Introduction
The basic mechanism underlying functional preload indices, such as stroke volume variation (SVV), pulse pressure variation (PPV), or systolic pressure variation (SPV), is that mechanical ventilation induces cyclic alterations in ventricular filling and, in consequence, in stroke volume and cardiac output. This phenomenon is most easily recognized in clinical practice as periodical variations in the arterial pressure signal. Based on the understanding of the Frank-Starling-relationship, i.e., the relation of cardiac preload and stroke volume, the ventilation-synchronous vari- ations of cardiac output, or the indices named above, which serve as surrogates, allow assessment of left ventricular (LV) filling, and, more importantly the evalua- tion of the steepness of the patient-individual LV function curve [1]. The usefulness of these functional preload indices in assessing cardiac preload and in predicting whether a patient will respond to fluid administration with an increase in cardiac output (fluid responsiveness) has been demonstrated in many studies.
In the last two decades, numerous investigations on heart-lung-interactions have not only led to the integration of these functional preload indices into clinical prac- tice, but also to a better understanding of their interdependence from other physio- logical mechanisms besides preload. In addition, due to the complexity of heart- lung-interactions, it is obvious that functional preload indices must be influenced by other factors than cardiac preload, which may also probably limit, in specific clinical situations, their ability to assess preload and fluid responsiveness. Considering the physiology behind the functional preload indices, these factors can be grouped into respiratory issues and cardiovascular issues.
Respiratory issues
Tidal VolumeAugmenting tidal volumes increases lung inflation and, thereby, affects cardiac pre- load and afterload. It is predominantly the right ventricle that is affected. An increase in intrathoracic pressure, which is associated with an augmentation of tidal volumes impedes venous return, a) by decreasing the pressure gradient between the right atrium and the venous capacity vessels [2], and b) by compression of the vena cava due to an increased pleural pressure during inspiration [3]. Therefore, aug- menting tidal volumes essentially results in a larger variation in venous return, right ventricular (RV) and, consequently, LV stroke volume during the respiratory cycle.
Further, both hyperinflation and hypoinflation may increase RV afterload by differ-
for tidal volumes of at least 8 ml/
kg and 8 % below it. From [5] with permission.
ent mechanisms. Hyperinflation induces pulmonary hypertension by compressing alveolar and pulmonary vessels. Such hyperinflation may occur in only a few alveoli or in the whole lungs. Hypoinflation can increase RV afterload, too, by the well known hypoxic pulmonary vasoconstriction. LV preload, which is what we estimate with the functional preload indices, depends on RV output and the factors influenc- ing this output as described. LV afterload, too, is altered by an increase in intratho- racic pressure. LV afterload is, in contrast to RV afterload, decreased by a reduced systolic transmural pressure.
The influence of tidal volume on functional preload indices (SVV, PPV) has been a point of ongoing discussion. An increase in tidal volume necessarily increases the change in intrathoracic pressure during the respiratory cycle and should, thereby, increase functional preload indices such as PPV and SVV. In cardiac surgery patients, it was shown that both PPV and SVV increased with tidal volumes from 5 to 15 ml/kg body weight both before and after fluid loading [4]. This increase in PPV and SVV correctly reflects fluid responsiveness, as venous return and LV filling decrease with augmentation of tidal volume, but the intravascular volume status may not change. However, at low tidal volumes, the change in intrathoracic pressure during the respiratory cycle may be too small, so that PPV and SVV may loose their usefulness as markers of fluid responsiveness, as reported by De Backer and col- leagues for tidal volumes ‹ 8 ml/kg of body weight (Fig. 1) [5].
Positive End-expiratory Pressure
Whereas augmenting tidal volumes increases the degree of change in intrathoracic pressure during the respiratory cycle, the application of positive end-expiratory pressure (PEEP) constantly increases pleural pressure and intrathoracic pressure.
Thus, the ventilation-induced cyclic changes in intrathoracic pressure occur at a higher pressure level. The increase in intrathoracic pressure following the applica- tion of PEEP reduces venous return, thereby ventricular filling and, consequently, cardiac output, and this not in a cyclic fashion but constantly. Further, PEEP increases transpulmonary pressure resulting in an increased RV afterload. Both effects lead to a reduced LV filling (i.e., also to an increased fluid responsiveness of the left ventricle) with a concomitant increase in functional preload indices. In con- sequence, the application of PEEP results in a decrease in cardiac output in the
Fig. 2. Left and right ventricular stroke volume variation (SVV) during open and closed chest conditions.
a Left ventricular SVV (LV SVV) (14 animals); b Right ventricular SVV (RV SVV) (12 animals). Thin lines: indi- vidual changes in SVV during ventilation without positive end-expiratory pressure (PEEP) and with PEEP 15 cmH2O. Thick line, dots and error bars: mean value „ SEM. *p‹ 0.05, vs. open chest, same PEEP level.
†p‹ 0.05, vs. no PEEP. From [9] with permission
majority of mechanically ventilated patients, except for patients with LV backward failure. However, in the absence of a decrease in cardiac output following application of PEEP, functional preload indices (SVV, PPV, SPV) will also not be affected [6, 7].
Moreover, as was shown by Michard and colleagues, PPV measured prior to the application of PEEP was strongly correlated with the reduction in cardiac index induced by this application of PEEP. Thus, these functional indices of preload may also serve as a useful tool for predicting the hemodynamic effects of PEEP [8]. In accordance with those data, it has also recently been demonstrated in an animal model that PEEP increases LV SVV, and that this effect is found during open as well as during closed chest conditions [9] (Fig. 2).
Chest and Lung Compliance
The change in intrathoracic pressure caused by a mechanical breath is dependent on chest compliance. If chest compliance is high, a given tidal volume will result in a minor change in intrathoracic pressure and, consequently, in ventricular filling as if chest compliance is low. In animals, a decrease in chest compliance induced by a pneumoperitoneum has been shown to increase SPV [10]. A more profound change in chest compliance occurs with a sternotomy; the opening of the thoracic cavity increases chest compliance tremendously. Both, in animals [9] and in patients [11]
it could be shown that sternotomy led to an increase in cardiac output and a con- comitant decrease in SVV, indicating an augmented ventricular filling and thus, a higher preload during open-chest conditions (Fig. 3).
Lung compliance is the important determinant for the transmission of alveolar pressure to the pleural space. The higher the compliance, the more pressure is trans- mitted from the alveoli to the pleural space [12]. If we apply this information at a given intravascular volume status on functional preload indices, these indices will theoretically be higher in healthy than in damaged lungs for the same alveolar pres- sure. This is because in the healthy lung more pressure is transmitted to the pleural space resulting in higher pleural pressures and a stronger decrease in venous return
Fig. 3. a Stroke volume variation (SVV) of each patient before (T1) and immediately after (T2) mid-line thoracotomy and pericardiotomy. b Aortic pulse pressure variation (PPV) of each patient before (T1) and immediately after (T2) mid-line thoracotomy and pericardiotomy. From [11] with permission
to the right ventricle. On the other hand, higher airway pressures are frequently needed to ventilate patients with reduced lung compliance, such as patients with acute respiratory distress syndrome (ARDS), so that pleural pressure will theoreti- cally not be much different from normal lungs. Unfortunately, so far there are no experimental or clincial data describing sufficiently the relationship between lung compliance and the variation in functional preload indices.
Cardiovascular Issues
Heart Rate and RhythmHeart rate and heart rhythm have an influnece on ventilation-induced heart-lung interactions. A decrease in heart rate, or a lower ratio of heart beats to respiratory cycles, seem to reduce the hemodynamic consequences of heart-lung interactions; in mechanically ventilated patients receiving esmolol, for example, administration of the beta-blocker led to a reduction in the respiratory-related arterial pressure vari- ability and the systolic pressure variation [13] (Fig. 4). Beta-blockers seem to sup- press the autonomic, sympathetic response to lung inflation which usually causes cardiac acceleration (respiratory sinus arrhythmia). It has to be noted that massive hyperinflation will reduce heart rate due to high intrathoracic pressures, as known from alveolar recruitment maneuvers.
Cardiac arrhythmias affect both systolic and diastolic ventricular function and stroke volume. Depending on the nature of the arrhythmia, it will be the predomi- nant factor determining stroke volume variation. In patients with atrial fibrillation and frequent extrasystoles, the functional preload indices will no longer reflect ven- tilatory-induced changes in ventricular filling. PPV has recently been reported to become a poor predictor of preload responsiveness in mechanically ventilated patients with severe arrhythmias [14]. However, so far we have insufficient data to finally decide at which grade of arrhythmia functional preload indices can no longer be used to predict fluid responsiveness.
Fig. 4. Mean value (a) and maximal change (b) of respiratory-related arterial pressure variation (RAPV) and percentage systolic pressure variation ( %SPV) in response to control and esmolol. Values are mean „ SEM.
*p ‹ 0.05 compared with saline control (Con), as determined using Student’s t test (n = 10). From [13] with permission
Ventricular Function
The influence of ventricular dysfunction or failure on functional preload indices is different for the right and the left ventricle. In right heart failure, the right ventricle is not able to provide a sufficient output for adequate LV filling. This may be due to impaired RV contractility or increased RV afterload, which can be aggravated by the cyclic increase in transpulmonary pressure during mechanical ventilation. In the case of RV overload, LV end-diastolic volume (LVEDV) is reduced not only because of a reduced RV output but also due to a leftward shift of the interventricular sep- tum. The LVEDV will then, at the same end-diastolic pressure, be smaller than prior to the septal shift. Further, the shape of the left ventricle may be distorted due to the septal shift resulting in reduced LV end-diastolic compliance and contractility [15].
Therefore, in a situation of RV failure with RV overloading, we would expect a large variation in parameters derived from the arterial pressure wave (SPV, PPV, SVV), while the heart is not responsive to fluid administration. This was recently clearly described by Jardin [16].
Functional preload indices, such as PPV, SPV, or pulse contour SVV, describe the steepness of the LV function curve. In comparison to a non-compromised left ventri- cle, the ventricular function curve of the failing left ventricle is flat. Thus, the same changes in LVEDV induced by mechanical ventilation will result in smaller LV SVVs in the failing heart compared to the non-compromised heart. However, in the pres- ence of isolated LV dysfunction, i.e., which is not accompanied by RV failure, these functional parameters should also allow LV fluid responsiveness to be assessed. This was demonstrated in patients undergoing cardiac surgery with documented impaired LV function (ejection fraction ‹ 0.35), where a high SVV was associated with a posi- tive response to fluid loading. Thus, in these patients also, functional indices of pre- load seem to be a valuable tool to assess fluid responsiveness [17] (Fig. 5). However, in this context it seems important to differentiate whether the LV failure is a global or a regional myocardial failure. In the presence of regional myocardial failure, as, for example, in acute regional myocardial ischemia, regionally confined dyskinesias will attribute a different variation in LV stroke volume from one respiratory cycle to another. However, experimental or clinical data on this issue are lacking.
Fig. 5. Linear correlation analysis of the relation between changes in preload variables stroke volume varia- tion ( 2 SVV; left panel) and left ventricular end-diastolic area index ( 2 LVEDAI; right panel) caused by vol- ume loading and the associated changes in stroke volume index ( 2 SVI). From [17] with permission
Cardiac Afterload
Cardiac afterload changes dynamically during ventricular ejection. In normal hearts, it is maximum, in terms of maximal LV wall tension, at the end of isovolu- metric contraction. In patients with LV overload, as in cardiac backward failure, the maximal wall stress occurs during LV ejection, as ejection pressure increases during systole while LV volume approaches normal values [18]. Therefore, in such patients, stroke volume is theoretically more sensitive to the arterial pressure than in healthy patients and we would expect the functional preload indices to decrease if cardiac afterload increases. However, in dogs with normal cardiac function and hemor- rhagic shock, the application of the vasopressor, norepinephrine, led to a decrease in PPV and SPV (Fig. 6) [19]. In this study, however, the time interval between the
Fig. 6. Box plots showing changes in comparison with baseline in pulse pressure variation (PPV, a) and arterial systolic pressure variation (SPV, b) following hemorrhage and treatment with norepinephrine. The line in each box indicates the median. The upper and lower limits of each box indicate the 75thand 25th percentiles, respectively. The error bars above and below each box represent the 90thand 10thpercentiles, respectively. *p‹ 0.05 vs. baseline; **p‹ 0.05 vs. hemorrhage. From [19] with permission
and, therefore, reduced vasomotor tone, the delta down component of SPV allowed accurate assessment of fluid responsiveness [20].
Arterial Compliance
The relationship between changes in stroke volume and changes in arterial pressure is dependent on arterial compliance. Clinical determination of arterial compliance is difficult at the present time. One proposed method is the stroke volume-to-aortic- pulse-pressure ratio (SV/PP) [21]. If arterial compliance is low, small changes in LV stroke volume will result in large changes in arterial pressure. Vice versa, if arterial compliance is high, large alterations in LV stroke volume will only cause minor changes in arterial pressure [7]. One would, therefore, assume that measuring LV SVV, for example, by pulse contour analysis would be superior to SPV and PPV.
However, there are so far no data to confirm this hypothesis. PPV, SPV [21], and LV SVV [23] have all been reported to be valuable tools for guiding fluid therapy in sep- tic patients, in which arterial compliance is probably altered in the course of the dis- ease. However, whether one parameter is superior to the others has still not been conclusively determined.
Conclusion and Perspective
The interaction of mechanical ventilation and LV function is complex. Both ventila- tory issues – tidal volume, PEEP, chest and lung compliance – and cardiovascular issues – heart rate and rhythm, ventricular function, cardiac afterload, arterial com- pliance – may affect functional preload indices. How these factors influence these indices has to be known for correct interpretation of the values derived from the arterial pressure signal and real-time continuous cardiac output devices.
In clinical situations, in which the confounding factors described above play more than a subordinate role in the generation of the functional preload indices, as, for example, during weaning from mechanical ventilation, we are still looking for the
‘perfect’ method to predict the hemodynamic reaction to fluid administration. Such alternatives might be, at least in part, volumetric parameters of preload [24]. The measurement of changes in aortic blood flow following a passive leg raising maneu- ver, which has been reported to have a high sensitivity and specificity in a critically ill population including patients with spontaneous respiratory efforts and arrhyth- mias [22], may be of particular interest. In addition, the recently proposed systolic variation test [25, 26] may in the future provide further helpful information on fluid responsiveness. However, further data are necessary to confirm these first stimulat- ing results.
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