variable 3,tidal volume. The over-all within patient partial correla-tion coefficient rW12.3 was computed by means of thestandard formula (33),

rWI2- rw3 X rw23 8rWl2.=1 (r )2 X 1 - (rw23)2 [8]

Significance levels (p) for rW12.3 were determined taking nto equal N - G - (m - 1) in the tables of Fisher andYates (19) (N is the total number of observations beingconsidered, G is the number of patients from whom thoseobservations came, and m ( = 3) is the number of variablesconsidered in calculating rW12.3)-

Acknowledgments

Wethank Professor W. G. Cochran of the Departmentof Statistics, Harvard University, for advice about thestatistical analysis of the data. We are grateful to R.Castriotta, Miss M. VanDernet, and Miss V. A. Smithfor technical assistance.

References1. Hedley-Whyte, J., H. Pontoppidan, and M. J. Morris.

The relation of alveolar to tidal ventilation duringrespiratory failure in man. Anesthesiology 1966,27, 218.

2. Saxton, G. A., Jr., G. E. Rayson, E. Moody, T. Mc-Grath, and J. W. Kaminski. Alveolar-arterial gastension relationships in acute anterior poliomyelitis.Amer. J. Med. 1961, 30, 871.

3. Pontoppidan, H., J. Hedley-Whyte, H. H. Bendixen,M. B. Laver, and E. P. Radford, Jr. Ventilationand oxygen requirements during prolonged artifi-cial ventilation in patients with respiratory failure.New Engl. J. Med. 1965, 273, 401.'

4. Laver, M. B., A. J. Murphy, A. Seifen, and E. P.Radford, Jr. Blood 02 content measurements us-ing the oxygen electrode. J. appl. Physiol. 1965,20, 1063.

5. Hedley-Whyte, J., E. P. Radford, Jr., and M. B.Laver. Nomogram for temperature correction orelectrode calibration during Po2 measurements.J. appl. Physiol. 1965, 20, 785.

6. Nunn, J. F., N. A. Bergman, A. Bunatyan, and A. J.Coleman. Temperature coefficients for Pco2 andPo2 of blood in vitro. J. appl. Physiol. 1965, 20,23.

7. Bradley, A. F., M. Stupfel, and J. W. Severinghaus.Effect of temperature on Pco2 and Po2 of blood invitro. J. appl. Physiol. 1956, 9, 201.

8. Adamsons, K., Jr., S. S. Daniel, G. Gandy, and L. S.James. Influence of temperature on blood pH ofthe human adult and newborn. J. appl. Physiol.1964, 19, 897.

9. Enghoff, H. Volumen inefficax: Bemerkungen zurFrage des schiidlichen Raumes. Upsala Lik.-F6ren. F6rh. 1938, 44, 191.

10. Rossier, P. H., A. A. Buhlmann, and K. Wiesinger.Physiologie und Pathophysiologie der Atmung,2nd ed. G6ttingen, Springer-Verlag, 1958. Englishtranslation, Respiration: Physiologic Principles andTheir Clinical Applications. St. Louis, C. V.Mosby, 1960, chap. 1.

11. Berggren, S. M. The oxygen deficit of arterial bloodcaused by non-ventilating parts of the lung. Actaphysiol. scand. 1942, 4 (suppl. 11), 1.

12. Said, S. I., and C. M. Banerjee. Venous admixtureto the pulmonary circulation in human subjectsbreathing 100 per cent oxygen. J. clin. Invest.1963, 42, 507.

13. Lambertsen, C. J., P. L. Bunce, D. L. Drabkin, andC. F. Schmidt. Relationship of oxygen tension tohemoglobin oxygen saturation in the arterial bloodof normal men. J. appl. Physiol. 1952, 4, 873.

14. Hedley-Whyte, J., H. Corning, M. B. Laver, W. G.Austen, and H. H. Bendixen. Pulmonary ventila-tion-perfusion relations after heart valve replace-ment or repair in man. J. clin. Invest. 1965, 44,406.

15. Barratt-Boyes, B. G., and E. H. Wood. The oxygensaturation of blood in the venae cavae, right-heartchambers, and pulmonary vessels of healthy sub-jects. J. Lab. clin. Med. 1957, 50, 93.

16. Theye, R. A., and G. F. Tuohy. The value of ve-nous oxygen levels during general anesthesia.Anesthesiology 1965, 26, 49.

17. Hedley-Whyte, J., and H. Corning. Unpublishedobservations.

18. McNemar, Q. Psychological Statistics. New York,John Wiley, 1962, chap. 18.

19. Fisher, R. A., and F. Yates. Statistical Tables forBiological, Agricultural and Medical Research.Edinburgh, Oliver and Boyd, 1963.

20. Severinghaus, J. W., and M. Stupfel. Alveolar deadspace as an index of distribution of blood flow inpulmonary capillaries. J. appl. Physiol. 1957, 10,335.

21. Donald, K. W., A. Renzetti, R. L. Riley, and A.Cournand. Analysis of factors affecting concen-trations of oxygen and carbon dioxide in gas andblood of lungs: results. J. appl. Physiol. 1952, 4,497.

22. Filley, G. F., D. J. MacIntosh, and G. W. Wright.Carbon monoxide uptake and pulmonary diffusingcapacity in normal subjects at rest and duringexercise. J. clin. Invest. 1954, 33, 530.

23. Wilson, R. H., B. E. Jay, R. S. Meador, and R. Evans.The pulmonary physiologic dead space as an in-dex of effective alveolar perfusion. Amer. J. med.Sci. 1957, 234, 547.

J. HEDLEY-WHYTE,H. PONTOPPIDAN, AND M. JOCELYNMORRIS

24. De Coster, A., H. Denolin, and M. Englert. etudede la ventilation alveolaire et de le'space mortphysiologique au repos et 'a 'effort chez les sujetsnormaux et'pathologiques. Acta med. scand. 1958,162, 47.

25. Bates, D. V., and R. V. Christie. Respiratory Func-tion in Disease. An Introduction to the IntegratedStudy of the Lung. Philadelphia, W. B. Saunders,1964, chap. 2.

26. Mead, J., I. Lindgren, and E. A. Gaensler. Themechanical properties of the lungs in emphysema.J. clin. Invest. 1955, 34, 1005.

27. Neergard, K. von, and K. Wirz. Die Messung derStromungswiderstinde in den Atemwegen desMenschen, insbesondere bei Asthma und Emphysem.Z. klin. Med. 1927, 105, 51.

28. Cournand, A., H. L. Motley, L. Werko, and D. W.Richards, Jr. Physiological studies of the effectsof intermittent positive pressure breathing on

cardiac output in man. Amer. J. Physiol. 1948,152, 162.

29. Sanders, C. A., J. W. Harthorne, H. Heitmann, andM. B. Laver. Effect of vasopressor administrationon blood gas exchange in mitral disease (abstract).Clin. Res. 1965, 13, 351.

30. Gerst, P. H., C. Rattenborg, and D. A. Holaday.The effects of hemorrhage on pulmonary circula-tion and respiratory gas exchange. J. clin. In-vest. 1959, 38, 524.

31. Hedley-Whyte, J., M. B. Laver, and H. H. Bendixen.Effect of changes in tidal ventilation on physiologicshunting. Amer. J. Physiol. 1964, 206, 891.

32. Hedley-Whyte, J., H. Pontoppidan, M. B. Laver, P.Hallowell, and H. H. Bendixen. Arterial oxy-

genation during hypothermia. Anesthesiology 1965,26, 595.

33. Fisher, R. A. Statistical Methods for ResearchWorkers. Edinburgh, Oliver and Boyd, 1954,chap. 6.

1554

response patients failure cardiopulmonary disease...

Documents