Oscillatory hyperventilation in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy

OscillatoryHyperventilationin SevereCongestive Heart FailureSecondaryto IdiopathicDilated Cardiomyopathy or to IschemicCardiomyopathy CYNTHIA B. KREMSER, MD, MICHAEL F. O’TOOLE, MD, and ALAN R. LEFF, MD

Thirty-one subjects with chronic congestive heart failure (CHF) were separated into 3 groups according to ventilatory patterns during graded exercise: Group l-osoillators (n = 6); group P-intermedlate oscillators (n = 14); and group 3-nonoscillators (n = 11). Group 1 patients showed cyclic fluctuations in minute ventilation (change of 30 to 40 ffters/min) and arterial PCs (change of 36.0 f 4.1 mm Hg) and PCOl (change of 11 f 2.6 mm Hg). The nadir in arterial PCs occurred at times when wasted ventilatory effort was maximal. The amplitude of ventilatory oscillatfons fn group 1 patients increased In the transition from rest to 6gM exercise and damped with heavy exercise. There was no ev-

klence of afveolar hypoventilatlon at the nadirs of minute ventilation; arterial PC02 was always 40 mm Hg or less. Substantial hyperventilatfon (ventilatory equfvalent for Cop twke normal) occurred with maximal minute ventilation in group 1 patients. OScillatory hyperventilation correlated with severity of CHF. Maximal oxygen uptake was slgnffkantly lower in group 1 (11.7 f 1.1 ml/kg/min) than group 3 (17.9 f 1.6 ml/kg/min) (p
E

Methods

From the Sections of Pulmonary and Critical Care Medicine, Cardiology and General Internal Medicine, and the Committee on Clinical Pharmacology, Division of the Biological Sciences, University of Chicago, Chicago, Illinois. This study was supported by Grant HL-01398, from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Manuscript received September 17, 1988; revised manuscript received November 10, 1986, accepted November 11,1986. Address for reprints: Alan Leff, MD, Box 98, Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637.

Patients: Cardiopulmonaryexercisetestswere performed on 63 consecutivesubjectswith chronic, dilated cardiomyopathyduring a %)-monthperiod (January 1983 through June 1985). Subjects were excluded if they had evidence of a ventilatory limitation to exercise,basedon a breathingreserveof lessthan 15liters. Subjects also were excluded from the test if graphic breath-by-breathgasexchangedatawere unavailable, technical difficulties were encounteredduring testing, or the patient would not cooperate adequately for testing. Thirty-one patients(27 men, 4 women) met criteria for inclusion in this study. Ages ranged from 20 to 71 years (mean 53). All patients were New York Heart Associationfunctional class II, III or IV, and all had evidenceof left ventricular dysfunction by echocardiography(mean left ventricular end-systolicdiameter 5.6 f 0.2 cm], left ventricular angiography(meanejection fraction 26 f 2.3%) or routine chest films (cardiothoracicratio greaterthan 0.5with cephalizationof blood flow). CHF was attributed to coronary artery diseasein 15 patientsand idiopathic dilated cardiomy opathy in 16. All patientshad stable symptoms for at

xercise intolerance in patients with congestive heart failure (CHF) has been attributed to inability of the cardiovascularsystemto deliver oxygento tissues with increasedmetabolic demands.1-4 Although a mild restrictive pulmonary defect has been found at rest5 and during exerciseI.2in patientswith CHF, the respiratory systemis not believed to contribute substantially to the limitation of aerobiccapacityin thesepatients. We describea subsetof patientswith ischemic or idiopathic dilated cardiomyopathywho had an oscillatory pattern of hyperventilation during exercise.

April 1.1987

least 2 months before study. Drug therapy was withheld beginning midnight before the test. Twelve normal subjects(9 men, 3 women] without symptomatic evidence or a history of systemichypertension or cardiovascular or pulmonary diseasealso were tested.Agesrangedfrom 30to 65years(mean43). Three were cigarettesmokers,10were sedentaryand 2 engagedin regular aerobic exerciseprograms. Exercise protocols: Exercise testswere performed after a 2-hour fast. Subjects were seatedon an electronically brakedcycle ergometer(Minjhardt KEM-2). which maintained externally applied workloads with pedaling rates of 20to 100rpm. After baseline values were measuredthe flywheel was startedmanually and all subjectsthen performed 3 or 4 minutes of unloaded cycling. The workload was then increasedeither continuously or at l-minute intervals until the subjects could not continue becauseof dyspneaor fatigue.The rate of increasewas 6 to 10 W/min in subjects with heart failure and 15 to 25 W/min in normal subjects. One subject also performed steady-stateexerciseat a workload of 15 W for 10 minutes. Restspirometric data were obtained in 21 subjects using the 6-liter volume-displacement, water-sealed spirometer (Warren E. Collins). Gas exchange: Subjects breathed into a mouthpiece equipped with a 2-way nonrebreathing valve (Rudolph)with a dead spaceof 95ml. Expired air was directed through a condensationchamber to a heated pneumotachograph(Rudolph) equipped with a variable reluctancepressuretransducer(Validyne DP250). Volume measurementwas calibrated againsta standardized pulsatile flow before each test.Inspired and expired air was siphoned off at the mouthpiece at a rate of 1,200ml/min to measure02 and CO2content. This volume was excluded in the calculation of gas flows. Oxygen content was measuredby a solid-state zirconium cell accurateto within 0.01%(Applied Electrochemistry).Carbon dioxide content was measured by an infrared absorptionanalyzer accurateto within 0.2% (NormocapCD-102,Datex Corp.).The analyzers were calibrated againsta known standardcertified to within 0.02% (Medical Graphics Corp.) before each test. The analog data for flow, 02 and COZcontent and time were digitized and fed into a host computer(Tektronix 4050)which provided breath-by-breathand 3Osecondaverageddata for respiratory frequency,total volume, minute ventilation, end-tidal POZand PC02, minute 02 uptake and CO2output and their respective ventilatory equivalents.Breathswith a tidal volume of lessthan 250ml were not analyzed.Predictedmaximal O2uptake was calculatedusing the method of Hansen et a16to account for intersubject differences in age, gender and body size. Arterial blood gaslevels were measuredduring exercise using an indwelling cannula inserted into the radial artery.During the last 20secondsof eachminute during the test,a volume of fluid in excessof the dead spacewas withdrawn from the tubing and discarded. A l-ml sample of blood then waswithdrawn for analysis. The cannula was flushed with heparinized saline

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solution after each sample was taken. Analysis was performed with a Corning 175pH/blood gas system. Graphic breath-by-breathdatafor end-tidal COavs time were evaluatedin single-blind fashion by 5 observersunaware of the project design. Subjectswere assignedto 1 of 3 groups according to the following criteria: group 1 (ventilatory oscillators)-subjects showing ventilatory oscillations lasting longer than 66% of the exerciseprotocol, with an amplitude more than 15% of the averagevalue at rest;group 2 (intermediate oscillators)-ventilatory oscillationsof inadequateduration or amplitude to qualify asgroup 1; and group 3 (nonoscillators)-no ventilatory oscillations at rest or during exercise. Statisticalcomparisonof differencesin maximal O2 consumption, ventilatory equivalent for COZ,breathing reserve and spirometric data among groups was performed using l-way analysis of variance. When a significant F ratio was achieved, t testswith the Bonferroni correction’ were usedfor further comparisons. Minimal significance required p <605/n, where n is the number of comparisons performed. Values are mean f standard error.

Results Six patients were classified as ventilatory oscillators (groupl), 14 as intermediate oscillators (groupZ), and 11 as nonoscillators(group3).Figure 1 shows the ventilatory patternsat rest, during unloaded exercise and during progressiveexternalwork for the 6 subjects in group 1. All group 1 subjectsshowedoscillations in minute ventilation at rest.Rangein amplitude of minute ventilation was 5 to 30 liters/min. In 1 subject (Fig. 1C) periods of apnea occurred at rest. No apneawas seen in the other subjects;all had minimal tidal volumes above 250ml. During unloadedcycling the amplitude of the oscillations in minute ventilation increasedfrom 11.7f 3.5 liters/min (rest)to 24.0i 4.6liters/min (p <0.02).In 1 group 1 patient (Fig. 1A) the amplitude of oscillation was greatestat rest;in 5 group 1 subjects,amplitude of oscillation increasedwith unloadedpedaling.No subject had apneaduring unloadedcycling. With increasing external work, all group 1 subjects showed progressivedamping of ventilatory oscillations. Figure 2 showsthe ventilatory patternduring steady-state,lowlevel exercise(15W) in another patient from group 1. The increased amplitude of the ventilatory oscillations, stimulated by light exercise, did not dampen spontaneouslyover time. Arterial blood gas analysis in 4 group 1 subjects revealedcyclic fluctuation in PO2(decreaseof 36f 4.1 mm Hg) and PCOZ(increaseof 11 2.6mm Hg) (Fig. 1). Differencesin sampling frequencyprecludedcomparison of phaseduration betweenminute ventilation and arterial blood gas pressures.However, when PC02 was high, minute ventilation also increasedand PO2 was low. Cycle amplitude diminished as exercise intensified. Alveolar hypoventilation did not occur in any group 1 subject, even at the nadir of the ventilatory

902

OSCILLATORY

HYPERVENTILATION

IN SEVERE

HEART

FAILURE

TIME (se3

TIME (se3

TIME (sed

FIGURE 1. Arterial blood gases, minute ventllatlon (iE), ventllatory equivalent for carbon dioxide productlon (GE/irCO& and partlar pressure of end-tidal carbon dloxlde concentration (PETCO1) at rest, unloaded exercise, and progressive external work In the 6 subJects from group 1. Each polnt represents the results of a single breath. Each number presents the mean of the data for the last 30 seconds of a l-

cycles.Minimal values for the ventilatory equivalent for CO2 in group 1 at rest (47 & 561and unloaded cycling 38 f 2] were similar to thosein groups2 and 3 and in normal subjects(Fig.3).There was no elevation

s I5

1

REST

II

II

II

I

( II

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(

I

I

I

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11

I200

Timfkx) FIGURE 2. End-tidal carbon dloxlde concentration (PETCO*) at rest and during steady-state exercise at 15 W In the same subjects as In Flgure 1. The amplitude of oscillations Increases at the onset of exercise and does not dampen over time. WL = workload, In watts.

of arterial or end-tidal COz at any point during the exerciseroutines(Fig. 1).At the peaksof the cycles,the hyperventilation in group 1 was substantial;maximal ventilatory equivalent for COz at rest (93 f 10) and during unloadedcycling (83f 7)was more than twice the correspondingvalues in normal subjects (40 f 3 and 30 f 1, respectively,p
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minute interval. Cyclic fluctuations occur in all variables. With the exception of patient A, cycle amplitude increases at exercise subjects show damping of oscillations in severe exercise. When PC02 is high VE is high and POP is low. No subject had eievatlon PCO, or PETC02. BTPS = body temperature and pressure, saturated.

TABLE

I

Rest

Spirometric

Data

Group 1 (n = 4) l

Group

.

Group

1 (Peak) 1 (Trough)

90 80 mN < 8

60.

.>”

50.

903

FVC (% predicted) FE’/, (% predicted) FEV,/FVC X 100 (actual) FEV,/FVC (% predicted) WV (% predicted)

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with 2

(n = 10)

onset. Ail of arterial

Heart

Failure

Group

3

(n = 7)

F

66 *

10

74 f

3

87 f

9

NS

75 l

10

76 f

4

85 f

7

NS

83 f

2

75 f

3

72 f

3

NS

114 f

5

102 f

4

79zk

11

80 f

4

99 f 96f

FEV, = forced expiratory volume in 1 second; FVC = forced ty; MVV = maximal voluntary ventilation; NS = not significant.

5

NS

11

NS

vital capaci-

40.

&ST

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MA&AL EXERCISE

FIGURE 3. Ventiiatory equivalent for CO* production (VE/VCO,) at rest, unloaded cycling and peak exercise in normal subjects and heart failure groups 1, 2 and 3. Both peak and trough values of VE&OI are shown for group 1. At its nadir, VE/VCO* in group 1 is similar to that in ail other groups (difference not significant). At its peak, VE/VCOr in group 1 is more than twice as high as corresponding values in normal subjects. ‘p
904

OSCILLATORY

HYPERVENTILATION

IN SEVERE

HEART

FAILURE

ventilation among any of the groups. Breathing reserve also was similar for all groups. The ratio of maximal minute ventilation to maximal voluntary ventilation (estimated by 40 times the forced expiratory volume in 1 second) was 0.60 f 0.06 in group 1, 0.48 f 0.04 in

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FIGURE 4. Minute oxygen in all subjects with heart

uptake fallure.

I GROUP2

I GROUP

at maximal ‘p
3

exercise (+O, max) group 1 vs group 3.

In

100 -

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FIGURE 5. Minute oxygen uptake at maximal percent of predicted value, In all subjects CO.05, group 1 vs group 3.

group 2, 0.51 f 0.05 in group 3, and 0.63 f 0.08 in normal persons. None of these groups differed significantly from each other. Maximal 02 consumption was significantly higher in normal study subjects (32.2 f 3.8 ml/kg/min, 100 f 12% predicted) than in all other groups (p
GROUP

3

exercise (i0, max), wlth heart failure. ‘p

We have identified a subset of patients with severe heart failure who demonstrate an oscillatory pattern of hyperventilation during exercise. In most instances the oscillatory abnormality is exaggerated during lowlevel exercise and diminishes with severe exercise. This pattern of oscillatory hyperventilation may be associated with cyclic decreases in arterial PO2 that can compound the difficulty in peripheral O2 delivery by the failing heart. Oscillatory ventilation is not associated with alveolar hypoventilation. The appearance of oscillatory hyperventilation predicts severe functional incapacitation (Fig. 4 and 5). Weber et al2 noted that as maximal O2 consumption declined in chronic heart failure, minute ventilation became higher for any level of COZ excretion during exercise. This finding is reproduced in our series (Fig. 3 and 4). In addition, we have noted that subjects with oscillatory hyperventilation show cyclic fluctuations in minute ventilation. At the nadir of the ventilatory cycles, level of ventilatory equivalents for COa resemble those seen in our normal subjects, and those reported in a larger series by Hansen et a1.6 At the peaks of the cycles, values of ventilatory equivalents for CO;! among group 1 subjects are markedly higher than those in normal subjects or in CHF subjects without oscillatory hyperventilation. This wasted ventilatory effort is apparent at all levels of exercise (Fig. 3). Alveolar hypoventilation did not occur during exercise even at the nadir of ventilatory cycles in group 1 patients [Fig. 1). This has also been noted during the evaluation of Cheyne-Stokes respiration at rest*; after periods of apnea, arterial PC02 never exceeds the normal range. Arterial POa varied in a cyclic fashion during exercise in patients with oscillatory hyperventilation. The decrease in PO2 occurred at times when wasted ventilatory effort was high, compounding the inadequacy of O2 delivery by the failing heart. The origin of the cyclic hypoxemia noted in our patients remains unexplained. Potential causes include either fluctuating

April

ventilation/perfusion mismatching or transient rightto-left pulmonary or intracardiac shunting. Maximal O2 consumption is the best objective measure of the functional impairment caused by CHF.g We have observed that ventilator-y oscillations occur in patients with the most severe functional cardiac impairment (group 1, maximal O2 consumption less than 50% of predicted values for all patients [Fig. 41). In contrast, oscillatory hyperventilation is not seen in patients (group 3) with lesser degrees of CHF as quantitated by maximal O2 consumption. Acknowledgment: We are grateful to Theodore Karrison, Research Associate (Assistant Professor), Department of Medicine, for his help in the statistical design of this study. We thank Nancy Trojan for typing the manuscript.

1, 1987

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References 1. Weber KT. Janicki. Cardiopulmonary exercise testing for evaluation of chronic cardiac failure. Am J Cardiol 1985;55:22A41A. 2. Weber KT, Kinasewitz GT, Janicki JS. Oxygen utilization and ventilation during exercise in patients with chronic cardiac failure. Circulation 1982; 65:1213-1223. 3. Wasserman K, Whipp BJ. Exercise physiology in health and disease. Am Rev Respir

Dis 1975;112:219-249.

4. Weber KT, Janicki JS. Pathophysiologic responses to exercise in patients with chronic cardiac failure. Heart Failure 1985;1:131-139. 5. Rubin SA, Brown HV. Ventilation and gas exchange during exercise in severe chronic heart failure. Am Rev Respir Dis 1984;129:563-S64. 6. Hansen IE. Sue DY. Wasserman K. Predicted values for clinical exercise testing. Am Rev Respb Dis 1984;129:S49-555. 7. Wallenstein S, Zucker CL, Fleiss JL. Some statistical methods useful in circulation research. Circ Res 1980;47:1-9. 8. Morse SR, Chandrasekhar AJ, Cugell DW. Cheyne-Stokes respiration redefined. Chest 1974;66:345-346. 9. Franciosa JA, Ziesche SA, Wilen M. Functional capacity of patients with chronic left ventricular failure. Relationship of bicycle exercise performance to clinical and hemodynamic characterization. Am J Med 1979;67:480-466.