Intravenous isoproterenol: Rationale for bronchial asthma William B. Klaurtermeyer, M.D., Rorario 1. Di Bernardo, M.D., and

Frank C. Hale, B.S. Los Angeles, Cdif.

Intraveltous iaoproterenol was inficsed into 7 adult asthmatic patients with refractory bronchial ol&ruotion. Over a dose range of O.OS75 to 0.885 pg per kilogram per minute, maximal bronohodilator effect (or reversal of effect) ooozlrrea within 8 to 5 minutes of starting (or stopping) the Cnfwim. Obstrzlotion to a&-@~ improved with each increment of dose. Average heart rate reaohed a ma&mum at O.Or5 cg per

kilogram per minde. Over the lower dose range alveolar to arterial oxygen gradients widened and heart rate increased; over the higher dose range, as heart rate platema, bronchodilator effect continued and oxygen gradient narrowed. When combined with adequate oxygenation and oont&uzl monitoring of oardiac rhythm and blood pres- swre, intravenm isoproterenol appears safe for asthma% patients. Major ad- vantages are (1) odmi&tration of brmohodilator to airwqs not reaohed by Qhala- ticm, (8) prompt onset and offset of effects, and (8) reversal of un&&able side effeots. l’he use of intravenous isoproterenol may obviate the need for intuhation and ventilatory assist.

Isoproterenol is used extensively in the treatment of bronchial asthma. It is an effective bronchodilator when administered by inha1ation.l The mechanism of action may relate to stimulation of beta adrenergic receptors with relaxation of bronchial smooth muscle, a concept first introduced by Ahlquist? in 1948. It is also clear that asthma.tic patients may fail to respond to inhaled isoproterenol for any one of several reasons: They may overuse the nebulizer, with exacerbation of symptoms3; there may be an idiosyncratic intolerance to isoprotereno14; small airways obstructed by smooth muscle contraction, edema, or mucus may prevent aerosolized isoproterenol from reaching the sites of obstruction. The latter type of bronchial obstruction may be more effectively reversed by isoproterenol infused into the circulation.

There is evidence that parenteral epinephrine may be more effective than inhaled isoproterenol or epinephrine (by inhalation) .5 It is possible that intravenous isoproterenol would be a more effective bronchodilator than inhaled isoproterenol in severely obstructed asthmatic patients.

This study evaluates the dose-response, time-course, and physiologic changes observed with the use of intravenous isoproterenol in adult asthmatic patients with acute bronchial obstruction.

From the Department of Medicine, Wadsworth Veterans Administration Hospital and the University of California at Los Angeles School of Medicine.

Received for publication May 14, 1974. Reprint requests to: William B. Klaustermeyer, M.D.,

Veterans Administration Hospital Center, Los Angeles, Chest/Allergy Section, Wadsworth

Calif. 90073.

Vol. 55, No. 5, pp. 3.85~SSS

326 Klaustermeyer, Di Bernardo, and Hale

TABLE I. Clinical data

J. ALLERGY CLIN. IMMUNOC. MAY 1975

I A. 0. I 0. J. II. P.

Sex Male Male Male Age (yr.1 56 44 39 Height (in.) 71 67 71 Weight (lb.) 175 150 142

6 /M/ P / B jM/ P IBjMiP

Blood (mm. pressure 146 140 160 Hg) x0 -iii3 no

Heart rate (beats/ 90 140 96 64 164 84 1 I5 160 120 min. )

Khythm SC. shj SC SC 8s SE 8 H s

Rare VPC VPC Rare VPC Rare VPC VPC Ow. VPC Auscwltntion

IW mild IW 0 IW IW IW 1w EW EW EW &Z E EW mv EW

1~ baseline I W inspiratory wheeze EW expiratory wheeze M maximal dose

TABLE II. Physiologic data

Fvc (L.) FVC (% predicted) FEV1.o CL.)

PB VCO, (d. STI'D) vo, (ml. STPD)

VT CL.1 V, (TJmin.1

A. 0. 0. 1. I_ R* p: _ - ..-- ._ - . . --._ B M P B j M P 1 B jr/ P

1.04 2.80 1.85 2.92 3.72 3.50 1.02 1.83 O&t 22 60 40 62 80 75 20 37 13

0.38 1.09 0.53 .90 2.16 1.79 0.37 0.54 0.12 ii3 117 31 i: 25 99 114 61 50 93 81 9 108 14 46 3

74 81 67 72 72 60 61 49 46 29 38 43 32 :; 54 40 7.38

7.40 7.51 7.42 7.42 7.49 7.40 7.37 7.47 323 433 314 235 370 208 336 334 383 487 474 262 398 289 464 348

0.56 1.33 0.87 0.45 0.77 0.42 0.67 0.74 10.1 17.3 10.1 7.0 13.3 7.1 11.4 34.5

f I(breaths/min.) 18 13 12 19 17 17 17 20 VJdVT 0.50 0.39 0.42 0.46 0.39 0.51 0.61 0.59

B baseline 31 maximum dose FEV,., forced expiratory volume at 1 serond P post (1)5W) FVC forced vital capacity Pn arterial tension

METHODS ABiD MAFPWAU

Seven adult patients were studied : 6 men and 1 woman; their ages ranged from 39 to 55 years. Informed consent was obtained from all.

Bronchial asthma was defined as reversible obstructive airways disease without evideak of emphysema or chronic bronchitis. All seven patients had a documented history of severe

refractory asthma and were considered to have severe asthma. All had required repeated hospitalizations and high-dose corticosteroid therapy to control their bronchocoustrictios.

Fivo of the 7 patients had evidence of an allergic component and immunotherapy was added to their medical program at later dates. Although the patients mere not in status asthmatieus,

all had moderately severe to severe bronchial obstruction at the time of the study. Critkally ill patients in status asthmaticus would have been unsuitable for this typo of investigation,

because physiologic measurements such as serial forced expiratory flow rates could not have been obtained.

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Intravenous isoproterenol 327

J. P. c. 1.

Male Male 48 55 69 68

170 130

R. 1.

Female 52 64

230

w. M.

Male 47 71

189

B M P ~B~M~P]B~M~P~B~M(P

125 140 122 150 160 140 155 375 170 130 90 135

85 70 70 80 56 70 90 70 80 95 40 90

96 152 108 120 144 108 72 152 80 96 128 94

S S S s S S S S S S S S

ET 0

i; ZIG 0 IW

i: EW 0 IW IW 0 IW

EW EW EW

P post (D5W) VPC ventricular premature contraction S sinus 0 no wheeze

J. P. I c. 1. I R. 1. I w. M. t I

I) M P 6 M P 0 M P B MI p

2.59 2.58 2.47 1.78 3.27 1.49 1.53 1.72 1.30 3.16 3.59 2.76 57

1.06 30

:ri 39

7.46 302 434

0.8 9.9

12 0.45

56 54 1.26 1.15

38 32 112 102

71 78 34 38

7.49 7.47 451 284 495 366

1.04 0.88 17.0 10.0 16 11

0.45 0.47

30 0.47

1;: 77 44

7.41 336 390

0.64 11.3 18

0.52

76 1.63

50 107

79 30

7.43 306 373

0.7 12.4 18

0.51

35

91

0.54

69 44

16

7.37 216 302

0.5 7.8

16 0.55

50

it 55

0.59

7.37 212

23

300 0.31 5.5

18 0.5

57 0.81

32 86 58 46

7.42 269 379

0.42 8.3

20 0.5

43 0.57

22 67 57 53

7.37 213 358

0.35 6.0

17 0.53

66 1.81

48 119

95 37

7.45 413 367

0.5 15.0 30

0.47

75 2.18

58 94 64 34

7.49 256 410

0.45 18.9 38

0.71

58 1.69

2 70 41

7.43 211 267

0.35 9.4

27 0.62

Pa0, alveolar oxygen tension VE expired minute volume V volume VT tidal volume VDP/VT physiological dead space/tidal volume

The patients were admitted to the intensive respiratory care unit at Wadsworth Veterans

Administration Hospital. Rronehodilator medication was withheld for 4 hours prior to the

infusion of isoproterenol, with one exception in which inhaled isoproterenol was given 2 hours prior to the infusion. Serial blood gas determinations were obtained after cannnlation of a

brachial or radial artery. Cardiac rhythm was monitored continuously. With the patient

supine an intravenous solution of 5 per cent dextrose in water (D5W) was started. Baseline forced vital capacity (FVC), one-second forced expiratory volume (FEV,), three-second

forcrd expiratory volume (FEV,), pulse, and arterial blood gases were measured. Physiologic baseline studies were obtained after the patient had been stable for at least 30 minutes. The

isoproterenol was then infused with a graded dosage from 0.0375 to 0.225 gg per kilogram of body wright per minute. Each dosage level of the drug was infused for a period of 20 to

25 minutes. FVC, FEV,, FEV,, heart rate, and ansenltatory findings were recorded at 2- to

5-minute intervals before and during the infusion. After the 20 to 25 minute infusion of each

328 Klaustermeyer, Di Bernardo, and Hale J. ALLERGY CLIN. IMMUNOL. MAY 1975

dosage level, arterial blood and expired gas lvere collected and analyzed. The isoproterenol

was discontinued and during 115W infusion measurements were again repeated during anot,her

20-minute period. In 4 patients after the IXW infusion the isoproterenol infusion K:M

restarted at the maximal dosage level and studies were repeated. The patients breathed room air through a valve system and expired gas mas collected in

a J)ouglas bag. The concentrations of 0, and CO, in the expired gas were measured \vith

Beckman gas analyzers for the calculation of O? consumption and respiratory quotient (R).

Expired gas was collected with a simultaneous arterial blood gas. The expired gas volume, was measured with a dry gas meter. Alveolar oxygen tension (Pnol) was calculated from

the alveolar gas equation; physiologic dead space mas calculated Sth Enghoff’s modification

of the Bohr equation. Arterial blood gases were measured with 0,, CO,, and pH electrodes (Instrumentation Laboratories). The vital capacity and forced expiratory flolv rates Tvert!

recorded with an Electra-Med spirometer and digital meter.

RESULTS

1soproterenol was administered intravenously to 7 adult asthmatic patients during acute bronchial obstruction. The clinical data are tabulated in Table I and the physiologic data in Table TT.

Clinical data

All seven patients demonstrated bronchodilation with isoproterenol infusion. Patients reported prompt relief of dyspnea and auscultation revealed complete reversal of wheezing during quiet breathing except in 2 cases in which expiratory wheezes persisted. Wheezing promptly recurred when D5W infusion was substituted for isoproterenol. In 4 patients the isoproterenol infusion was restarted at the maximal dose and a similar bronchodilatory ef&& occurred within 2 to 4 minutes. A sinus tachycardia occurred in all seven patients; 3 patients had a heart rate of over 100 before the infusion. Two patients had rare premature ventricular contractions that disappeared during the infusion and reappeared when the isoproterenol was discontinued. Two patients com- plained of pain at the needle site during the infusion of the highest dose. This may have been related to the markedly acidic pH of the isoproterenol and D5W solution.

Blood pressure was recorded at &minute intervals on 5 patients. All subjects experienced a significant drop in diastolic pressure. The infusion was discon- tinued on Patient W. M. when the diastolic blood pressure fell to 40 mm. Hg at the dose of 0.15 rg per kilogram per minute. Patient IL P. developed a marked pulsus paradoxus during the infusion of the maximal dose.

Physiologic data

The isoproterenol infusion resulted in a prompt bronchodilator effect within 2 to 5 minutes of starting the infusion. The offset was equdly rapid. The dose- response curve for the entire group is demonstrated in Fig. 1 and for a single patient (C. L.) in Fig. 2. During the infusion the FEV, continued to inersasc with increasing dose while the heart rate reached a maximum at a dose of 0.075 pg per kilogram per minute and then plateaued (Fig. 3).

The arterial oxygen tension was normal or low at the onset and deerea& during the infusion of the lower dosage levels (Fig. 4). The art&&l oxygen

VOLUME 55 NUMBER 5

300

FEVl

% CoNlRol

200

loo

Intravenous isoproterenol 329

MN 0 20 40 60 80 loo I20 140 160 .

DOSE RATE 0.8375 0.0562 0.075 0.113 0.15 0.225 D.C.

FIG. 1. FEV, as per cent of control value at various isoproterenol infusion rates. Data are averaged for all patients (pg/kg/min).

level decreased in all seven patients at some dosage level, although only 2 patients developed hypoxemia during the infusion of the maximum dose (Table II). The alveolar oxygen increased during the infusion and thus the A&* gradient widened. The gradient widened maximally during the infusion of the lower dosage levels (Fig. 4).

The patients’ minute ventilation volumes increased due to a change in tidal volume as there was no change in respiratory frequency. The oxygen uptake increased with increasing doses of infused isoproterenol. The effect of the drug on physiologic dead space was variable.

DISCUSSION

The mortality rate from asthma in the United States is approximately 4,000 deaths per year.6 Since bronchial asthma is by definition reversible airways obstruction, changes in the therapeutic approach are needed to further reduce this mortality rate. A uniform finding at postmortem examination is mucous impaction of the small airways.7 The mechanism of death in asthma has not been defined and may be the end result of one of many factors. Acute hypoxemia is observed and perhaps associated with fatal cardiac arrhythmias. There are good

330 Kloustermeyer, Di Bernordo, and Hole

300

FEV ,

PEFcEN7

anlmol

200

loo

J. ALLERGY CLIN. IMMUNOI. MAY 1975

YIN 0 20 40 60 Do loo t20 140 . . ‘ ‘t

DDSE @WE 0.0373 0.075 0.11s 0.15 0.225 D.C.

FIG. 2. FEV, as per cent of control value at various isaproterenol infusion rates for

Patient C. L. (bg/kg/min).

data to suggest that profound disturbances of arterial blood gases may occur in asthma where clinically the degree of bronchosppasm does not appear to be severe?- !I

Patients in status asthmatieus invariably have hypoxemia, and inhaled isoproterenol may further decrease the arterial oxygen tension (Pao,) .I03 ‘I It is critical that hypoxemia must be corrected with a margin of safety prior to and then monitored during the isoproterenol infusion. Our data suggest that intravenous isoproterenol, while relieving airways obstruction, may worsen hypoxemia. When the infusion is diseuntiaued oxygenation must be continued, as the patient,% alveolar ventilation may diminish and Ppao, could decrease to an unacceptable level.

Arterial hypoxemia has bcwn reported as a side effect of intravenous isoprotcrenol used after cardiltc surgery.*2 The meeh%tnism may be inezq&l perfusion to poorly ventilated regions.‘” In the present study the akolar- arterial gradient widetied, probably by the latter me&thsnism. Isyp6xemia did

VOLUME 55 NUMBER 5

Intravenous isoproterenol 331

.oiY .5 . . . .

0 a71 .I00 .I25 .I¶0 .I75 .mo .m msl

msfutf

FIG. 3. Comparison of heart rate and FEV, as per cent of control values at various isoproterenol infusion rates. Data represent coincident measurements for both parameters

and are averaged for all patients (pg/kg/min).

not result from hypoventilation, as minute ventilation increased with a reduc- tion in arterial carbon dioxide tension ( Paoo,) (Tables I and II).

Animal studies indicate that cardiac toxicity from isoproterenol is enhanced in the face of hypoxemia.l* It has been established that a beta agonist (isoproterenol) may become an antagonist if given in excessive doses, so that a large dose of isoproterenol may result in a paradoxical response with con- striction of blood vessels and contraction of smooth muscle.15 In view of the potential toxicity it is advisable that intravenous isoproterenol be used for short-term therapy, i.e., less than a 6-hour period. In a recent study in children, however, intravenous isoproterenol has been used effectively in status asthmati- cus for prolonged periods up to 48 hours.16

The data suggest that intravenous isoproterenol is a safe and effective therapy for bronchial asthma when combined with adequate monitoring in an intensive care unit. The major advantage is the control of airway response with the prompt onset and offset of action. The rapid response time in this study correlates well with reported radioisotope clearance data in dogs that indicate a half-life of intravenous isoproterenol of less than 3 to 4 minutesl’

The response observed is not a placebo response, as each person served as

332 Klaustermeyer, Di Bernardo, and Hale J. ALLERGY CLIN. IMMUNOL. MAY 1975

-ns

m

50

M t MIN 0 50 4 50 00 tm I20 140

40

50

20

1-.

-l

lo

Do55Mt5 wm5 0.0505 O&95 0.05 0.15 0223 D.C.

FIG. 4. Partial pressure of arterial ( f ) and alveolar (*) oxygen tensions (kft ordinate)

at various isoproterenol infusion rates. Superimposed is the Aao2 gradient (0) bight

ordinate). Data are averaged fvr all patients (pg/kg/min).

his own control and D5W infusion had no effect. The dose-response curve indi- cated increasing response with an increased dose (Fig. 1) and abruptly termi- nated with D5W. In 4 patients in whom isoproterenol infusion was then restarted, bronchodilating effect occurred within 2 to 4 minutes.

The administration of isoproterenol by the intravenous route should be re- served for the severely obstructed asthmatic patient not responding to the usual aggressive therapeutic regimen including hydration, expectorants, antibiotics, bronchodilators (inhaled and parenteral) , and glucocortiooids. The technique of isoproterenol infusion requires a highly trained staff that can monitor and maintain a satisfactory blood pressure, cardiac rhythm, and arterial blood gas levels.

After the administration of parenteral corticosteroids to many pstients in status asthmaticus there is often a delay in onset of e&e&. In our expkence the use of intravenous isaproterenol while waSting for an initial response to cortico- steroids has obviated endotracheal intubation and as&ted ventila~on.

1 Lowell, F. C., Curry, J. J., +d &hi&r, I. W.: .A &tial and exnerirnentsl &adv oi Isuprel in spontaneous and %wMed ati, N. IE&t@. J. Bd

2 Ahlquist, R. P. : A soody of the admtotrupk ~se&@fm, Am. 3. Fyfi$ak& fpia: Bf@, N49.

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Intravenous isoproterenol 333

3 Van Metre, T. E.: Adverse effects of inhalation of excessive amounts of nebulized isoproterenol in status asthmaticus, J. ALLERGY 43: 101, 1969.

4 Keighley, J. F.: Iatrogenic asthma associated with adrenergic aerosols, Ann. Intern. Med. 65: 985, 1966.

5 Crompton, G. K.: A comparison of responses to bronchodilator drugs in chronic bronchitis and chronic asthma, Thorax 23: 46, 1968.

6 Dairs, D. J. : NIAID initiatives in allergy research, J. ALLERGY 49: 323, 1972. 7 Houston, J. C., Navasquez, S. A., and Trunce, J. R.: A clinical and pathologic study of

fatal cases of status asthmaticus, Thorax 8: 207, 1953. 8 Tai, E., and Read, J.: Blood-gas tensions in bronchial asthma, Lancet, p. 644, 1967. 9 Rees, H. A., Millar, J. S., and Donald, K. W.: A study of the clinical course and arterial

blood gas tensions of patients in status asthmaticus, Q. J. Med. 148: 541, 1968. 10 Knudson, R. J., and Constantine, H. P.: An effect of isoproterenol on ventilation-

perfusion in asthmatic versus normal subjects, J. Appl. Physiol. 22: 405, 1967. 11 Ingram, R. H., Krumpe, P. E., and Duffeugm, M. B. : Ventilation-perfusion changes after

aerosolized isoproterenol in asthma, Am. Rev. Respir. Dis. 101: 364, 1970. 12 Fordham, R. M., and Resnekov, L.: Arterial hypoxaemia, Thorax 23: 19,196s. 13 Dulfano, M. J.: Bronchodilators, pulmonary function, and asthma, Ann. Intern. Med. 68:

955, 1968. 14 Collins, J. M., McDevitt, D. F., Shanks, R. G., and Swanton, J. G.: The eardiotoxicity of

isoprenaline during hypoxia, Br. J. Pharmacol. 36: 35,196Q. 15 Butterworth, K. R.: The /3-adrenergic blocking and pressor actions of isoprenaline in the

cats, Br. J. Pharmacol. 21: 378, 1962. 16 Woods, D. W., Downes, J. J., Scheinkopf, H., and Leeks, H. I.: Intravenous isoproterenol

in the management of respiratory failure in childhood status asthmaticus, J. ALLERGY CLIN. IMMUNOL. 50: 75,1972.

17 Conway, W. D., Minatoya, H., Lands, A. M., and Shekosky, J. M.: Absorption and elimina- tion profile of isoproterenol. III, J. Pharm. Sci. 57: 1135, 1968.