Hemodynamic parameters to guide fluid therapy

The cornerstone of treating patients with shock remains as it has for decades: intravenous fluids. Surprisingly, dosing intravenous fluid during resuscitation of shock remains largely empirical. Too little fluid may result in tissue hypoperfusion and worsen organ dysfunction; however, over-prescription of fluid also appears to impede oxygen delivery and compromise patient outcome. Recent data suggest that early aggressive resuscitation of critically ill patients may limit and/or reverse tissue hypoxia, progression to organ failure, and improve outcome [1]. In a landmark study, Rivers et al. demonstrated that a protocol of early goal-directed therapy reduces organ failure and improves survival in patients with severe sepsis and septic shock [2]. Similarly, a protocol to optimize preload and cardiac output in patients undergoing major surgery reduced postoperative complications and length of stay [3]. Uncorrected hypovolemia, leading to inappropriate infusions of vasopressor agents may increase organ hypoperfusion and ischemia [4]. However, overzealous fluid resuscitation has been associated with increased complications, increased length of intensive care unit (ICU) and hospital stay, and increased mortality. A review of the ARDSNet cohort demonstrated a clear positive association between the mean cumulative daily fluid balance and mortality [5]. Murphy and colleagues demonstrated a similar finding in patients with septic shock [6]. Data from the "VAsopressin in Septic Shock Trial" demonstrated that the quartile of patients with the highest fluid balance at both 12 hours and 4 days had the highest adjusted mortality [7]. The extravascular lung water index (EVLWI) can be accurately "measured" in critically ill patients by using the single indicator transpulmonary thermodilution method) [8, 9]. The EVLWI appears to be a useful tool to quantify "capillary leakiness" and the degree of interstitial edema [10]. A number of authors have demonstrated a positive relationship between EVLWI and mortality in critically ill patients [11, 12].

Fundamentally, the only reason to give a patient a fluid challenge is to increase stroke volume (volume responsiveness). If the fluid challenge does not increase stroke volume, volume loading serves the patient no useful benefit (may be harmful). According to the Frank-Starling principle, as the preload increases left ventricular (LV) stroke volume increases until the optimal preload is achieved at which point the stroke volume remains relatively constant (Figure 1). This optimal preload is related to the maximal overlap of the actin-myosin myofibrils. It is important to note that in an intact heart the actin-myosin links cannot be disengaged and hence there is no descending limb of the Frank-Starling curve. Once the left ventricle is functioning near the "flat" part of the Frank-Starling curve, fluid loading has little effect on the stroke volume. In normal physiologic conditions, both ventricles operate on the ascending portion of the Frank-Starling curve [16]. This mechanism provides a functional reserve to the heart in situations of acute stress. In normal individuals, an increase in preload (with volume challenge) results in a significant increase in stroke volume [17] (Figure 1).

Traditionally the central venous pressure (CVP) has been used to guide fluid management. A European survey of intensivists/anesthesiologists reported that more than 90% used the CVP to guide fluid management [18]. A Canadian survey reported that 90% of intensivists use the CVP to monitor fluid resuscitation in patients with septic shock [19]. The basis for using the CVP to guide fluid management comes from the misguided dogma that the CVP reflects intravascular volume; specifically, it is widely believed that patients with a low CVP are volume-depleted, whereas patients with a high CVP are volume-overloaded. Furthermore, the "5-2" rule, which was popularized in the 1970 s [20], is still widely used today for guiding fluid therapy. According to this rule, the change in CVP after a fluid challenge is used to guide subsequent fluid management decisions. The CVP is a good approximation of right atrial pressure, which is a major determinant of right ventricular (RV) filling. It has been assumed that the CVP is a good indicator of RV preload. Furthermore, because RV stroke volume determines LV filling, the CVP is assumed to be an indirect measure of LV preload. However, due to the changes in venous tone, intrathoracic pressures, LV and RV compliance, and geometry that occur in critically ill patients, there is a poor relationship between the CVP and RV end-diastolic volume. Furthermore, the RV end-diastolic volume may not reflect the patients' position on the Frank-Starling curve and therefore his/her preload reserve. More than 100 studies have been published to date that have demonstrated no relationship between the CVP (or change in CVP) and fluid responsiveness in various clinical settings [21]. Indeed, there have only been two studies published in the world literature that demonstrate "some relationship" between the CVP and intravascular volume; both of these studies were conducted in standing horses [22, 23]! Based on this information, we believe that the CVP should no longer be routinely used for guiding fluid management in the ICU, operating room, or emergency room.

Until recently, it has been unclear as to which hemodynamically unstable patients are volume-responsive and likely to benefit from fluid resuscitation (fluid boluses). However, during the past decade a number of dynamic tests of volume responsiveness have been reported. These tests dynamically monitor the change in stroke volume after a maneuver that increases or decreases venous return (preload). These tests allow the clinician to determine the individual patient's position on his/her Frank-Starling curve, and thus determine whether the patient is likely to be fluid-responsive. These techniques use the change in stroke volume during mechanical ventilation or after a passive leg raising (PLR) maneuver to assess fluid responsiveness.

In the initial stages of resuscitation in the emergency room, ward, or ICU, most patients are not intubated and are breathing spontaneously. In addition, with the reduced use of sedative agents in the ICU, many critically ill patients are ventilated with modes of ventilation that allow spontaneous breathing activity. Because the respiratory variability of hemodynamic signals cannot be used for predicting volume responsiveness in spontaneously breathing patients, other techniques, such as passive leg raising (PLR), have been proposed for this purpose [41, 42]. Lifting the legs passively from the horizontal position induces a gravitational transfer of blood from the lower limbs toward the intrathoracic compartment (Figure 4). Accordingly, increases in the pulmonary artery occlusion pressure and the LV ejection time [43] have been reported during PLR, supporting the evidence that the volume of blood transferred to the heart during PLR is sufficient to increase the left cardiac preload and thus challenge the Frank-Starling curve. Beyond its ease of use, this method has the advantage of reversing its effects once the legs are tilted down [43, 44]. Therefore, PLR may be considered a reversible "autotransfusion."

The concept of detecting preload responsiveness by using PLR emerged from a study in mechanically ventilated patients, where the increase in thermodilution stroke volume after a fluid infusion correlated with the increase in arterial pulse pressure produced by PLR [44]. The ability of PLR to serve as a test of preload responsiveness has been confirmed in additional studies performed in critically ill patients [40, 43, 45–51]. The change in aortic blood flow (measured by esophageal Doppler) during a 45° leg elevation was shown to predict the changes in aortic blood flow produced by a 500-mL fluid challenge even in patients with cardiac arrhythmias and/or spontaneous ventilator triggering, situations in which PPV lost its predictive ability [43]. A recent meta-analysis, which pooled the results of eight recent studies, confirmed the excellent value of PLR to predict fluid responsiveness in critically ill patients with a global area under the receiver operating characteristic curve of 0.95 [51]. The best way to perform a PLR maneuver to predict volume responsiveness is to elevate the lower limbs to 45° (automatic bed elevation or wedge pillow) while at the same time placing the patient in the supine from a 45° semirecumbent position (Figure 4). Starting the PLR maneuver from a total horizontal position may induce an insufficient venous blood shift to elevate significantly cardiac preload [52]. By contrast, starting PLR from a semirecumbent position induces a larger increase in cardiac preload because it induces the shift of venous blood not only from both the legs but also from the abdominal compartment [53]. In should be noted that intra-abdominal hypertension (intra-abdominal pressure > 16 mmHg) impairs venous return and reduces the ability of PLR to detect fluid responsiveness [54].

Because the maximal hemodynamic effects of PLR occur within the first minute of leg elevation [43], it is important to assess these effects with a method that is able to track changes in cardiac output or stroke volume on a real-time basis. In this regard, the response of descending aortic blood flow (measured by esophageal Doppler) to PLR [43, 45], of the velocity-time integral (measured by transthoracic echocardiography) [46, 47], and the femoral artery flow (measured by arterial Doppler) [50] to PLR have been demonstrated to be helpful in predicting the response to volume administration in patients with spontaneous breathing activity. Echocardiographic techniques are, however, operator-dependent and not conducive to continuous real-time monitoring. Until recently, continuous real-time cardiac output monitoring required a thermodilution pulmonary artery catheter. During the past decade, several less invasive methods have been developed. These techniques include transpulmonary thermodilution, pulse-contour analysis, and bioreactance. The PiCCO™ system (Pulsion Medical Systems, Munich, Germany) uses transpulmonary thermodilution to calibrate the pulse-contour-derived stroke volume, whereas the stroke volume derived from the FloTrac-Vigileo™ (Edward Lifesciences, Irvine, CA) device is uncalibrated. Both of these devices may be useful to determine the hemodynamic response to PLR. In this regard, an increase in "pulse contour" cardiac output by more than 10% in response to PLR has been shown to accurately predict volume responsiveness in mechanically ventilated patients with spontaneous breathing activity [40, 48]. Although less invasive than pulmonary artery catheterization, these techniques are not ideally suited to resuscitation in the emergency room or ward or on initial presentation in the ICU. In these situations, the change in stoke volume after a PLR maneuver can be assessed noninvasively by bioreactance. Bioreactance cardiac output measurement is based on an analysis of relative phase shifts of an oscillating current that occurs when this current traverses the thoracic cavity. It differs from traditional bioimpedance-based systems, which rely on measured changes in signal amplitude [55]. The NICOM™ (Cheetah Medical, Portland, OR, USA) is comprised of a high-frequency (75 kHz) sine wave generator and four dual electrode "stickers" that are used to establish electrical contact with the body. The cardiac output as measured by bioreactance has been shown to be highly correlated with that measured by thermodilution and pulse contour analysis [55–57]. In a cohort of patients after elective cardiac surgery, Benomar and coauthors demonstrated that the NICOM™ system could accurately predict fluid responsiveness from changes in cardiac output during PLR [58]. The NICOM™ system has an algorithm with user prompts and an interface that rapidly facilitates the performance of a PLR maneuver.

Although the dynamic changes of the plethysmographic waveform have been demonstrated to be predictive of volume responsiveness in ventilated patients, this technology is poorly predictive of volume responsiveness in spontaneously breathing persons after a PLR challenge [59]. The hemodynamic effects of PLR must be assessed by a direct measure of cardiac output or stroke volume; assessing the PLR effects solely on the arterial pulse pressure leads to a significant number of false-negative cases [51]. This suggests that in spontaneously breathing patients, pulse pressure is not of sufficient sensitivity for detecting changes in stroke volume.

A number of minimally invasive and noninvasive diagnostic tools are currently available that allow clinicians to assess volume responsiveness using dynamic procedures that challenge the patients' Frank-Starling curve. These technologies complement one another; each has a useful place in the continuum of the resuscitation process.