pennsylvania, pa.) have...

PULMONARYFUNCTION IN HYPERTHYROIDISM*

By MYRONSTEIN,t PHILIP KlMBELT AND ROBERTL. JOHNSON,JR.§

(From the Department of Physiology, Graduate School of Medicine, University ofPennsylvania, Philadelphia, Pa.)

(Submitted for publication March 9, 1960; accepted October 17, 1960)

Previous investigators, including Peabody andWentworth in 1917 (1), have described dyspneaand a decreased vital capacity in hyperthyroidpatients (2, 3). Following successful therapy ofhyperthyroidism, an increase in the vital capacityto normal levels has been observed. The preciserelationship of these changes to other measurablederangements of pulmonary or cardiac functionhas not been determined. Therefore, the presentstudy was undertaken using recently developedtechniques to determine the correlation betweenthe changes in vital capacity in hyperthyroidismand changes in 1) lung compliance, 2) strength ofthe respiratory muscles, 3) airway resistance, orother factors. Also, an attempt has been made toexplain the symptom of dyspnea associated withhyperthyroidism (4, 5) in the absence of obviouscongestive heart failure.

MATERIALS AND METHODS

Patients. The patients studied were from the wardsor clinics of the Philadelphia General Hospital or theHospital of the University of Pennsylvania. The diag-nosis of hyperthyroidism was based upon 1) clinicalevaluation, 2) I131 uptake by the thyroid gland, 3) basalmetabolic rate, and 4) serum protein-bound iodine.

Thirteen patients, 12 of whom were female (Table I),were studied. The ages ranged from 21 to 55 years (meanage 41). In addition to other symptoms of hyperthyroid-ism, 9 patients had decreased exercise tolerance. Fourdescribed "hard breathing" or "inability to get enoughair" on moderate exercise and 5 had shortness of breath

* Presented in part before the Federation of AmericanSocieties for Experimental Biology, April 18, 1958. Thisinvestigation was supported in part by a grant from theMedical Laboratories of the Army Chemical Center.

tWork performed during tenure of a fellowship fromthe American Trudeau Society. Present address: BethIsrael Hospital, Boston, Mass.

t Work performed during tenure of a fellowship fromthe National Institutes of Health. Present address: Al-bert Einstein Medical Center, Philadelphia, Pa.

§ Work performed during tenure of a fellowship fromthe National Foundation for Infantile Paralysis. Presentaddress: University of Texas, Southwestern MedicalSchool, Dallas, Texas.

on mild exertion. There was none with difficult breath-ing at rest.

One patient (RR) had acute pulmonary edema 1 monthprior to study, treated with digitalization, low salt diet,and bed rest. Although she had not received antithyroidmedication, there was no evidence of congestive failureat the time of the pulmonary function studies. Electro-cardiographic, X-ray and fluoroscopic studies were withinnormal limits. Patient SC had been in mild congestiveheart failure but was not believed to be in failure at thetime of the studies.

Fluoroscopic and X-ray examinations were carriedout in all patients to determine whether there was trachealcompression by an enlarged thyroid gland. No definitetracheal compression was observed except in RR.

Methods. Inspiratory capacity, expiratory reserve vol-ume, and vital capacity were measured with a 13 L spi-rometer. Distribution of inspired air was measured bythe nitrogen meter single breath test (6). Maximalbreathing capacity was measured by inspiring from a120 L spirometer through a low resistance valve. Re-spiratory rate, tidal volume, and minute volume at restand during the third to seventh minutes of exercise weremeasured using the 120 L spirometer. The minute vol-ume was corrected to BTPS (body temperature and pres-sure saturated with water vapor). Exercise studies wereperformed by walking on a treadmill (slope 41/4', speed2.4 mph unless otherwise indicated). Ventilation duringexercise was measured with the subj ects inspiring airor oxygen. Arterial (brachial) blood samples were ob-tained while the subjects were breathing air at rest, airduring exercise, and oxygen at rest. Arterial blood oxy-gen content, capacity, and carbon dioxide content weredetermined using the Van Slyke and Neill apparatus (7).Arterial blood pH readings were made at room tempera-ture using a glass electrode and the correction factors ofRosenthal to convert to 37' C (8). Partial pressures ofarterial blood carbon dioxide were calculated by apply-ing the line charts of Van Slyke and Sendroy (9) to thepH and carbon dioxide content values obtained on wholeblood.

Oxygen consumption and carbon dioxide production atrest and during the fourth and fifth minutes of exercisewere measured by collection of expired gas in a Douglasbag and analysis in a Scholander 0.5 ml gas sample ap-paratus (10), with correction to 0' C and 760 mmHgdry. Duplicate samples from each bag were analyzed andrequired to check within ± 0.05 per cent. Physiologicaldead space during resting and exercising ventilation wascalculated by the Bohr formula (11).

348

PULMONARYFUNCTION IN HYPERTHYROIDISM4

TABILE I

Physitcal characteristics, laboratory data beforc therapy, land results of therapy

Basal Radio-meta- active Protein- Anti-bolic iodine bound thyroid Clinical statusPatient Sex Age Ht Wt rate uptake iodine Dyspnea* treatment post-therapy

yrs in lbs % % jg/1OO mlRRt F 41 62 131 +72 12.2 xxxDS F 21 66 131 +28 77 xxxx Propyl.t Euthyroid

SurgeryFC F 41 65 173 +40 78 9.3 xxx RaI§ EuthyroidMC F 52 68 131 +35 91 10.2 xx RaI HypothyroidLF F 34 63 103 +52 87 11.0 x Propyl. Euthyroid

SurgerySCjJ F 45 64 148 +57 94 11.5 xxxx RaI EuthyroidAT F 42 68 159 67 11.6 xxxxEL F 34 65 105 + 3 58 6.5 xxxALI F 55 62 107 +63 78 9.5 xxxx Ral EuthyroidHR F 46 65 124 88 7.5 xMB M 43 73 157 +31 78 9.4 xxxEM F 56 63 162 +70 14.0 x Propyl. EuthyroidEQ F 33 64 137 +28 59 6.7 xxxx

* x = No change in exercise tolerance; xx = dyspnea on severe exertion; xxx = dyspnea on moderate exertion;xxxx = dyspnea on mild exertion.

t Episode of acute pulmonary edema 1 month prior to study and compression of trachea by enlarged thyroid observedon fluoroscopy.

I n-Propylthiouracil.§ Radioactive iodine-131.

Slight pulmonary congestion.¶T Aortic stenosis, no clinical evidence of decompensation.

Functional residual capacity (FRC) and airway re-sistance were measured in the body plethysmograph (12,13). Lung compliance was measured during normal ven-tilation by the method of Mead and Whittenberger (14).Maximal inspiratory and expiratory pressures at themouth were measured against a closed airway using acapacitance manometer.

Apparent CO diffusing capacities (DL)1 were esti-mated by a modification of Krogh's single breath methoddescribed previously (15). Alveolar samples were ana-lyzed for COwith an infrared analyzer,2 and for He and02, with a continuous sampling mass spectrometer.3Plasma CO tension in equilibrium with mixed venouscarboxyhemoglobin was estimated at the start and at theend of each series of breath-holding measurements with arebreathing technique and subtracted from the alveolarCO tensions in a manner previously described (16) forestimating true CO tension gradients during breath-hold-ing.

Diffusing capacity of the pulmonary membrane (DM)and pulmonary capillary blood volume (Vc) were cal-culated from measurements of DL at more than one alve-olar oxygen tension using the following relationship de-

1 The subscript referring to carbon monoxide (CO) isomitted in this paper; DL, DM and 9 refer to DLco,DMco, and Oco, respectively, unless specifically statedotherwise.

2 Beckman Instruments, Inc., Fullerton, Calif.3 Consolidated Electrodynamics Corporation, Pasadena,

Calif.

rived by Roughton and Forster (17):1/DL = 1/DM + 1/(Vc9). [1]

DL and DMare expressed in ml/ (min X mmHg), and 9is the rate of COuptake by the red cells in 1 ml of wholeblood expressed as milliliters per minute per millimeterHg plasma CO tension; Vc then is in milliliters. Thereciprocal of 9 was approximated from the alveolar oxy-gen tension (PAo2) as follows (17):

1/9 = 0.72 + 0.0058 PAO2. [2]The reciprocals of DL for each subject were plotted against1/9 and the best straight lines to describe these relation-ships were determined by the method of least squares.Vc was calculated from the slopes and DM from the in-tercepts of these lines at (1/9) = 0. Since the valuesof 1/9 are based on an assumed oxygen capacity of 20vol of gas per 100 ml of blood, estimates of Vc were cor-rected to the patient's oxygen capacity by multiplying themeasured capillary volume by the ratio,

20patients 02 capacity (vol %)

Mean and instantaneous pulmonary capillary bloodflows were measured in duplicate by the plethysmographicnitrous oxide method of Lee and DuBois (18).

All measurements at rest were made with subjectsseated comfortably in a chair. Three to 16 months aftertherapy, 7 of the 13 patients were re-evaluated by theendocrine clinics of the University and Philadelphia Gen-eral Hospitals and were restudied as described above.

349

MYRONSTEIN, PHILIP KIMBEL AND ROBERTL. JOHNSON, JR.

'rABLE, 11

Lung volumews bcforc and (ft/cl' Itlcra/)y

Vital capacity

Before AfterPatient therapy therapy

Residual volume

Before Aftertherapy therapy

Functional residualcapacity Total lung capacity

Before After Before Aftertherapy therapy therapy therapy

ml ml ml mlRR 2,580 (91)* 1,540 (95) 2,000 (88) 4,200 (99)DS [7]t 2,460 (67) 2,830 (77) 1,000 (67) 635 (43) 2,180 (94) 2,100 (90) 3,460 (71) 3,465 (71)FC [6] 2,700 (83) 3,400 (105) 1,190 (66) 1,370 (77) 2,400 (86) 2,630 (94) 3,890 (81) 4,470 (93)MC[4] 2,480 (77) 3,160 (97) 2,430 (135) 1,390 (77) 3,400 (121) 2,390 (85) 4,960 (104) 4,650 (97)LF [5] 2,520 (81) 3,040 (97) 1,600 (104) 1,390 (90) 2,600 (116) 2,660 (118) 4,120 (93) 4,440 (101)SC [3] 2,420 (81) 2,600 (87) 850 (51) 890 (53) 1,920 (81) 1,380 (58) 3,270 (74) 3,490 (79)AT 2,230 (63) 1,235 (75) 1,870 (76) 3,465 (71)EL 3,090 (92) 1,070 (68) 2,480 (102) 4,160 (90)AL [3] 3,220 (122) 2,940 (111) 1,990 (120) 1,750 (106) 3,280 (100) 2,700 (88) 5,040 (123) 4,360 (107)HR 2,590 (83) 1,590 (95) 2,590 (108) 4,180 (92)MB 4,625 (95) 1,945 (74) 2,685 (72) 6,570 (93)EM [3] 2,640 (100) 3,240 (123) 2,290 (129) 1,315 (74) 2,690 (80) 2,340 (69) 4,940 (118) 4,690 (112)EQ 3,080 (95) 1,330 (85) 2,460 (106) 4,410 (97)Mean 2,820 (87) 3,030 (100) 1,540 (90) 1,250 (74) 2,500 (95) 2,315 (85) 4,380 (93) 4,220 (94)

* Per cent of predicted values in parentheses. Since the predicted values of Needham, Rogan and McDonald (20) were measured at ATPSand the measured values in our subjects were corrected to BTPS, 9% has been added to the predicted figures.

t Number of months between studies in brackets.

Calculations of standard deviations (SD) were per-

formed by conventional methods. The t test was usedto determine the probability that the observed changeswere significant (19).

RESULTS

Lung volumes (Table II, Figure 1). The vitalcapacities of three of the hyperthyroid patients(DS, MCand AT) were significantly less thanthe predicted normal values of Needham, Roganand McDonald (20). The other ten patientshad vital capacities within the predicted normalrange. The mean inspiratory capacity generallywas decreased, and the mean expiratory reserve

volume generally was greater than predicted, al-though the deviations from predicted values were

not significant. Mean FRC, residual volume, andtotal lung capacity were within normal limits. Itis noteworthy that 3 of 13 patients prior to therapyhad total lung capacities less than 75 per cent ofpredicted values. On the other hand, AL had a

total lung capacity of 123 per cent of the predictedvalue before therapy. The small variations ob-served are in reference to predicted values, butcritical evaluation can be made only by measure-

ment of the lung volumes following successfultherapy (Figure 1). No correlation was foundbetween the vital capacity or other lung volumesmeasured at rest and the dyspnea frequently ob-served on exercise. The mean vital capacityincreased in seven patients who were restudiedafter treatment (p < 0.02). The inspiratory ca-

pacity was slightly increased (p < 0.05) and the

residual volume was not significantly changed.The total lung capacity did not change. Theseresults are similar to those of Richards, Whitfield,Arnott and Waterhouse (21).

Mechanics of breathing (Table III). Maximalbreathing capacity was less than 80 per cent ofpredicted values in three patients, according to theprediction formula of Baldwin, Cournand andRichards (22). In contrast to the observation ofnormal "elastic resistance" in two hyperthyroidpatients by McIlroy, Eldridge and Stone (23),

7 5000-

1 4000_-

D 3000-

0

2000-

z 1000 -

HYPERTHYROID P'VITAL CAPACITY 26401260INSP. CAP. 1540 *270ExP RES. VOL. 1010 1 310FRC 2630±O 2RESIDUAL VOL. 1620t 580TOT. WNGCAP. 4240!700 4

HYPER- POSTTHYROID THERAPY

MEAN FC

)ST THERAPY3030± 250 p 0.021920±300 p 0.0S

1065±! 310 pO0.?2315 400 p>O.'12501350 p>O04220t500 P>09

ICERVRV

r

MC

FIG. 1. MEANLUNG VOLUMESAND STANDARDDEVIA-TIONS IN 7 PATIENTS BEFORE AND AFTER THERAPY. Pa-tients FC and MCrepresent variations among group, FCshowing an increase in inspiratory capacity post-therapy,and MC an increase in inspiratory capacity and a de-crease in residual volume. IC = inspiratory capacity;ERV= expiratory reserve volume; RV= residual vol-ume.

350

O-_

PULMONARYFUNCTION IN HYPERTHYROIDISM

,U.08FI.. IUNG OMLINC PRE- AND POST--wig AP IN7%#X

-J

<.06

0

lulng complianlce inl the presenlt studcy was lower

thlan the predictedl valule inl practically all the

platienlts. Airw-ay resistanlce as normal, except

inl onle paltient who bad a large goiter anld a small

inlcrease inl airwXay resistanlce. M~aximal pressures

mleasulrecl at the mouth on bsoth inspirationl and

expirationl againlst a closed alirway were decreased

signlificanltly xvhenl comupared to those measured on

a conltrol group of six female euthv-roid sub~jectsof similar age anld b~ody size. One patient, LF,

-60-

I z

E 0 -40-

Icra. -20-wcn

D0-

LL)Z +20-

0 O

C z +40

e Xc +60R

OHYPERTHYROID* POST THERAPY0(6) CONTROLS

I'lLlll I

DS FC LF SC AL EM M EAUT ID

FIG. 3. MfAXIMAL INSPIRATORY AND EXPIRATORY PRES-

SURES MEASUREDAT THE MOUTHAGAINST A CLOSED AIR-

WAYPRE- AND POST-ThIERAPY.

had exceediingly low values of maximal inspiratorypressure before therapy.

After treatment, lung compliance increased tonormal levels (Figure 2). Airway resistancemeasurements wvere unchanged when compared tothe pre-therapv measurements. There were sig-

nificant increases in maximal inspiratory and

expiratory pressures measured at the mouth(Figure 3).

TABLE III

.Mlechanics of breathing

Maximal pressuresMaximal

Inspiration Expiration breathing Lung coil)liance Airway resistancecapacity --

Before After Before After Before After Before AfterPatient therapy therapy therap)y therapy Before therapy tlherap)y therapy therapy therapy

mn Hig L/min ' pred. L AYo H-.O cm HO/I.,/secRR 59 70 2.94DS 30 45 29 53 72 68 0.070 0.112 1.98 1.70FC 30 55 30 55 123 123 0.053 0.091 1.73 1.14MC 59 75 0.110 0.140 1.69 1.45LF 3 35 11 45 92 108 0.029 0.100 1.26 1.48SC 22 35 29 55 86 100 0.052 0.100 0.90 1.30AT 20 61 79 82 0.066 1.46EL 20 32 77 96 0.092 1.83AL 19 60 22 60 87 130 0.106 0.117 0.66 0.83HR 40 55 78 98 0.090 1.32MIB* 35 40 146 116 0.015 1.49EM\ 40 45 60 80 88 i11 0.090 0.120 0.71 1.04EQ 15 30 87 95MIeani 24 46 35 58 86 98 0.076 0.111 1.50 1.27SD ± 11 ±9 ± 16 ± 11 ±0.025 ±0.015 ±0.60 ±0.27

p < 0.01 p < 0.01 p < 0.01 p > 0.05Normal 49 60 Female 0.09-0.19 0.7-2.4

SD ±I0 ±17 Male 0.14-0.24

* \IB13ot ilicIluded i,, the meaii.

351


TABLE IV

Distribution of inspired air, ventilation, and oxygen consumption before therapy

Alveolar Minute volume Frequency 02 consumption 02 extraction*distri-

Patient bution Rest Exercise Rest Exercise Rest Exercise Rest Exercise

%change L/min/m2 BTPS resp./min mi/min/M2 STPD %(750-1,250

ml)RR 1.0 6.2 21DS 1.7 4.4 30.3 16 33 160 515 3.92 4.55FC 0.8 6.1 24.7 27 42 660 5.25MC 0.8 6.7 17.8 25 30 208 710 4.10 4.00LF 0.3 7.3 23.6 30 40 216 420 2.96 3.63SC 1.5 6.4 27.lt 28 48 200 640 4.25 3.74AT 0.2 6.4 36.2 29 54 212 810 4.20 3.26EL 2.5ALI 1.9 5.5 17 182 4.20HR 0.8 5.9 27.7 23 43 194 850 3.50 3.64MB 0.5 8.8 30.1 32 49 175 496 2.50 4.65EM 0.3EQ 0.3 5.6 17.4 25 179 530 3.80 3.62

Mean 1.0 6.3 26.1 25 42 191 625 3.71 4.04SD il .3 ±5.7 ±5 ±8 ±19 ±t139 ±0.58 ±0.6

Mean euthyroid controls§ 4.5 12.5 19 20 138 523 4.07 5.51SD ±0.2 43.8 ±6 ±4 ±22 ±158 ±0.94 ±1.06

p Values p <0.01 p <0.01 0.05 >p >0.02 p <0.001 p <0.01 p >0.05 1) >0.05 p <0.01

* Ventilation measured during period of oxygen consumption.t 1 mph, 4*° slope.t Could not tolerate exercise.§ Average age 35 yrs; average weight 123 lbs.

Ventilation and gas exchange (Table IV). Inall patients studied, distribution of inspired airwas within normal limits. Frequency of breathingat rest was increased in hyperthyroid patients com-pared to that of a group of seven euthyroid femalesof similar body size and age. The hyperthyroidpatients at rest had an increased minute ventilationper unit of body surface area (BSA) with de-

creased tidal volumes. The respiratory quotientof the hyperthyroid patients was within normallimits at rest. There was a significant increase inminute ventilation in the hyperthyroid patientsduring exercise on a treadmill (26.1 + 5.7 L perminute per M2) compared to the minute volume ofexercising euthyroid controls (12.50 + 3.8 L perminute per M2). The increase in minute volume

A EUTHYROID CONTROLS* HYPERTHYROID* POST THERAPY

40-

30-

z

N 20-

W 10-4- REST4 U-EXERCISE-4

I

5 10 15

VENTILATION-L/MIN /M20

gn

0

ex

hi1

hi

hiw

0

x

I BEFORE POST20 THERAPY THERAPY

FREQUENCYof RESP.

FIG. 4. OXYGENCONSUMPTION, MINUTE VENTILATION, AND FREQUENCYOF RESPIRATION AT

REST AND DURING EXERCISE IN EUTHYROIDAND HYPERTHYROIDSUBJECTS PRE- AND POST-THERAPY.

The mean results for rest and exercise have been connected by straight lines.

352

600

400 -

200-

N

zN

z

0

F:o-0

0


O c Cro cI 'IC

-H0 .n .t. ON

ON omc 00

C4CNet- e;Nch oE N ~00Oi01 1

0

000

0) -t- 0 '-,t

-nu1 0 \0 0s

cIf M In

C1ooo--4Cl o

C)

ON00ON

Uf) 0 ti) cq Uf) If)\0 t -tO -cCi4 mf OF) "f) CIA mf

mf -' -) -1- 00Ci4 cll mOfCi4 ci

OfC)4 C)0000

Of)m I'fl elf) -I ci

- m~in ci C'I '-%\00C- -4f) N-- -f

CONOf)

ecI- f)Cic='-I- n

---C1cqm C4 --4 Ci4-

- -- oK4Cmf \Q C4 Ofn 0 U')_ Co4 ci c it1C11- c"I- c"I e

OO00 ci c0

'e,oo6 4 qV) -t ci mf -t

m in 0 t--)aLn If)n f) f cO

.f)

.n

.-0

- o 6o6 o6

-f -

ciE

C. 4

v00

.11

crO

-I.. .f c

during exercise was accomplished for the mostpart by an increase in frequency of breathing inthe hyperthyroid subjects (42 + 8; controls, 20+ 4). At rest, mean oxygen consumption per unitBSA was significantly higher in hyperthyroid pa-tients than it was in euthyroid controls, but duringexercise oxygen consumption was not significantlydifferent in the patient and control groups (Fig-ure 4).

The oxygen extraction (rate of oxygen con-sumption divided by minute volume of ventila-tion) was not significantly different in the hyper-thyroid patients and euthyroid controls at rest, butduring exercise it was significantly less in thepatients than in control subjects.

After treatment, frequency of breathing andminute ventilation during rest and exercise de-creased significantly in the seven patients whowere restudied (Table V, Figure 4). Oxygenextraction during rest was not significantly differ-ent after therapy, but during exercise this ratio in-creased significantly above the pre-therapy levels.

Dyspnea. The euthyroid subjects accomplishedthe required exercise without dyspnea. Preced-ing the exercise test, the hyperthyroid patientswere instructed to signal by hand if they experi-enced respiratory discomfort. In four patients

4-;W

cC)

01)0U-

00.00)

(n -r-

x -e

0 ..

00X 'S

z

TIME (SECONDS)

FIG. 5. MEANPULMONARYCAPILLARY BLOOD FLOWBE-

FOREANDAFTER THERAPY (ON THE LEFT). Range bars de-_ X fine 1 standard deviation. Pulsatile pulmonary capillary

blood flow of Patient DS appears on the right. Flow in.z ° liters per minute is on ordinate; time in seconds is on

wD abscissa. O-R (---) indicates one R-R interval on

<, < electrocardiogram; 0 =pulsatile flow in Patient DS be-fore therapy; * = after therapy and prior to clinical ap-

pearance of hypothyroidism; (ED =after treatment withthyroid hormone.

353

r.0

xcu

0

ZI._

0uoTo

-

0

-0

0

-0o

0T_0

*a04

c

Uo

.I!t(1)m

.uvx

.4

¢-.

m)W

0

I


who so signalled, the inspiratory gas was changedfrom air to oxygen by manipulation of a hiddenvalve. In all four subjects dyspnea disappearedand there was a fall in rate of respiration. Onre-examination, all patients had noticed improve-ment in exercise tolerance (Table V). AL, whowas unable to tolerate the exercise test prior totherapy, stated that she could climb two or threeflights of stairs without discomfort.

Pulmonary capillary blood flow and diffusingcapacity. In the hyperthyroid patients at rest,peak levels of pulsatile flow in the pulmonarycapillaries reached levels as high as those obtainedon normal euthyroid subjects immediately aftermild exercise (18). A representative pattern of

pulsatile flow in Patient DS is shown in Figure 5.Following remission of symptoms, mean flow rates

and peak flow rates decreased (Table VI andFigure 5). The low pulmonary capillary bloodflow observed following therapy in three of thepatients appears to be related to impending hypo-thyroidism, since these patients subsequently be-came grossly hypothyroid. In one of these latterthree patients, DS, there was a substantial increasein pulmonary capillary blood flow during therapywith thyroid hormone (Figure 5). Apparentdiffusing capacity, true membrane diffusing capac-

ity and pulmonary capillary blood volume at restwere not elevated before treatment of hyperthy-roidism and significant changes did not occur

TABLE VI

Pulmonary capillary blood flow (Q,), apparent diffusing capacity for CO(DL) at different alveolar oxygen tensions,true membrane diffusing capacity (DM) and pulmonary capillary blood volume (Va) *

Before treatment After treatment

DmVB DM V.

Patient Q, PA02 DL Meas. Pred.t Meas. Pred.t QO PA2 DL Meas. Pred.t Meas. Pred.t

RR 113 18.7 30 47 80 66560 10.8

DS 19.4 99 20.7 72 49 57 69 8.5 124 19.3 48 50 54 72230 15.2

362 13.0 403 11.9622 8.0 574 9.1

FC 7.5 105 18.3 34 56 59 80 10.4 120 16.9216 13.2504 9.5

MC 9.6 112 20.4 48 48 65 68 4.3 144 19.6 63 51 62 73469 10.7 428 11.9614 9.1 571 9.4

LF 12.3 125 18.6 43 41 80 58 8.4 133 18.7314 14.2609 9.2

SC 7.2 126 15.6 58 51 45 73 3.0 146 14.5 53 56 46 80308 10.2609 6.5 581 6.7

AL 14.0 126 14.7 65 41 50 58 3.1 120 12.4248 11.3423 9.0568 5.8

EM 12.2 120 14.3 6.2 120 15.0

AT 129 22.5 56 55 75 79317 16.4608 10.8

Mean 11.7 48 51 69 64 6.3 55 52 54 75

* Units: QC is in L/min; DL and DMare given in ml/(min X mmHg); V, is in ml; PAO2 is given in mmHg.t Predicted DMand V, were calculated from predicted DL utilizing the observation that the membrane and corpuiscu-

lar resistances to COdiffusion in a normal resting subject are approximately equal (17). For this, Di, was predicted witha standard formula using body surface area (15).

354


40

30

20

40

0 5 10 45 20

FIG. 6. THE RELATIONSHIPS OF LUNG DIFFUSING CA-

PACITY (DL) AND PULMONARYCAPILLARY BLOOD VOLUME

(Ve) TO PULMONARYBLOOD FLOw. Results for each pa-tient before (0) and after (0) successful treatment ofhyperthyroidism have been connected by straight lines.The solid diagonal lines are the regression lines describ-ing the changes in DL and V. as blood flow was alteredby physical activity in 4 normal male subjects (43); theparallel dashed lines delimit two standard errors of esti-mate on either side of the regression lines.

following successful therapy (Table VI). Theabsence of any significant correlation betweenchanges of pulmonary blood flow and changes ofeither diffusing capacity or pulmonary capillary

lood volume before alid after treatinecit arc illus-trate(d iii Figure 6.

Arterial blood gases (Table VII). The arterialoxygen saturation measured in seven of the hyper-thyroid subjects was normal at rest and on exer-cise. There was not an abnormal right to leftshunt as indicated by the normal amount ofoxygen dissolved in plasma while breathing 100per cent 02 Arterial blood carbon dioxide ten-sion and pH were within normal limits, but inseveral patients decreases in arterial blood Pco2occurred during exercise. During resting ventila-tion the total dead space comprised 38 per cent ofthe tidal volume, but during exercise, the totaldead space increased to an average of 50 per centin the four patients so studied.

DISCUSSION

Vital capacityThe present studies once again demonstrated a

decreased vital capacity in some patients withhyperthyroidism. Although the mean pretreat-ment value was not significantly less than pre-dicted, there were large rises of vital capacity infive of the seven patients restudied after therapy.

The low vital capacity prior to therapy may berelated to the low lung compliance and to themuscular weakness which has been observed toaccompany the hyperthyroid state (24). How-ever, the fact that the total lung capacities of thegroup were the same before and after treatmentis evidence against changes in lung compliancebeing the major determinants of the observedchanges in vital capacity. An alternative explana-tion would be that sufficient effort to complete

TABLE VII

Arterial blood studies

Arterial oxygensaturation pH PAco2

DissolvedPatient Rest Exercise oxygen* Rest Exercise Rest Exercise

% vol % mmHgDS 98.3 98.4 2.11 7.35 7.32 46 41FC 95.1 1.77 7.36 42MC 97.5 98.7 2.00 7.40 7.33 42 43LF 98.5 96.6 1.65 7.37 7.35 43 40SC 94.8 96.1 1.93 7.37 7.38 46 39AT 97.7 98.6 1.78 7.38 7.32 42 37MB 99.0 98.3 1.90 7.34 7.41 46 36

Mean 97.3 97.8 1.76 7.37 7.36 44 39Normal 96-99 > 1.5 7.34-7.44 35-45

* After breathing 99.6% oxygen for 15 minutes.

-*-DL at PAO2 - 120 rnm.Hg - i

(mn. xrm.Hg).---

PULMONARYBLOOD FLOW(L./mrin.)II

355


maximal expiration could not be sustainedagainst 1) the opposing elastance of the rib cage,2) frictional forces in the lung and chest wall, and3) increased inspiratory muscle tone (25). Al-though it is possible that congestion of the lungswith blood is a major factor causing the low vitalcapacity, the application of tourniquets on severalof the hyperthyroid subjects did not elevate vitalcapacity to predicted or post-therapy levels. Sinceairway resistance measurements were normal inall but one of the patients, it is unlikely that gen-eralized bronchial obstruction played a prominentpart in the observed changes in vital capacity.RR, who had a large goiter with tracheal com-pression, had a slight increase in airway resistance,which did not decrease after an aerosolized bron-chodilator and was therefore probably not due tobronchospasm. The normal values for distribu-tion of inspired air in these patients also is notconsistent with diffuse obstructive pulmonarydisease.

ComplianceThe mechanism of the decreased lung compli-

ance observed in the hyperthyroid patients is notclear at the present time. Five possible mecha-nisms have been considered: 1) changes in theFRC; 2) pulmonary congestion and edema; 3) in-creased intrathoracic blood volume; 4) alterationsin the retractile properties of alveolar septa; 5) adecrease in the number of functioning alveolarunits during quiet breathing.

1) FRC. A marked decrease or elevation ofFRCmay affect the lung compliance (26, 27). Adecrease in FRC may be related to closure of asufficient number of alveolar units so that an in-creased "opening pressure" is required (28). Anincrease in FRC, on the other hand, may be ac-companied by an increase or decrease in the lungcompliance. If the FRC be sufficiently increasedto expand the volume to a position on the pres-sure-volume curve near its plateau, the compli-ance would decrease. If, after therapy, the FRCwere increased sufficiently so that previously col-lapsed alveoli were expanded, the compliancewould increase. Analysis of our data, however,reveals no significant change in mean pre- andpost-treatment FRC to account for the observedchanges in lung compliance.

2) Pulmonary capillary congestion and edema.

We have demonstrate(l that the peak pulmonarycapillary blood flow of the hyperthyroid patientsat rest reaches levels greater than that in mosteuthyroid subjects after moderate exercise. Atpeak levels of flow, the hydrostatic pressure in thecapillaries may force fluid into the interstitialspaces from which colloidal osmotic pressure orlymphatic flow cannot remove it rapidly enough tolrevent accumulation. Such an increase in inter-stitial fluid, although this is pure conjecture, mightlroduce a decrease in pulmonary compliance.Evidence to implicate ventricular failure in thegenesis of pulmonary edema in exercising hyper-thyroid subjects is lacking. Bishop, Donald andWade (29) measured "wedge" pressures in threeresting hyperthyroid subjects and observed anelevation in only one subject without overt con-gestive heart failure. Our finding of a normal DMand a normal Vc during rest in these hyperthyroidpatients makes the presence of pulmonary edemaseem unlikely. Furthermore, in 11 of the 13hyperthyroid subjects, there was no clinical orX-ray evidence of pulmonary congestion andedema. The normal arterial oxygen saturationsat rest and on exercise and the normal airwayresistance measurements also would be inconsist-ent with the presence of pulmonary edema andcongestion as causative factors in the decreasedcompliance.

3) Changes in intrathoracic blood volume otherthan in pulmonary capillaries. An increase in totalblood volume has been previously observed inhyperthyroidism (30). However; an increase inintrathoracic blood volume displacing pulmonarygas does not seem likely as a factor in the observeddecrease of compliance in view of the normalvalues for total lung capacity and the failure oftourniquets to elevate the vital capacities to pre-dicted or post-therapy levels in these patients.

4) Alterations in the retractile properties ofalveolar septa. These alterations might occur asthe result of changes in composition, structure, orconfiguration of the elastic components of thealveolar septa (31). However, evidence relatingto such changes caused by hyperthyroidism is notavailable. Changes in composition of the alveolarmucoid film (32, 33) might alter tension at theair-liquid interface of alveoli and of small airways.This also could significantly alter the retractileforces in the lung. Depositions of mucoid mate-

356


rials have been observed in the orbit and lowerextremities of hyperthyroid patients, althoughthere have been no observations of a change in thealveolar mucoid film in hyperthyroidism.

5) Alterations in the number of functioningalveolar units. Lung compliance is the sum of thecompliance of the smallest functioning volumeunits. Occlusion of unstable alveolar units byinterfacial forces might result from muscle weak-ness in hyperthyroidism. Such changes wouldproduce a decreased compliance. Similar de-creases in lung compliance have been observed inpatients with poliomyelitis (34).

Exercise ventilation and oxygen consumptionThe hyperthyroid subjects had significantly

greater respiratory minute volumes and rates ofrespiration during exercise in comparison withpost-therapy studies or measurements on euthyroidcontrols. These findings could be the result ofseveral factors. 1) Muscular weakness and de-creased lung compliance may induce a rapid rateof respiration as a means of minimizing the worknecessary to achieve a given ventilation (35, 36).2) An abnormally large production of carbondioxide during exercise may act as a respiratorystimulant. Although these studies do not precludean increased sensitivity of the respiratory centersto carbon dioxide in hyperthyroid patients, carbondioxide production and arterial Pco, during mod-erate exercise were no greater than they were aftertherapy or in euthyroid controls. 3) Increasedheat may have been a stimulus to the respiratorycenter. An increase in rate of respiration andventilation usually accompanies an increase inbody temperature (37). Maley and Lardy (38)and Hoch and Lipmann (39) have demonstratedby in vitro techniques that thyroxine produces abiochemical alteration whereby energy in the cellis dissipated as heat rather than by the formationof high energy phosphates. Heat intolerance is afrequent clinical observation in hyperthyroid pa-tients, and many of the patients studied com-plained of warmth and sweating during the exer-cise test. 4) The respiratory center may bestimulated directly by thyroid hormone or itsmetabolites. Williams, Winters, Clapp and Welt(40) have recently observed an increase in ventila-tion in animals treated with dinitrophenol. Intheir experiments, hyperventilation occurred even

in the presence of respiratory alkalosis. Theypostulated that dinitrophenol might act as a respir-atory stimulant. Since thyroxine and dinitrophe-nol have many similar actions, it is possible thatthyroid hormone may also exert a direct or in-direct effect on the respiratory center. 5) Thesubjects who observed dyspnea on exercise experi-enced rapid relief of this symptom when allowedto breathe 100 per cent 02 while continuing theexercise, even though arterial oxygen saturationwas normal prior to oxygen. Ventilation per unitof oxygen consumption may be decreased when100 per cent 02 is administered to certain types ofpatients, usually those with hypoxia. This mayindicate that tissue demand for oxygen may beoperative in the increased ventilation observed inpatients with thyrotoxicosis.

The decreased oxygen extraction in exercisinghyperthyroid patients is probably due to an in-crease in total dead space ventilation produced byan increased frequency of breathing and an aug-mented alveolar or parallel dead space ventilation.Similar results in exercising hyperthyroid patientshave been reported by Bates (41). Alveolar ven-tilation appears to have been adequate duringexercise as there was no evidence of arterialoxygen unsaturation or carbon dioxide retentionin any of the patients studied.

The dyspnea observed in many of the patients,while they were hyperthyroid, did not appear tobe related to the size of the goiter or to an increasein minute ventilation accompanying an increasein oxygen uptake (23), but rather to a combina-tion of several factors. In no patient was theairway resistance increased to a level consideredsufficient to cause dyspnea of airway obstruction,and the increment of minute ventilation duringexercise was consistently greater than that of ox-ygen consumption. Therefore, the dyspnea ofhyperthyroidism appears to be related to otherfactors such as decreased compliance, decreasedrespiratory muscular strength (42), increaseddead space ventilation, and perhaps an abnormalstimulus to respiration.

Diffusion and capillary blood flowIn each of these hyperthyroid patients the di-

menisions of the pulmonary capillary bed, as re-flected by DL, DMand Vc, were essentially normalat rest even though the resting blood flow was

357


approximately twice to three times normal. Bateshas made similar observations in patients withhyperthyroidism during light exercise, showingthat DL is low in respect to the oxygen consump-tion (41), and by inference, even lower in respectto the cardiac output.

These findings in hyperthyroid patients are notinconsistent with reported findings in other cir-cumstances where pulmonary blood flow is in-creased and DL is not. Ross, Frayser and Hickam(43) have shown that increases of pulmonaryblood flow induced by epinephrine or norepineph-rine are not accompanied by changes of diffusingcapacity; and Turino, Brandfonbrener and Fish-man (44) have shown that diversion of the totalresting cardiac output through one lung in a mandoes not increase DL in the over-perfused lung.Therefore, failure to find DL increased during restin these hyperthyroid patients in response to theincreased resting pulmonary blood flow does notnecessarily indicate an abnormal response of thevascular bed.

These observations in hyperthyroid patients areof interest because of the still pending question asto which factors control the size of the pulmonarycapillary bed. It may be that the pulmonary intra-vascular pressures are not sufficiently increased bythe increased blood flow in hyperthyroidism tocause the capillaries to expand. The data ofBishop and associates (29) indicate that the rela-tionship between pulmonary blood flow and pulmo-nary arterial pressure is normal in patients withhyperthyroidism, but significant data are not avail-able concerning pulmonary capillary pressure.Thus, the possibility that lung capillaries havefailed to expand in these patients, owing to a trans-mural capillary pressure lower than normal in re-spect to blood flow, cannot be eliminated. Fur-thermore, if the low lung compliances observed inthese hyperthyroid patients reflect a true change inthe elastic properties of the septal tissues of thelung, it is not unreasonable to suspect that septalcapillaries are similarly affected. This would meanthat the vascular volume would tend to be lessthan normal for the same transmural pressuredifference.

In contrast to the findings in hyperthyroid pa-tients, a close reproducible relationship has beenfound between pulmonary capillary blood flow(Qc) and DL in normal subjects at rest and dur-

ing various grades of exercise (45, 46). It isreasonable to suspect that DL is increased duringexercise by passive distention of the capillary bedowing to an increase in intravascular pressureaccompanying the increased flow. The observa-tion that an increase in intravascular pressure atconstant pulmonary blood flow causes DL to in-crease in the isolated perfused cat lung (47)confirms this explanation. However, the increaseof DL during exercise in normal subjects may becaused by a mechanism or mechanisms other thanpassive distention of capillaries: 1) The size of thepulmonary capillary bed may actually remain fixedduring exercise but an apparent change of DL, DMand Vc could occur if the relationship betweenintracorpuscular oxygen tension and the reactionrate (0) between CO and oxyhemglobin werealtered during physical activity. This possibilityhas not been entirely disproved, but it seems un-likely, since 0 is relatively insensitive to the changesof blood pH, CO. tension and lactic acid concen-trations normally associated with exercise (48-50). 2) Increased ventilation has been suggestedas the principal cause for the increase of DL duringexercise (43, 44). Hyperventilation at rest causesDL to increase significantly when measured bysteady state methods, but hyperventilation cannotexplain the increases of DL, DM and Vc duringexercise measured by breath-holding methods(15). The increase of DL by steady state meas-urements during hyperventilation may be relatedin part to an associated increase of mean lungvolume as suggested by the work of Marshall(51). 3) The size of the pulmonary capillary bedmay be primarily determined by vasomotor activ-ity in small pulmonary blood vessels. For in-stance, changes in chemical composition of venousblood returning to the lungs during exercise mightmediate the observed expansion of the pulmonarycapillary bed either by a direct action on the bloodvessels or by reflex vasodilatation. In support ofthis, inhalation of CO2 by normal subjects hasbeen found to increase DL before significant risesin pulmonary capillary blood flow can be demon-strated (52). In patients with hyperthyroidism,arteriovenous oxygen differences are smaller thannormal, therefore, CO2 tension in mixed bloodmay be normal or low, providing no stimulus forcapillary bed expansion. This possibility requiresfurther evaluation.

358


TABLE, VIII

Right ventricular stroke volume, pulmonary capillary bloodvolume, and mean transit time for blood through pulmonary

capillaries

Before treatment After treatment

Mean Meancapillary capillary

Stroke transit Stroke transitPatient vol. Vc time vol. VC time

ml ml sec ml ml secDS 164 5 7 0.18 106 54 0.38FC 62 59 0.47 120 59* 0.34MC 120 65 0.41 67 62 0.86LF 111 80 0.39 73 80* 0.57SC 63 45 0.38 46 46 0.92AL 127 50 0.21 39 50* 1.01EMMean 108 59 0.34 75 58 0.68

* These values were assumed to be the same after treatment as theywere before treatment.

Transit times through pulmonary capillaries

Another aspect of these data which stimulatesspeculation concerns the short intervals that redcells apparently remained in lung capillaries ofthese hyperthyroid patients during one circulation(Table VIII). In normal subjects at rest theaverage time spent in pulmonary capillaries duringa single circulation is about 0.75 second and, dur-ing moderate exercise, expansion of the capillarybed tends to keep transit time at 0.5 second ormore even though blood flow may be tripled (43).Also, the pulmonary capillary blood volume innormal subjects tends to be larger than the cardiacstroke volume and this insures a fairly uniformtime of exposure of red cells to the lung diffusingsurface, despite the pulsatile nature of pulmonarycapillary flow. In the hyperthyroid patients, therate of blood flow during rest was doubled ortripled, whereas the volume of the pulmonarycapillary bed remained fixed at normal restingdimensions and the capillary blood volume wasless than the cardiac stroke volume (Table VIII).Therefore, the mean pulmonary capillary transittime was not only short in these patients, but somered cells must have flowed past the alveolar capil-lary diffusing surface in much less than the esti-mated mean transit time, as indicated in the lowerhalf of Figure 7. As a consequence, the oxygentension gradient between alveolar air and end-capillary blood in the lungs of these patientsshould have been larger than in normal subjectsunder the same conditions. In order to estimatethe possible magnitude of this increased gradient,

aplproximations of the time course of intracorpus-cular oxygen tension during capillary transit in thelung have been constructed for Subject DS, usingthe Bohr integration procedure (53) (Figure 8).In order to construct these curves, DL was esti-mated with Equation 2, assuming that the DMforoxygen is 1.23 times that for CO and assumingtwo different average values for 9o,. Only re-cently, 602 has been measured within the physio-logical range of oxygen saturations, and although ithas been found to remain relatively constant withinthe range of zero to 85 per cent blood oxygen sat-uration, 902 falls as the oxygen saturation risesabove 85 per cent and approaches zero as oxygensaturation approaches completion (54). Assum-ing that the average 6O2 for blood traversing the

V--0 0.4 0.2 0.3 0.4 0.5

FIG. 7. ESTIMATES OF INSTANTANEOUS FLOW (QC)AND TRANSIT TIME THROUGHTHE CAPILLARY BED OF REDCELLS ENTERINGLUNGCAPILLARIES AT DIFFERENT MOMENTSWITHIN A CARDIAC CYCLE. The subject is DS beforetreatment of the hyperthyroid condition. The temporalpositions of the ECGR waves in relation to flow eventsare indicated by vertical lines. In making estimates oftransit time it was assumed that the pulmonary capillaryblood volume remained 57 ml throughout the cardiac cycle(Table VI).

359


AR HESfo=,.mmmm.Hmv.~90 -

80 TENSION(mvvn. Hg)

70-MfEAN _o2f.0 mm. Hg 'men

50 0

__

100A02- ff04rm.H9g90

7*02

60

0 0.2 0.4 0.6 0.8 .0FIG. 8. OXYGENTENSION IN RED CELLS AS THEY PASS ALONGAN ALVEOLAR

CAPILLARY IN SUBJECT DS BEFORETREATMENTOF HYPERTHYROIDISM. Twolimiting values of 002 have been assumed. PAO, and PvO, are the alveolarand mixed venous oxygen tensions, respectively. The dashed curves repre-sent the oxygen tension in a red cell traversing the alveolar capillary bed inthe calculated mean transit time (0.175 second, see Figure 7), and the solidlines forming the upper and lower boundaries of the cross-hatched areas rep-resent the oxygen tension in red cells traversing capillaries in the longestand shortest times, respectively, during pulsatile flow (Figure 7). Pc'o2represents the end-capillary blood oxygen tension after mixing has smoothedout temporal as well as regional non-uniformity of oxygen saturation. Be-cause of the shape of the blood oxygen dissociation curve, the end-capillaryoxygen saturation of blood which has remained in the lung capillaries forlonger than the mean transit time cannot take up sufficient additional 02 tomake up for the lesser end-capillary 02 saturation of that blood which hastraversed the capillaries in less than the mean transit time. For this reasonoxygen tension of the mixed end-capillary blood (Pc'o2) is less than the oxy-gen tension of blood which has passed through the alveolar capillaries in themean transit time, unless, of course, the transit time is constant throughoutthe cardiac cycle.

capillary bed in DS might reasonably lie between1.0 anded 0.3 mmHg-1 min-' (17), the mean DLO2would lie between 28 and 11 ml (per minutex mmHg), respectively. The curves in Figure 8were constructed, using these assumptions. Thetransit times were obtained from the data plottedin Figure 7. The rates of 02 diffusion at differentpoints along a pulmonary capillary and, conse-

quently, the shape of the 02 tension rise with timeare critically dependent upon the manner in which002 decreases as hemoglobin saturation increases,

but even at the lower assumed value for mean 002,the mixed end-capillary 02 tension in this patientshould have been within 10 mmHg of the alveolaroxygen tension. This end-capillary gradient isstill compatible with the normal resting arterialoxygen saturations measured in these patients(Table VII).

SUMMARY

1. The vital capacity was decreased in some,but not all, of the hyperthyroid patients studied.

360


Following therapy, the vital capacity reached pre-dicted normal or higher levels in the majority ofpatients restudied.

2. The lung compliance in hyperthyroidism wasdecreased.

3. Elevation of airway resistance observed inonly one patient was insufficent to produce symp-toms of respiratory obstruction.

4. Measurements of pressures at the mouth onmaximal expiratory and inspiratory effort againsta closed airway indicated weakness of the respir-atory muscles.

5. On exercise the patients' ventilation was in-creased in excess of the oxygen uptake when com-pared to a group of controls of similar age andbody size. This was apparently related to anincrease in the dead space ventilation due to anincrease in -frequency of breathing and alveolardead space ventilation.

6. Following remission of symptoms producedby surgical thyroidectomy, radioactive iodine, orpropylthiouracil drugs, the previously describedabnormalities reverted to normal levels.

7. In hyperthyroid patients, apparent diffusingcapacity of the lung (DL), pulmonary capillaryblood volume (Vc), and membrane diffusing ca-pacity (DM) at rest were not elevated in thepresence of significant elevations of pulmonarycapillary blood flow. Reductions of pulmonarycapillary blood flow following successful therapywere not associated with significant changes inDL, Vc, or DM.

ACKNOWLEDGMENT

The authors wish to express their gratitude to Drs.Julius H. Comroe, Jr., Arthur B. DuBois and Robert E.Forster for their help and encouragement and to Drs.Edward Rose and Norman Schneiberg for referring thehyperthyroid patients for pulmonary function studies.

REFERENCES

1. Peabody, F. W., and Wentworth, J. A. Clinicalstudies of the respiration. IV. The vital capacityof the lungs and its relation to dyspnea. Arch.intern. Med. 1917, 20, 443.

2. Rabinowitch, I. M. The vital capacity in hyperthy-roidism with a study of the influence of posture.Arch. intern. Med. 1923, 31, 910.

3. Lemon, W. S., and Moersch, H. J. Basal metabo-lism and vital capacity. Arch. intern. Med. 1924,33, 130.

4. Means, J. H. Dyspnoea. Medicine (Baltimore)1924, 3, 309.

5. Blumgart, H. L., Gargill, S. L., and Gilligan, D. R.Studies on the velocity of blood flow. XIII. Thecirculatory response to thyrotoxicosis. J. clin. In-vest. 1930, 9, 69.

6. Comroe, J. H., Jr., and Fowler, W. S. Lung functionstudies. VI. Detection of uneven alveolar ventila-tion during a single breath of oxygen. A newtest of pulmonary disease. Amer. J. Med. 1951, 10,408.

7. Van Slyke, D. D., and Neill, J. M. Determinationof gases in blood and other solutions by vacuumextraction and manometric measurement. J. biol.Chem. 1924, 61, 523.

8. Rosenthal, T. B. The effect of temperature on pH ofblood and plasma in vitro. J. biol. Chem. 1948,173, 25.

9. Van Slyke, D. D., and Sendroy, J., Jr. Studies ofgas and electrolyte equilibria in blood. XV. Linecharts for graphic calculations by Henderson-Has-selbalch equation, and for calculating plasma carbondioxide content from whole blood content. J. biol.Chem. 1928, 79, 781.

10. Scholander, R. F. Analyzer for accurate estimationof respiratory gases in one-half cubic centimetersamples. J. biol. Chem. 1947, 167, 235.

11. Comroe, J. H., Jr., Forster, R. E., DuBois, A. B.,Briscoe, W. A., and Carlsen, E. The Lung. Chi-cago, Year Book Publishers, 1955, pp. 181-183.

12. DuBois, A. B., Botelho, S. Y., Bedell, G. N., Mar-shall, R., and Comroe, J. H., Jr. A rapid plethys-mographic method for measuring thoracic gasvolume: A comparison with nitrogen washoutmethod for measuring functional residual capacityin normal subjects. J. clin. Invest. 1956, 35, 322.

13. DuBois, A. B., Botelho, S. Y., and Comroe, J. H., Jr.A new method for measuring airway resistance inman using a body plethysmograph: Values innormal subjects and in patients with respiratorydisease. J. clin. Invest. 1956, 35, 327.

14. Mead, J., and Whittenberger, J. L. Physical proper-ties of human lungs measured during spontaneousrespiration. J. appl. Physiol. 1953, 5, 779.

15. Ogilvie, C. M., Forster, R. E., Blakemore, W. S.,and Morton, J. W. A standardized breath hold-ing technique for the clinical measurement of thediffusing capacity of the lung for carbon monoxide.J. clin. Invest. 1957, 36, 1.

16. Forster, R. E., Fowler, W. S., Bates, D. V., and VanLingen, B. The absorption of carbon monoxideby the lungs during breathholding. J. clin. Invest.1954, 33, 1135.

17. Roughton, F. J. W., and Forster, R. E. Relativeimportance of diffusion and chemical reactionrates in determining rate of exchange of gases inthe human lung. With special reference to truediffusing capacity of pulmonary membrane and

361


Volumiie of blood in the lung capillaries. J. appl.Phlysiol. 1957, 11, 290.

18. Lee, G. de J., and DuBois, A. B. Pulmonary capil-lary blood flow in man. J. clin. Invest. 1955, 34,1380.

19. Fisher, R. A. Statistical Methods for ResearchWorkers, 12th ed. London, Oliver and Boyd,1954.

20; Needham, C. D., Rogan, M. C., and McDonald, I.Normal standards for lung volumes, intrapulmo-nary gas-mixing, and maximum breathing ca-

pacity. Thorax 1954, 9, 313.21. Richards, D. G. B., Whitfield, A. G. W., Arnott,

W. M., and Waterhouse, J. A. H. The lung vol-ume in hyperkinetic states. Brit. Heart J. 1953,15, 83.

22. Baldwin, E. deF., Cournand, A., and Richards, D. W.,Jr. Pulmonary insufficiency: 1. Physiologicalclassification; clinical methods of analysis; stand-ard values in normal subjects. Medicine (Balti-more) 1948, 27, 243.

23. McIlroy, M. B., Eldridge, F. L., and Stone, R. W.The mechanical properties of the lungs in anoxia,anaemia and thyrotoxicosis. Clin. Sci. 1956, 15,353.

24. Boothby, W. M., and Sandiford, I. The total andnitrogenous metabolism in exophthalmic goitre.J. Amer. med. Ass. 1923, 81, 795.

25. Greene, J. A., and Heeren, R. H. Clinical studiesof respiration. V. Relation of dyspnea and airhunger to changes of the expiratory volume of thechest. Arch. intern. Med. 1936, 57, 100.

26. Nisell, 0. I., and DuBois, A. B. Relationship be-tween compliance and FRC of the lungs in cats,and measurement of resistance to breathing. Amer.J. Physiol. 1954, 178, 206.

27. Marshall, R. The physical properties of the lungs inrelation to the subdivisions of lung volume. Clin.Sci. 1957, 16, 507.

28. Mead, J., Whittenberger, J. L., and Radford, E. P.,Jr. Surface tension as a factor in pulmonary-vol-ume hysteresis. J. appl. Physiol. 1957, 10, 191.

29. Bishop, J. M., Donald, K. W., and Wade, 0. L. Cir-culatory dynamics at rest and on exercise in thehyperkinetic states. Clin. Sci. 1955, 14, 329.

30. Gibson, J. G., 2nd, and Harris, A. W. Clinical stud-ies of the blood volume. V. Hyperthyroidism andmyxedema. J. clin. Invest. 1939, 18, 59.

31. Bull, H. B. Symposium on Tissue Elasticity, JohnW. Remington, Ed. Washington, D. C., AmericanPhysiological Society, 1957, pp. 33-42.

32. Macklin, C. C. The pulmonary alveolar mucoid filmand the pneumonocytes. Lancet 1954, 1, 1099.

33. Clements, J. A., Brown, E. S., and Johnson, R. P.Pulmonary surface tension and the mucus liningof the lungs: Some theoretical considerations. J.appl. Physiol. 1958, 12, 262.

34. Ferris, B. G., Jr., Mead, J., Whittenberger, J. L.,

and Saxton, G. A., Jr. Pulmonary function inconvalescent poliomyelitis patients. III. Compli-ance of lungs and thorax. New Engl. J. Med. 1952,247, 390.

35. Otis, A. B. Work of breathing. Physiol. Rev. 1954,34, 449.

36. McIlroy, M., Marshall, R., and Christie, R. V. Thework of breathing in normal subjects. Clin. Sci.1954, 13, 127.

37. Landis, E. M., Long, W. L., Dunn, J. W., Jackson,C. L., and Myer, U. Studies on the effects of bathson man. III. Effects of hot baths on respiration,blood and urine. Amer. J. Physiol. 1926, 76, 35.

38. Maley, G. F., and Lardy, H. A. Metabolic effects ofthyroid hormones in vitro. II. Influence of thy-roxine and triiodothyronine on oxidative phos-phorylation. J. biol. Chem. 1953, 204, 435.

39. Hoch, F. L., and Lipmann, F. The uncoupling ofrespiration and phosphorylation by thyroid hor-mones. Proc. nat. Acad. Sci. (Wash.) 1954, 40,909.

40. Williams, T. F., Winters, R. W., Clapp, J. R., andWelt, L. G. Respiratory alkalosis as a result ofadministration of 2,4-dinitrophenol (abstract).Amer. J. Med. 1957, 22, 977.

41. Bates, D. V. Personal communication.42. Friedberg, C. K. Diseases of the Heart, 2nd ed.

Philadelphia, Saunders, 1956, p. 1005.43. Ross, J. C., Frayser, R., and Hickam, J. B. A study

of the mechanism by which exercise increases thepulmonary diffusing capacity for carbon monoxide.J. clin. Invest. 1959, 38, 916.

44. Turino, G. M., Brandfonbrener, M., and Fishman,A. P. The effect of changes in ventilation andpulmonary blood flow on diffusing capacity of thelung. J. clin. Invest. 1959, 38, 1186.

45. Johnson, R. L., Jr., Spicer, W. S., Bishop, J. M., andForster, R. E. Pulmonary capillary blood vol-ume, flow, and diffusing capacity during exercise.J. appl. Physiol. 1960, 15, 893.

46. Shepard, R. H., Varnauskas, E., Martin, H. B.,White, H. A., Permutt, S., Cotes, J. R., andRiley, R. L. Relationship between cardiac outputand apparent diffusing capacity of the lung innormal men during treadmill exercise. J. appl.Physiol. 1958, 13, 205.

47. Rosenberg, E., and Forster, R. E. Changes in dif-fusing capacity of isolated cat lungs with bloodpressure and flow. J. appl. Physiol. 1960, 15, 883.

48. Hartridge, H. The action of various conditions on

carbon monoxide haemoglobin. J. Physiol. (Lond.)1912, 44, 22.

49. Roughton, F. J. W. Kinetics of haemoglobin. VI.Competition of carbon monoxide and oxygen forhaemoglobin. Proc. roy. Soc. B 1934, 115, 473.

50. Roughton, F. J. W., Forster, R. E., and Cander, L.Rate at which carbon monoxide replaces oxygenfrom combination with human hemoglobin in solu-

362

PULMONARYFUNCTION IN HYPERTHYROIDISM 363

tion and in the red cell. J. appl. Physiol. 1957, 11, 53. Bohr, C. tber die spezifische Thtigkeit der Lungen269. bei der respiratorischen Gasaufnahme and ihr Ver-

5l. Marshall, R. A comparison o5 methods of measuring halten zu der durch die Alveolarwand stattfinden-the diffusing capacity of the lungs for carbon den Gasdiffusion. Skand. Arch. Physiol. 1909, 22,monoxide. Investigation by fractional analysis of 221the alveolar air. J. clin. Invest. 1958, 37, 394.

52. Rankin, J., McNeill, R. S., and Forster, R. E. In- 54- Staub, N. C., Bishop, J. M., and Forster, R. E. Ef-fluence of increased alveolar CO2 tension on pul- fect of partial O2Hb saturation on the initial ratemonary diffusing capacity for CO in man. J. of 02 uptake by human erythrocytes. Fed. Proc.appl. Physiol. 1960, 15, 543. 1959, 18, 152.

pennsylvania, pa.) have...

Documents