Application of noninvasive techniques for measuring cardiac output in hypertensive patients

PART IV: THE MEASUREMENT

Application measuring patients

AND MANAGEMENT

of noninvasive cardiac output

OF HYPERTENSION

techniques for in hypertensive

The hemodynamic hallmark of hypertension is increased systemic vascular resistance, although this variable is usually not determined in hypertensive patients because it has generally required invasive procedures to measure cardiac output. Reliable, totally noninvasive methods are now available that measure cardiac output accurately enough under a variety of conditions, including rest, exercise, and pharmacologic interventions. These methods include echocardiography, Doppler echocardiography, CO? rebreathing, and impedance cardiography. Their serial application to large numbers of patlents offers the opportunity to eigniflcantly broaden our understanding of the spectrum and course of hemodynamic alterations associated with hypertension. A more complete knowledge of underlying hemodynamics could improve our diagnostic and prognostic accuracy in hypertensive patients and enhance our understanding of the pathophysiology of hypertension and the mechanism of action of antihypertensive interventions. (AM HEART J 1988; 118:850.)

Joseph A. Franciosa,

MD Wilmington,

Del.

Many factors contribute to the pathophysiology of hypertension, which can be defined hemodynamitally as the product of cardiac output and systemic vascular resistance. The hemodynamic hallmark of hypertension is an increase in systemic vascular resistance, even in those patients with elevated cardiac output, since the systemic vascular resistance may be viewed as inappropriately high for any given cardiac output in such cases.’ Using plasma renin activity as an indicator of systemic vascular resistance, hypertensive patients have been profiled as having exaggerated vasoconstriction with normal or reduced cardiac output and normal or increased cardiac output without vasoconstriction.2 The patients with increased systemic vascular resistance may be at greater risk for cardiovascular complications than hypertensive patients with normal systemic vascular resistance and normal or increased cardiac output.3 Our understanding of the hemodynamics of hypertension is based on sparse data. Until recently, measurement of cardiac output, which is required to calculate systemic vascular resistance, necessitated invasive procedures, which have become increasing-

From the Cardiovascular Section, Pennsylvania School of Medicine, Department, ICI Pharmaceuticals Reprint requests: ICI Pharmaceuticals

850

Department of Medicine, University of and the Clinical and Medical Affairs Group, ICI Americas Inc.

Joseph A. Franciosa, MD, Director, Cardiorenal Group, ICI Americas Inc., Wilmington, DE

Drugs, 19897.

ly difhcult to justify in patients with mild or asymptomatic disease, who make up most of the hypertensive population. Thus our hemodynamic data base has been limited predominantly to one-time measurements obtained invasively in hospitalized patients who are frequently atypical of the hypertensive population in general. Little is known about longitudinal changes in cardiac output in hypertensive patients, with or without treatment. Although the clinical relevance of measuring cardiac output in patients with hypertension is not fully understood, knowledge of cardiac output could be of considerable value in elucidating the pathophysiology of hypertension and the mechanism of action of therapeutic interventions. The ability to follow systemic vascular resistance, in addition to blood pressure, might also be of prognostic value. Several methods have been developed for measuring cardiac output by noninvasive techniques, and the possibility now exists for obtaining cardiac output easily and repeatedly in patients with hypertension to more fully characterize their hemodynamic status.4-8 NONINVASIVE OUTPUT

METHODS

FOR MEASURING

CARDIAC

~chneardinqmphyM-mde echocardiography can be used to measure cardiac output as the product of stroke volume and heart rate. Theoretically, this is physiologically sound, but the technique assumes that a single-dimensional view of left ventricular

Volume Numbw

116 2, Part 2

Noninvasive

ECHO 250 -

STROKE

VOLUME

measurement

of cardiac output

651

(ml/beat)

+ 200 -

+ +

150 -

+

CO2 REBREATHING STROKE VOLUME (r = -0.22. NS)

(ml/beat)

Fig. 1. Relationship between stroke volume determined noninvasively by M-mode echocardiography (ECHO) and carbon dioxide (CO& rebreathing in patients with congestive heart failure. T = coefficient of correlation; NS = not significant.

chamber diameter can be translated into an accurate calculation of three-dimensional ventricular volumes with the use of geometric models. The technique is notoriously invalidated by asymmetry of the left ventricle. Thus patients with asymmetric left ventricular hypertrophy, akinetic scars from previous myocardial damage, or abnormal wall motion in the region of the “ice-pick” echocardiographic view may yield erroneous results. Furthermore, considerable technical expertise is required to obtain good quality echocardiograms, and some patients with underlying pulmonary disease or chest deformities will not have an acceptable window for echocardiography. Finally, the technique is difbcult to apply and standardize during changes in posture or exercise because the window is difficult to obtain and maintain under these conditions. The actual experience with echocardiography in hypertensive patients has provided some useful information.’ In patients with heart failure, we compared stroke volume determined by M-mode echocardiography with that measured by CO, rebreathing, a noninvasive method previously validated in these patients9 We observed that M-mode echocardiography systematically overestimated the stroke volume (Fig. 1). Furthermore, when stroke volumes from these two different methods were used to calculate left ventricular ejection fraction (by means of left ventricular end-diastolic volume from the M-mode echocardiogram), the correlation with ejection fraction measured by standard radionuclide ventriculography was better with the CO, rebreathing method (Fig. 2). The use of Doppler echocardiography offers great-

er accuracy in measuring cardiac output.“” With this technique, flow velocity across the aortic valve can be measured. Simultaneous measurement of aortio root diameter permits conversion from flow velocity to volume flow. The method assumes constancy of aortic root diameter if this is measured only once, and this variable can be altered by physiologic variations.6 If aortic diameter is measured for each cardiac output determination, reproducibility and standardization of windows are assumed. The method is subject to the other problems of M-mode echocardiography; that is, it requires considerable technical expertise and is not readily applicable to changes in posture or physical activity.6*7 The actual experience with Doppler echocardiography in measuring cardiac output has been better than that with standard M-mode echocardiography; however, the variability in techniques has limited standardization of the methodology.6~6~‘0-‘3 Although Doppler methods are reasonably accurate, and they can detect acute changes in cardiac output induced by pharmacologic or physiologic interventions,7 satisfactory recordings may not be obtainable for 10% to 20% of patients.” Radionuclide angiography. Radionuclide angiography can also be used to measure stroke volume.15 Whereas this method has become a standard one for measuring ventricular volumes, it remains impractical for serial measurements of cardiac output. It is not a totally noninvasive technique since radioisotopes must be injected. In addition, it requires major equipment, space, and computer facilities, resulting in high cost and limited availability. Finally, it cannot be easily repeated over short durations

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0

20

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I

100

2. Relationship between left ventricular ejection fraction (LVEF) measured by standard radionuclide angiography and by totally noninvasive techniques in patients with congestive heart failure. The totally noninvasive methods used were M-mode echocardiography (ECHO) to measure left ventricular end-diastolic volume and stroke volume (upper panel) or ECHO end-diastolic volume and stroke volume by CO, rebreathing (CORB) (Lower panel). NS = not significant; p = probability;

Fig.

r = coefficient of correlation.

because of radioactivity exposure and half-life limitations of isotopes, and it has not yielded consistently accurate results during exercise in hypertensive patients.1s Expired gas methods. Various technique that involve collection of expired gases after inhalation of -no-

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measure cardiac output. The CO, rebreathing method has been the one most widely evaluated and most commonly used. ’ -g*17-1g This method does not involve any new principles, since it simply represents an

indirect application of the long-established Fick procedure. Arterial and mixed venous CO, contents are estimated from expired gases to yield values that correlate closely with directly measured ones.& z”*21 The equipment required is simple and readily available commercially so that cardiac output measurements are relatively inexpensive. The method can be easily applied totally noninvasively and repeatedly to patients who are required only to breathe normally. The only discomfort involved is minimal and related to application of a face mask or nose clips to

vohlm* Numbu

116 2, Pari 2

enable collection of all expired air. The technical expertise needed is well within the skills of inhalation therapists and other cardiopulmonary laboratory technicians. The CO, rebreathing method has yielded very good correlations with standard invasive methods for measuring cardiac output in a variety of patients without requiring use of any correction for systematic errors.4 g*17-1gThe actual technique does not affect hemodynamics and is reliable at the extremes of cardiac output. It reliably detects changes caused by drugs, posture, or physical activity.7ee,22 However, because this method requires relatively preserved pulmonary function, it becomes unreliable in the presence of lung disease associated with significant ventilatory dysfunction, especially hypercapnia.Esg Other noninvasive methods. A newer method for measuring cardiac output is impedance cardiography, which involves new principles and assumptions for estimating blood flow as a function of the body’s electrical conductivity. 23 This method, which is described in greater detail elsewhere at this conference, has been associated in the past with a systematic error requiring the use of a correction factor to reliably estimate cardiac output, but better results have been obtained in recent years.24 Actual experience with impedance cardiography is still very limited, and the method should continue to be viewed as one still in development. Cardiac output can also be measured noninvasively by earpiece densitometry, but results with this method have not correlated well with invasive ones.% The Ideal nonlnvaslve method. Ideally, a noninvasive cardiac output method should yield accurate, reproducible results when compared with standard invasive methods such as indicator dye-dilution or direct Fick procedures in a variety of patients under varying conditions of posture and physical activity. The technique should be easily applied to patients without requiring special training or effort and without producing any discomfort. It should also require minimal technical expertise, use easily moveable equipment, and be inexpensive. The method should be easily repeatable for serial measurements of cardiac output. Of the methods previously described, the CO, rebreathing technique appears to satisfy these criteria most closely at present, and impedance cardiography may become an ideal method as it is further developed. The availability of an ideal, noninvasive method for measuring cardiac output offers important advantages over invasive techniques. In addition to less cost and patient discomfort, the most important advantage offered is the ability to perform serial

Noninvasive

measurement

of

cardiac output

653

measurements of cardiac output over both short and long intervals in large numbers of patients. In this way, the effect of single, aberrant measurements, which occur even with standard invasive methods, would be minimized. Thus a large data base of hemodynamic information would become available, thereby eliminating the need to extrapolate so much from the limited data currently available. APPUCATIONS METHODS

OF NONlNVASlVE

CARDIAC

OUTPUT

The availability of reliable noninvasive methods for measuring cardiac output provides the opportunity to obtain information that has not been readily available from invasive methods. The following section reviews examples of how noninvasive methods have been or might be used to yield useful new information that would otherwise be difficult, if not impossible, to obtain from invasive methods. Mechanism of action of antihypertensive drugs. The way in which most antihypertensive agents reduce blood pressure remains unknown. Virtually all antihypertensive drugs affect hemodynamics, but how these hemodynamic responses relate to blood pressure reduction may not always be fully understood. The antihypertensive action of /3-adrenergic blockers is not yet known. It has been presumed that reduction in cardiac output plays an important role in the mode of action, but how this occurs is unclear, since cardiac output falls within minutes after a first effective dose of a B-blocker, whereas the decrease in blood pressure does not become apparent until many hours later.26-29 Because cardiac output falls proportionately more than blood pressure does acutely after a &blocker, systemic vascular resistance increases. However, these hemodynamic responses occur after the first dose, and very little long-term data are available. One study showed that during long-term treatment with propranolol, blood pressure remains reduced, but cardiac output, although still significantly below baseline, rises some so that systemic vascular resistance returns toward baseline.% Thus the view that &blockers increase or do not lower systemic vascular resistance is based almost exclusively on short-term, first-dose observations and reflects a practical limitation imposed by the invasive methodology required in these earlier studies. Using the CO, rebreathing method to measure cardiac output before and 1 hour after each daily dose of atenolol for 5 days, we confirmed the early fall in cardiac output with a later fall in blood pressure. However, we observed a biphasic response of cardiac output, which returned toward control

654

Franciosa

American

August 1998 Heart Journal

46 CHANGE

-30

1 0

1

2 TIME AFTER

3

ATENOLOL

4

(days)

3. Sequential hemodynamic changes during administration of atenolol to patients with hypertension using noninvasive methods to measure mean arterial pressure (MAP) and cardiac output (CO). SVR = systemic vascular resistance. Note biphasic course of changesin CO. Fig.

level, whereas blood pressure did not fall until later, almost 24 hours after the first dose (Fig. 3). When blood pressure actually fell, systemic vascular resistance was unchanged.% Over subsequent days, cardiac output tended to fall again whereas blood pressure remained reduced. Thus without the availability of repeated daily cardiac output measurements, the results would have been entirely consistent with the propranolol experience, suggesting an early and sustained reduction of cardiac output. However, with serial noninvasive cardiac output measurements, it was possible to demonstrate an early return of cardiac output toward baseline. This suggested vasodilation, which was caused by total body autoregulation in response to the acute fall in cardiac output, as a mechanism for the initial antihypertensive action of atenolol. Noninvasive cardiac output measurements may also be of value in explaining the mechanism of adverse effects of ~-blocking drugs. Fatigue is a well-known side effect of B-blocker therapy and has been attributed to central nervous system effects or reduced aerobic exercise capacity from limited cardiac output response. Using noninvasive cardiac output measurements serially at rest and during exercise in patients with mild asymptomatic hypertension, we have shown that propranolol reduces maximal oxygen uptake and exercise cardiac output, whereas these variables are unaffected by oxpreno101, a D-blocker with intrinsic sympathomimetic activity.30 Fatigue was more common with proprano101 and was associated with reduced exercise capacity. Thus the availability of an easily applied cardiac

output measurement during exercise enabled acquisition of data to suggest a mechanism for a side effect and a potential advantage of one B-blocking drug over another. It would have been extremely difficult to obtain patient or institutional review board approval to do such a study with repeated invasive methods during exercise in this patient population. The antihypertensive mechanism of action of many other drugs is also incompletely understood because hemodynamic measurements have been limited largely to acute changes after single doses in few patients; therefore little serial longitudinal data are available. For example, diuretics lower plasma volume and cardiac output short-term, suggesting this as their mechanism of action. However, their maximal antihypertensive effect may be considerably delayed until a time when plasma volume and cardiac output are only minimally or not at all reduced, but systemic vascular resistance has fallens1 These observations of a major widely used class of drugs are based on very few studies and small numbers of patients .lm3* Similar sparse data bases also limit our understanding of the mode of action of other agents such as prasosin, clonidine, and (Ymethyldopa.’ Our knowledge of the mode of action of nonpharmacologic interventions for lowering blood pressure could also be markedly enhanced with the addition of more complete hemodynamic data. Such data are difficult to obtain in patients treated by these interventions because they usually have mild asymptomatic disease and invasive procedures are difficult to justify in this setting.

vo6mm Number

116 2, Part 2

Pathophysiology of hypertension. Cardiac output is generally thought to be normal in most hypertensive patients, but it varies with age, being higher in young patients and falling with age. Thus systemic vascular resistance rises progressively. However, these observations are based almost entirely on single measurements from cross-sectional studies, and very little data from longitudinal studies in the same patients are available. Indeed, numerous conflicting results are reported.’ Noninvasive cardiac output measurement permit acquisition of longitudinal data. It is unclear whether cardiac output falls with aging alone or if this is part of the hypertensive process independent of age. Serial studies in hypertensive and normotensive persons are needed to resolve this issue. Other areas of conflicting evidence persist. Invasive cardiac output has been used to demonstrate the existence of a population with early, labile hypertension characterized by a hyperdynamic circulation. 32 Others have questioned this observation, citing the need for repeat studies in the same patients to see if they truly represent a population destined to develop fixed hypertension. Knowledge of serial changes in systemic vascular resistance might be more useful in detecting and tracking a prehypertensive state in early, labile hypertensive patients as well as in children and adolescents. Blood pressure is now frequently monitored by ambulatory techniques, which have demonstrated that hypertensive patients often have long periods Knowledge of concomitant of normotension.33 changes in cardiac output and systemic vascular resistance would greatly enhance our understanding of the mechanisms responsible for such blood pressure 5uctuations. Prognostic applications. It is not known if increased cardiac output and elevation of systemic vascular resistance as underlying hemodynamic factors have the same significance as blood pressure in terms of risks to hypertensive patients. Increased systemic vascular resistance could indicate high levels of circulating catecholamines or plasma renin activity. It has been suggested that hypertensive patients with high plasma renin activity may be at greater risk of cardiovascular complications.2*3 Furthermore, increased plasma catecholamine levels and higher systemic vascular resistance correlate with reduced survival rates in patients with congestive heart failure.“s36 The effect of antihypertensive therapy in preventing morbidity and mortality from hypertension is well known, and greater emphasis is now placed on treating hypertension earlier when blood pressure is

Noninvasive

measurement

of cardiac output

655

only mildly elevated. Therefore larger numbers of asymptomatic patients are exposed to potentially harmful treatments because, using blood pressure measurements alone, we are unable to reliably identify those few hypertensive patients truly at risk. Noninvasive cardiac output techniques offer the possibility of determining systemic vascular resistance along with blood pressure in large numbers of patients repeatedly over time to see if these additional hemodynamic data offer greater prognostic accuracy. CONCLUSIONS

Adequate totally noninvasive methods now exist for measuring cardiac output and calculating systemic vascular resistance so that these data may be obtained serially over long periods of time in large numbers of patients. This ability offers great potential to investigators and clinicians to enhance our understanding of the pathophysiology of hypertension, assess the mode of action and efficacy of new treatments, and increase diagnostic and prognostic accuracy. However, a word of caution is in order since the knowledge of cardiac output may not always provide useful new information. Although measurement of cardiac output is valuable in situations characterized by acute hemodynamic derangement such as acute myocardial infarction with pump failure, knowledge of cardiac output in chronic conditions such as congestive heart failure has not been so helpful. Cardiac output is influenced by many factors other than intrinsic cardiac performance, and cardiac output measurements have been of little value in assessing symptomatic status or responses to treatment in patients with heart failure.96*37 On the other hand, cardiac output has prognostic value in these same patients in whom lower cardiac outputs are associated with higher mortality rates. 36 Thus it is not certain that broadening our data base of hemodynamic measurements in hypertension will add significantly to our current knowledge. However, at worst we would learn the value of such measurements. Because the ability to acquire this knowledge is now readily available and the potential value is so great, investigators and clinicians should make more extensive use of noninvasive cardiac output techniques. REFERENCES

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