Concise Denitive Review

Series Editor, Jonathan E. Sevransky, MD, MHS

The ups and downs of heart rate

Sheldon A. Magder, MD
Objective: To review the physiology of the regulation and determinants of heart rate and the signicance in the management of critically ill patients. Data Sources: The MEDLINE database, references from selected articles, and the authors personal database. Data Synthesis: This review begins with the regulation of cardiac output and heart rate during exercise because this demonstrates the range of physiological responses in the normal human. This analysis shows that change in heart rate is a major component of the cardiovascular systems ability to adjust cardiac output and a number of regulatory systems control heart rate. When heart rate responses are limited because of disease or pharmacologic reasons, changes in stroke volume must compensate, but the capacity to do so is limited by the passive lling characteristics of the ventricles. On the other side, high heart rates increase myocardial oxygen demand, which can be a problem in patients with xed coronary artery disease. Conclusion: Heart rate must be interpreted in the context of the patients overall hemodynamic condition. The prudent physician must ask why is the heart rate high, what will be achieved by lowering the heart rate, and, nally, what are the consequences of lowering the heart rate? (Crit Care Med 2012; 40:239 245) KEY WORDS: cardiac output; end-diastolic volume; end-systolic volume; oxygen consumption; stroke volume

eart rate is measured in almost every hospitalized patient and certainly in all those who are critically ill. It is easily and accurately measured with simple technology and high and low values are warning signs of underlying pathology. Despite its widespread measurement regulation of heart rate and the physiological implications of high and low, heart rates are complex and not always fully appreciated. However, proper interpretation of heart rate values and determination of the appropriate clinical responses require an understanding of the physiological implications of high and low heart rates.

Regulation of Cardiac Output

Basic functions of the circulatory system are to deliver oxygen and nutrients to tissues and to remove waste products of metabolism. These functions are dependent on the volume per minute of blood that moves through the vascular system as indicated by the cardiac output.

From the McGill University Health Centre, Montreal, Quebec, Canada. The author has not disclosed any potential conicts of interest. For information regarding this article, E-mail: sheldon.magder@muhc.mcgill.ca; sheldon.magder@ mcgill.ca Copyright 2012 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e318232e50c

Cardiac output is equal to the product of beats per minute (heart rate) and the output per beat (stroke volume) and normally is tightly regulated by metabolic demands of the body. This tight relationship is seen dramatically during aerobic exercise (Fig. 1). When a subject exercises on a cycle ergometer in which the workload progressively increases, consumption of oxygen (VO2), an indicator of aerobic metabolism, increases linearly with the increase in workload (1). The relationship is so tight that VO2 even can be used to calibrate the workload on the cycle ergometer. The rise in VO2 is matched by a linear increase in cardiac output (Fig. 1B) so that in a normal person, cardiac output can be estimated to within 5% to 10% from knowledge of the VO2 (2). This relationship of cardiac output to VO2 even is true whether a subject exercises legs or arms (2). However, maximum cardiac output and VO2 are higher with leg exercise than arm exercise because of the larger muscle mass. This tight relationship of cardiac output to VO2 even holds true in regional muscles; for example, coronary blood ow increases linearly with increases in myocardial oxygen consumption. Heart rate, too, increases almost linearly with the work load and VO2 (Fig. 2). However, the relationship of heart rate to VO2 is different from that of cardiac output (2). The maximum heart rate in an individual is the same at the aerobic limit of arm or leg exercise, although maxi-

mum VO2 is greater for leg exercise than arm exercise (Fig. 2). Because the peak heart rate with arm exercise occurs at a lower maximal VO2, heart rate must rise faster during arm exercise than leg exercise. Similarly, heart rate at any workload is higher in an unt person than in a t person because each workload is a greater percentage of the unt persons capacity but the maximum heart rates are similar. Heart rate is also higher at any workload in the average female compared with the average male because average maximum VO2 is higher in males than females as a result of the larger muscle mass in males (3). However, if workload is normalized to the maximum capacity for the muscle group, heart rate at a percent of that maximum capacity is the same with any muscle group or body size (2). This indicates that heart rate is regulated by the relative workload, that is, workload as a percent of the workload at maximum aerobic capacity of the muscle group, whereas cardiac output is regulated by the absolute workload regardless of the capacity of the muscles. Because cardiac output is regulated by absolute workload and heart rate by relative workload, and cardiac output is the product of heart rate and stroke volume, it becomes evident that during exercise, stroke volume normally is a derived variable and is not independently regulated. As a consequence of these principles, at a given workload, stroke volume is smaller and heart rate higher with arm exercise than
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with leg exercise and in exercising women than in men. The relationship of heart rate to the relative workload can be used to estimate the relative workload during exercise. For aerobic training, it often is recommended that the exercise be maintained at approximately 70% of ones aerobic capacity for 20 mins (3). This level of exercise easily can be estimated by determining if heart rate is approximately 70% of the persons maximum. Although heart rate increases with the increase in cardiac output during exercise, the increase in cardiac output should not be thought of as simply being the result of the increase in heart rate. Cardiac output is determined by the interaction of two functions: 1) cardiac function, which is determined by heart rate as well as contractility, afterload and preload; and 2) return function, which is determined by stressed vascular volume, venous compliance, the resistances draining the venous compliant regions, and the outow pressure, which is the right atrial pressure (4, 5). For cardiac output to go from 5 L/min at rest to 25 L/min, there needs to be dramatic increases in both cardiac and return functions (6) and these increases are related to the metabolic needs of the tissues as discussed previously. It is quite striking that after an initial increase in right atrial pressure at the start of exercise, there is almost no change in right atrial pressure even with two- to vefold increases in cardiac output indicating that increases in cardiac and return function are almost perfectly matched by the regulatory mechanism (7). There are some important limits to the cardiac and return functions. When pressure inside oppy veins is less than the pressure outside veins, veins collapse and produce what has been called a vascular waterfall (8). When veins are collapsed, an increase in heart rate does not result in an increase in cardiac output because inow to the heart does not change; however, there is a decrease in stroke volume. This is not an issue during exercise because return of blood increases and matches the increase in pump function (as long as blood volume is adequate). However, in patients ventilated with positive pressure, the cardiac function not infrequently operates on the plateau of the venous return curve because pleural pressure is higher than atmospheric pressure (Fig. 3A) (9). When this occurs, an increase in heart rate will decrease stroke volume and a decrease in
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Figure 1. Schematic plots of the linear relationship between consumption of oxygen (VO2) and aerobic work and VO2 and cardiac output. When hemoglobin is normal, the VO2 at a given workload and cardiac output at a given VO2 are the same whether the person is large or small or whether the exercise uses arms, legs, or both.

Figure 2. Schematic plot indicating the linear relationship of change in heart rate (HR) with increases in consumption of oxygen (VO2). Unlike the change in cardiac output vs. VO2 (Fig. 1), the change in HR is related to the relative workload, which is the percentage of maximum for that muscle. Maximum HR for arm and leg exercise is the same but the aerobic capacity (VO2max) of arms is smaller than legs as a result of the smaller muscle mass.

Figure 3. Venous return cardiac function plot with change in heart rate in (A) when venous return is limited and (B) when cardiac function is limited. In this example, right atrial pressure is less than pleural pressure (e.g., patient with positive end-expiratory pressure). The cardiac function curve in this case intersects the plateau of the venous return curve so that an increase in heart rate decreases stroke volume but does not change Q. In B, a shift to the right of the venous return curve does not increase Q. Increasing heart rate shifts the cardiac function curve upward and increases Q but the stroke volume likely decreases (end-diastolic pressure decreases). Q, Flow (cardiac output or venous return); PRA, right atrial pressure; HR, heart rate, Ppl, pleural pressure.

heart rate will increase stroke volume without changes in cardiac output and without changes in cardiac function. There is also a plateau to the cardiac function curve, which is the result of limits of diastolic lling created by the pericardium (10) or in its absence the cardiac cytoskeleton (Fig. 3B). During ex-

ercise in persons with normal cardiac function, the heart does not limit peak cardiac output during exercise because cardiac function keeps on improving as a result of increases in heart rate and stroke volume to match needs (7). The increase in heart rate likely is the more important factor and is essential for the
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Figure 4. Ventricular pressurevolume relationship indicating the importance of heart rate for aerobic performance. In a normal male, cardiac output can increase from 5 to 25 L/min with a 2.5-fold increase in heart rate (65180 beats/min) and approximately 1.7-fold increase in stroke volume (80 mL at rest to approximately 140 at peak exercise). An increase in end-systolic elastance provides some of the increase in stroke volume but the larger part is the result of an increase in end-diastolic volume and pressure. If heart rate does not increase, stroke volume would have to increase to 385 mL, but even a very large increase in end-diastolic pressure cannot do this because of pericardial or intrinsic myocardial constraint. If the end-diastolic volume starts high, there can be little further increase with exercise but there can still be a large rise in end-diastolic pressure. Eeslv, end-systolic elastance; EDP, end-diastolic pressure; HR, heart rate; SV, stroke volume; EDV, end-diastolic volume.

achievement of high cardiac outputs, but stroke volume also increases by an increase in end-diastolic volume and a decrease in end-systolic volume as a result of the increase in contractility. The decrease in end-systolic volume likely plays a smaller part because the normal slope of the left ventricular end-systolic pressurevolume relationship is steep even under resting conditions and there is little to gain by making it steeper. The increase in end-diastolic volume and the Frank-Starling mechanism thus is likely the more important factor in the increase in stroke volume. Although the FrankStarling relationship is critical for matching output of the heart to the return of blood, it operates under a narrow range of end-diastolic volumes, especially in the supine position (11), and thus provides a limited component to the increase in cardiac output over large ranges. To understand the limits of the preload mechanism, consider the following (Fig. 4). If cardiac output increases to 25 L/min, a reasonable number in a 70-kg young male, and heart rate remains at 65 beats/ min, stroke volume would have to be 385 mL, or more than three times the normal value. Left and right end-diastolic volumes would have to be 400 mL and total heart volume would be 900 mL. It is thus easy to understand why loss of chronotropic reserve severely limits aerCrit Care Med 2012 Vol. 40, No. 1

obic exercise performance. The impact of an inadequate chronotropic response even has an impact at lower aerobic levels for the larger end-diastolic volume that is required to maintain cardiac output, combined with the curvilinear shape of the passive pressurevolume relationship of the ventricles; this means that enddiastolic pressures can reach very high levels when the subject requires an increase in cardiac output. This is especially a problem in persons who have a decrease in their diastolic compliance (diastolic dysfunction) and explains why patients with this increasingly common problem are very dyspneac with exercise. The use of -blockers in such individuals can increase their dyspnea because the reduction in heart rate from the -adrenergic blockade means that end-diastolic volume must be greater to match cardiac output to VO2 and this can lead to greater pulmonary venous and capillary pressures. Furthermore, when the at part of the cardiac function curve is reached, changes in preload can no longer increase cardiac output and only changes in contractility, afterload, or heart rate can alter cardiac output. Pulmonary venous pressures rise in these patients even with small changes in end-diastolic volume. On the positive side, in these patients, decreasing afterload decreases in endsystolic volume, which allows a decrease

in end-diastolic volume for the same stroke volume and, even if the reduction in volume is small, the decrease in enddiastolic pressure could be large and important symptomatically. Thus, the benet of afterload reduction in patients whose left hearts are operating on the steep part of the end-diastolic pressure volume curve likely is attributable more to the decrease in pulmonary venous pressure than an increase in forward ow. A small increase in heart rate would have the same benet. This discussion has dealt with the physiological changes during exercise, but it is not uncommon to see cardiac outputs of 10 L/min in septic patients. Achievement of these high values requires the same kind of adjustments in stroke volume and heart rate as those seen during exercise except that there is no longer the coordinated response that occurs with central drive in the exercise response (12). Furthermore, sepsisinduced myocardial dysfunction limits the increases in contractility that can occur with neurohumeral activation and so heart rate becomes a more critical component of the adaptation. Changes in end-diastolic volume with changes in heart rate have some important implications for the assessment of changes in cardiac function after administration of a -adrenergic blocker with use of measurements of ejection fraction (end-diastolic minus end-systolic volume divided by end-diastolic volume) (Fig. 5). If cardiac output remains constant, which is usually the case with long-term -adrenergic blocker use because of the tight relationship of cardiac output to metabolic demand, end-diastolic volume must increase to compensate for the decrease in heart rate. Because end-diastolic volume is in the numerator and denominator of the ejection fraction, the fraction will increase and there will seem to have been an improvement in cardiac function, although there was no change in contractility. The lesson is that ejection fraction measurements are affected by changes in heart rate and not just contractility.

Regulation of Heart Rate

Heart rate normally is determined by the phase IV depolarization of the action potential of pacemaker cells in the sinus node. This depolarization is altered by neurohumeral inputs. Parasympathetic input slows the discharge rate and -1
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volume in normal volunteers (21). When tachycardia is observed in hypovolemic patients, it is likely related to an increased sensitivity because of the pain, anxiety, and inammatory processes associated with the cause of the hypovolemia.

Heart Rate and the SupplyDemand Balance of the Heart

Normal cardiac function requires a balance between the energy demands of the heart and the supply of energy. The three major determinants of myocardial oxygen demand are heart rate, contractility, and wall tension. Changes in contractility generally parallel changes in heart rate and systolic pressure is easily measured so that the product of heart rate and blood pressure can be used to provide a good estimate of myocardial energy demand. Furthermore, except at very high arterial pressures, changes in heart rate dominate the changes in energy demand, so that heart rate itself is an important indicator of myocardial oxygen demand. The supply of oxygen to the heart is determined by coronary blood ow, hemoglobin concentration, and the saturation of the hemoglobin molecules. Coronary blood ow is determined by the arterial pressure (especially in diastole for the left heart) and resistance to ow in the coronary arteries. The heart is in the difcult position of having to produce the arterial pressure that is necessary to maintain coronary perfusion pressure that is necessary for its blood ow. When coronary vessels are normal, the reserve for coronary ow is very large and should be adequate even at heart rates 200 beats/min as long as wall tension is not excessively high. Beta-blockers have an overall favorable effect on the supply demand of the heart. By decreasing heart rate and arterial pressure, they decrease myocardial oxygen demand. However, for cardiac output to be maintained, stroke volume must increase. Importantly, the heart handles shortening work more efciently than pressure work so that this change from pressure work to volume work is efcient for the heart. However, there must also be an increase in end-diastolic volume, which will lead to an increase in peak wall tension during systole because wall tension is related to the arterial pressure and the ventricular volume. This will contribute to a small increase in myocardial oxygen demand. If the -adCrit Care Med 2012 Vol. 40, No. 1

Figure 5. Ventricular pressurevolume relationship illustrating the improvement in ejection fraction that occurs with a decrease in heart rate but without an increase in contractility as assessed by the end-systolic pressure end-systolic volume relationship. Pre and post indicate before and after the decrease in heart rate. The decrease in heart rate results in a higher ejection fraction but there in no change of the end-systolic pressure volume/end-systolic pressure, which represents contractility. HR, Heart rate; ESV, end-systolic volume; ESP, end-systolic pressure; EF, ejection fraction; EDV, enddiastolic volume; SV; stroke volume.

adrenergic input increases it. The intrinsic heart rate without any autonomic input was studied by Jones and Collison by giving the muscarinic receptor antagonist atropine to block parasympathetic and the -adrenergic receptor antagonist propranolol to block sympathetic activity (13). In their sample of 432 healthy adults aged 16 70 yrs, the intrinsic heart rate was 106 beats/min in 25-yr-old subjects; there was an age-related decline in the intrinsic rate of 0.057 beats/min per year so that in a 60 yr old, intrinsic heart rate was only approximately 90 beats/ min. Importantly, they also found that intrinsic heart rate decreases in subjects who have a decrease in myocardial function (14), although some of the observed decreases possibly are related to the age effect and not actual myocardial disease (15). Because the normal resting heart rate is approximately 70 beats/min, parasympathetic input must dominate in the resting state. I say dominate because there also is resting sympathetic activation. Nature typically drives with her foot on the gas and break at the same time. Thus, propranolol still lowers the resting heart rate, although it is below the intrinsic rate. The selective advantage of having both active sympathetic and parasympathetic activity is that it allows rapid changes in heart rate at the onset of exercise or any other sudden stress by allowing rapid withdrawal of parasympathetic tone and a simultaneous increase in sympathetic activation (16, 17). Per242

haps not as advantageous, this also can result in large rapid changes in heart rate under pathologic conditions. Regulation of heart rate during exercise occurs through three mechanisms (12). When the motor signal from the cortex travel to the periphery to stimulate muscle contraction, some of the output stimulates hypothalamic and medullary centers to increase sympathetic output; this is called central drive and the same pathways can lead to increases in heart in nonexercise conditions. A second process is regulation by baroreceptors in response to changes in arterial pressure that would occur if the decrease in peripheral resistance with exercise is not met by an increase in cardiac output. The third factor, and one that might often produce pathologic increases in heart rate, is input from peripheral afferent bers that are activated by metabolic signals in peripheral tissues (18, 19). These latter signals can be activated by tissue ischemia and inammation (20). This could potentially be a major cause of the increased heart rate seen in patients with inammatory processes around the celiac axis such as pancreatitis because this region has a rich supply of sympathetic afferents. The important clinical point is that tachycardia induced by sympathetic afferents does not indicate hypovolemia and should not be treated by volume infusion. As it turns out, heart rate is a rather poor guide to hypovolemia as shown by removal of as much as 20% of blood

renergic blocker decreases heart rate by only a small amount, but through the decrease in contractility and slower heart rate increases end-diastolic volume, and especially if end-diastolic volume starts on the steep part of the diastolic pressure volume relationship and the plateau of the cardiac function curve, there could be even an increase in myocardial oxygen demand. There also will be an increase in pulmonary venous pressure and the possibility of increased pulmonary capillary ltration and a decrease in arterial oxygen. Changes in heart rate also impact on arterial diastolic pressure, which is important because perfusion of the left ventricle is primarily dependent on diastolic pressure. When heart rate is low, the length of diastole increases, which gives a longer time for coronary perfusion; however, the longer diastole also allows diastolic pressure to fall more so that the benet is reduced. On the other hand, at low heart rates, stroke volume is usually increased, which increases peak systolic pressure and increases peak wall tension and myocardial oxygen demand. At higher heart rates, there is less of a fall in diastolic pressure, but perfusion time is decreased. Fortunately, in most patients, coronary reserves are large and these small changes in supply demand are likely not of major importance, but they can become very important when the patients coronary blood ow is close to a critical limit in which case adjustments of heart rate and arterial pressures must be made very carefully and with close electrocardiographic monitoring. In the 1970s, a study by Buckberg and coworkers proposed monitoring patients with cardiac disease by measuring the ratio of the supply of oxygen as indicated by the area under the diastolic pressuretime relationship and the demand for oxygen as represented by the area under the systolictime index to track these interactions (2224). The specic measurements are hard to obtain in an intact person, but the principles are still important (25).

Pharmacologic Studies of Decreasing Heart Rate

An important distinction needs to be made between specically reducing heart rate vs. what is more typically done, which is reduction of heart rate with a -adrenergic blocker. Besides decreasing heart rate, -adrenergic blockade also can decrease cardiac contractility, alter metabolism, lead to decreased arterial reCrit Care Med 2012 Vol. 40, No. 1

sistance, and increase venous vascular resistance. The response to -blockade is thus an integration of all these effects. Still, important lessons have been learned from -blocker trials. Because heart rate is such an important determinant of myocardial oxygen demand, reduction of maximum heart rate as well as prevention of surges in heart rate make good sense in patients with xed coronary obstructions and limitations in the coronary supply of oxygen. Indeed, starting with the benecial effect observed in the Norwegian randomized trial of the use of a -adrenergic blocker after myocardial infarction (26), a series of studies showed benecial effects of -adrenergic antagonists in patients after myocardial infarction (2730). There is also evident improvement in clinical symptoms and an improvement in work capacity with use of -adrenergic blockers in patients with stable angina. However, a more complicated picture arose when -adrenergic blockade was used to prevent cardiac ischemic events in large populations at lower risk. In Peri-Operative Ischemic Evaluation study (POISE) 8351, noncardiac surgery patients with, or at risk of, atherosclerotic disease were randomized to receive the extended-release -adrenergic antagonist metoprolol succinate or placebo before and for 30 days after surgery with the aim of reducing a composite end point of noncardiac death, nonfatal myocardial infarction, and nonfatal cardiac arrest (31). The metoprolol group indeed had a signicant reduction in the composite primary end point. This was largely the result of a reduction in myocardial infarction as expected from a reduction in myocardial oxygen demand. Unfortunately, overall mortality was increased, which was primarily the result of increased deaths from strokes. There was more hypotension and a trend to more congestive failure in the metoprolol group. A similar observation was found in Clopidorgrel and Metoprolol in Myocardial Infarction Trial (COMMIT) in which 45,852 patients with an acute myocardial function were randomized to receive intravenous and then oral metoprolol or placebo (32). The end-points were a 1) a composite of death, reinfarction, or cardiac arrest; or 2) all-cause mortality. There was no overall benet but reinfarction and ventricular brillation were reduced with metoprolol. However, this benet was countered by an increase in cardiogenic shock. The lesson from

POISE and COMMIT is that controlling excess sympathetic activation and the accompanying increase in heart rate can be helpful for cardiac events but blocking defensive responses can be harmful or even fatal when hemodynamics are unstable and clinicians must nd the right balance for individual patients. Sympathetic activation and tachycardia are not always bad (33).

Prognostic Value of Resting Heart Rate From Observational Studies

A relationship between resting heart rate and life expectancy has been found in a large number of observational studies. In an interesting cross-species study, Levine (34) found that the number of total heart beats in a lifetime are between 108 and 109 in most species despite very different life expectancies; the implication is that the resting heart rate must be lower in those who live longer. In a French cohort study, resting heart rates 60 beats/min were associated with increased cardiovascular and all-cause 20-yr mortality in men and women; the importance of heart rate was greater in men than women (35). Another large French study also found that the risk of sudden death over 20 yrs increased with heart rates 60 beats/min. Resting heart rate was a predictor of death from cardiac and all-cause mortality in the Framingham cohort (36) as well as in the Coronary Artery Surgery Registry (CASS) (37). Resting heart rate was a strong predictor of hospital survival in patients with myocardial infarction (38) as well as 6-month survival after discharge (39). However, although higher resting heart rates are associated with higher mortality, one cannot conclude that lowering heart rate will improve survival because an association does not mean that there is a causal relationship. It is possible that the epidemiologic studies just indicate that an increased heart rate is a marker and not a cause of earlier mortality. The proper way to test this question is to decrease only heart rate without all the other consequences of -adrenergic blocker and determine the effect on cardiovascular events and mortality. This was recently done in the BEAUTIFUL (morbidity-mortality EvAlUation of the If inhibitor ivabradine in patients with coronary disease and left-ventriULar dysfunction) trial (40). Ivabradine selectively inhibits If channels in sinoatrial node
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Table 1. What to consider before lowering heart rate Why is the heart rate high? Physiological response Exercise Stress/fear/anxiety Baroreceptor response to hypotension Drug-induced increase Beta-adrenergic stimulation Isoproterenol Epinephrine Dobutamine Anticholinergic Atropine Hypovolemia (usually requires another factor such as anxiety or postural stress) Type III or IV thin ber afferent nerve activation What is achieved by lowering the heart rate? Net decrease in myocardial oxygen consumption Increased diastolic lling period (of signicance only at very high heart rates) Decreased mitral valve gradient in presence of mitral stenosis Increased ejection fraction (does not mean better function) What are the consequences of lowering heart rate? Increased ventricular diastolic volume and pressure (both right and left) Increased wall stress (increased myocardial oxygen demand) Decreased cardiac output if end-diastolic volume cannot increase Heart functioning on at part of the cardiac function curve Tamponade Decreased stroke volume if limit to venous return Possible increase in systolic arterial pressure Hypotension if medication used decreases cardiac function

toms. In the wake of COMMIT, one must ask whether in the original studies of use of -adrenergic blockade for all patients after myocardial infarction were successful because there was a true benet for all patients or failure to adequately treat hypertension and symptomatic coronary disease in the control groups.

Rate Control in Atrial Fibrillation

In atrial brillation, the atrium depolarizes at approximately 400 to 500 per minute but ventricular rates are lower because of blockage through the atrial ventricular node (42). Sudden onset of a rapid ventricular response in atrial brillation usually invokes a demand for a rapid clinical response, but it is not always clear what clinical objective actually is being achieved. When rheumatic heart disease and mitral stenosis were more common, it was not unusual to see patients with chronic atrial brillation develop pulmonary edema when ventricular rate was not controlled. This is predictable physiologically by realizing that at fast heart rates, diastole is shortened and ow across the mitral valve per beat must increase to maintain ow; when the mitral valve is signicantly narrowed, increased ow only can occur with increased pressure gradient across the valve. If ischemic signs and symptoms are present in a patient in atrial brillation with a rapid ventricular response, it also is clear that prompt rate control is indicated. However, the need for a rapid response in a patient with well-maintained blood pressure and no ischemic symptoms is less evident. Commonly used -adrenergic blockers and calcium channel blocker themselves lead to hypotension and can precipitate a less stable hemodynamic state and I sometimes wonder whether much of the hemodynamic instability that is observed with a rapid ventricular response in atrial brillation is actually the result of the treatment and not the rapid rate. In any case, an important clinical point is that the sudden onset of rapid atrial brillation is an important warning sign that something has happened and should make the clinician start looking for triggers such as a pulmonary embolism, new myocardial ischemia, hemorrhage, or even the onset of sepsis. It was long considered that maintenance of sinus rhythm was important for preserving ventricular function and for providing better functional capacity, but

cells and thereby slows phase IV depolarization and heart rate. In this doubleblind trial, ivabradine signicantly decreased resting heart rate but did not alter the composite end point of cardiac events or all-cause mortality. There were some trends to reductions in patients admitted for myocardial infarction, unstable angina, and revascularization, but these end points relate more to symptoms rather than events. A separate analysis of the control group in the study showed that increased heart rate was indeed associated with increased cardiovascular events (41). Overall, these results are more consistent with increased heart rate being a marker and not a cause of cardiovascular events and treatment should be aimed at subjects who have specic manifestations of cardiac symp244

this belief was not supported by a large randomized trial in which rhythm control was compared with rate control (43). In a more recent study, the question was asked whether in patients with atrial brillation and heart failure time to cardiovascular death is greater in those treated with tight rate control compared with those with what the investigators called lenient control in which almost two-thirds of subjects had ventricular rates 90 beats/min (44). There was no advantage for tight rate control. Based on these studies, it can be argued that patients with acute hemodynamic instability or evidence of ischemia with rapid ventricular responses to atrial brillation should be urgently treated, but there is less urgency in the hemodynamically stable patient and the clinician should concentrate on identifying the trigger for the rapid ventricular rate. It also is not necessary to reduce the ventricular response to very low rates and although the studies were not done in intensive care unit patients, it is quite possible this message is even more important in critically ill patients in whom rapid rates may be part of a physiological response to a stress. Based on the physiology of heart rate discussed in this review, I will make some recommendation for the management of heart rate (Table 1). When heart rate is high, the rst questions should be what is driving the high heart rate, what will be achieved by lowering the heart rate, and nally what are the consequences of lowering the heart rate? An important early assessment needs to be whether the high heart rate is causing a supply demand imbalance for the heart and if so, lowering heart rate needs to be done urgently. It also is important to determine whether the elevated heart rate is needed to maintain cardiac output because ventricular response is limited as a result of decreased systolic function or because of restrictions to diastolic lling. Diastolic lling could be limited by diastolic dysfunction or external constraints, including tamponade or restrictive processes in which case a rapid heart rate is advantageous and lowering the heart rate could be fatal. Finally, likely the most important point is that the prudent physician will treat the patient and not just the rate.

REFERENCES
1. Astrand P-O, Rodahl K: Physiological Bases of Exercise. Textbook of Work Physiology. Montreal, McGraw-Hill, 1977

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2. Clausen JP: Circulatory adjustments to dynamic exercise and effect of physical training in normal subjects and in patients with coronary artery disease. Prog Cardiovasc Dis 1976; 18:459 495 3. Astrand P-O: Quantication of exercise capability and evaluation of physical capacity in man. In: Exercise and Heart Disease. Sonnenblick EH, Lesch M, Eds. New York, Grune and Stratton, 1976, pp 87103 4. Magder S, Scharf SM: Venous return. In: RespiratoryCirculatory Interactions in Health and Disease. Scharf SM, Pinsky MR, Magder SA, Eds. New York, Marcel Dekker, Inc, 2001, pp 93112 5. Guyton AC: Determination of cardiac output by equating venous return curves with cardiac response curves. Physiol Rev 1955; 35:123129 6. Magder S: Theoretical analysis of the noncardiac limits to maximum exercise. Can J Physiol Pharmacol 2002; 80:971979 7. Notarius CF, Levy RD, Tully A, et al: Cardiac vs. non-cardiac limits to exercise following heart transplantation. Am Heart J 1998; 135: 339 348 8. Permutt S, Riley S: Hemodynamics of collapsible vessels with tone: The vascular waterfall. J Appl Physiol 1963; 18:924 932 9. Fessler HE, Brower RG, Wise RA, et al: Effects of positive end-expiratory pressure on the canine venous return curve. Am Rev Respir Dis 1992; 146:4 10 10. Holt JP, Rhode EA, Kines H: Pericardial and ventricular pressure. Circ Res 1960; VIII: 11711180 11. Magder SA, Daughters GT, Hung J, et al: Adaptation of human left ventricular volumes to the onset of supine exercise. Eur J Appl Physiol 1987; 56:467 473 12. Mitchell JH, Shephard JT: Control of the circulation during exercise. In: Exercise The Physiological Challenge. Hill PM, Ed. Conference Publ Ltd, 1993, pp 55 85 13. Jose AD, Collison D: The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 1970; 4:160 167 14. Jose AD, Taylor RR: Autonomic blockade by propranolol and atropine to study intrinsic myocardial function in man. J Clin Invest 1969; 48:2019 2031 15. Opthof T, Coronel R: The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 2000; 45:175176 16. Fagraeus L, Linnarsson D: Autonomic origin of heart rate uctuations at the onset of muscular exercise. J Appl Physiol 1976; 40: 679 682 17. Linnarsson D: Dynamics of pulmonary gas exchange and heart rate changes at start and

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

end of exercise. Acta Physiol Scand 1974; 415:1 68 McCloskey DI, Mitchell JH: Reex cardiovascular and respiratory responses originating in exercising muscle. J Physiol (Lond) 1972; 224:173186 Magder S: Effects of respiratory muscle afferent on the breathing and the afferent hypothesis. In: RespiratoryCirculatory Interactions in Health and Disease. Scharf SM, Pinsky MR, Magder S, Eds. New York, Marcel Dekker, Inc, 2001, pp 405 425 Kaufman MP, Iwamoto GA, Longhurst JC, et al: Effects of capsaicin and bradykinin on afferent bers with endings in skeletal muscle. Circ Res 1982; 50:133139 Hamilton-Davies C, Mythen MD, Salmon JB, et al: Comparison of commonly used clinical indicators of hypovolaemia with gastrointestinal tonometry. Int Care Med 1997; 23: 276 281 Hoffman JIE, Buckberg GD: Transmural variations in myocardial perfusion. In: Progress in Cardiology. Yu PN, Goodwin JF, Eds. Philadelphia. Lea and Febiger, 1976, pp 37 89 Brazier JR, Buckberg GD: Effects of tachycardia on the adequacy of subendocardial oxygen delivery in experimental aortic stenosis. Am Heart J 1975; 90:222230 Brazier J, Cooper N, Buckberg G: The adequacy of subendocardial oxygen delivery: The interaction of determinants of ow, arterial oxygen content and myocardial oxygen need. Circulation 1974; 49:968 977 Russell DC, Balcon R: Haemodynamic effects on the myocardial blood ow supply/oxygen demand ratio in pacing induced angina pectoris. Cardiovasc Res 1978; 12:358 363 Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981; 304: 801 807 The beta-blocker heart attack trial. BetaBlocker Heart Attack Study Group. JAMA 1981; 246:20732074 Gheorghiade M, Goldstein S: Beta-blockers in the post-myocardial infarction patient. Circulation 2002; 106:394 398 Hjalmarson A, Herlitz J, Holmberg S, et al: The Goteborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction. Circulation 1983; 67:I26 I32 Hjalmarson A, Elmfeldt D, Herlitz J, et al: Effect on mortality of metoprolol in acute myocardial infarction. A double-blind randomised trial. Lancet 1981; 2:823 827 Devereaux PJ, Yang H, Yusuf S, et al: Effects of extended-release metoprolol succinate in

32.

33.

34. 35.

36.

37.

38.

39.

40.

41.

42. 43.

44.

patients undergoing non-cardiac surgery (POISE trial): A randomised controlled trial. Lancet 2008; 371:1839 1847 Chen ZM, Pan HC, Chen YP, et al: Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet 2005; 366:16221632 Bangalore S, Sawhney S, Messerli FH: Relation of beta-blocker-induced heart rate lowering and cardioprotection in hypertension. J Am Coll Cardiol 2008; 52:14821489 Levine HJ: Rest heart rate and life expectancy. J Am Coll Cardiol 1997; 30:1104 1106 Benetos A, Rudnichi A, Thomas F, et al: Inuence of heart rate on mortality in a French population: Role of age, gender, and blood pressure. Hypertension 1999; 33:44 52 Gillman MW, Kannel WB, Belanger A, et al: Inuence of heart rate on mortality among persons with hypertension: The Framingham Study. Am Heart J 1993; 125:1148 1154 Diaz A, Bourassa MG, Guertin MC, et al: Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 2005; 26:967974 Hjalmarson A, Gilpin EA, Kjekshus J, et al: Inuence of heart rate on mortality after acute myocardial infarction. Am J Cardiol 1990; 65:547553 Zuanetti G, Mantini L, Hernandez-Bernal F, et al: Relevance of heart rate as a prognostic factor in patients with acute myocardial infarction: Insights from the GISSI-2 study. Eur Heart J 1998; 19(Suppl F):F19 F26 Fox K, Ford I, Steg PG, et al: Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): A randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 807 816 Fox K, Ford I, Steg PG, et al: Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): A subgroup analysis of a randomised controlled trial. Lancet 2008; 372:817 821 Nattel S: New ideas about atrial brillation 50 years on. Nature 2002; 415:219 226 Roy D, Talajic M, Nattel S, et al: Rhythm control versus rate control for atrial brillation and heart failure. N Engl J Med 2008; 358:26672677 Van GI, Groenveld HF, Crijns HJ, et al: Lenient versus strict rate control in patients with atrial brillation. N Engl J Med 2010; 362:13631373

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