THIS IS THE MOST IMPORTANT CHAPTER OF THIS BOOK. IT IS COMPULSORY READING.

Current “wisdom” suggests that aggressive fluid resuscitation is the best initial approach to the patient with hemodynamic instability. The source of this wisdom is difficult to discern, however, “Early Goal Directed therapy” (EGDT) as championed by River’s et al. [1] appears to have established this as the irrefutable truth. However, over the last decade it has become clear that aggressive fluid resuscitation is associated with increased morbidity and mortality across a diverse group of patients, including patients with severe sepsis (see Chap. 12), ARDS [2], as well as surgical and trauma patients and those with pancreatitis.

Multiple RCT’s and cohort studies have demonstrated that a conservative fluid strategy in patients undergoing elective non-cardiac surgery is associated with significantly fewer complications with a lower mortality (in the high risk patients) than patients managed with the traditional liberal fluid strategy in which fluids are administered to fill the non-existent “third space” [3–5]. For patients with traumatic injuries, high volume fluid resuscitation as promoted by the early Advanced Trauma Life Support (ATLS) strategy [6], has given way to a “damage control” resuscitation strategy [7]. This approach has seen a fall in the volume of crystalloid delivered in the emergency department and an associated fall in mortality. In a prospective analysis of 3,137 trauma patients’ treated in the Emergency Department, fluid volumes of 1.5 l or more were significantly associated with mortality [8]. This observation is supported by a meta-analysis which demonstrated in both RCT’s and cohort studies that a conservative fluid strategy was associated with a lower mortality in trauma patients [9]. Similarly, an aggressive fluid strategy in the resuscitation of patients with acute pancreatitis has been associated with an increased risk of complications [10]. The results of multiple studies across diverse patient populations have clearly demonstrated that aggressive fluid “loading” is associated with an increased risk of complications and death. The only published study conducted in humans that has demonstrated that early aggressive fluid resuscitation “improves” outcome is the EGDT study by Rivers et al. [1]. However the results of this study are implausible and likely not true. These observations have resulted in a major paradigm shift in the techniques used to assess volume status and the approach to fluid resuscitation; fluid resuscitation serves as the prime example of the “less is more” paradigm. While hypovolemia will result in decreased cardiac output (and blood pressure) with inadequate organ perfusion leading to organ dysfunction, overzealous fluid resuscitation and hypervolemia induces a cascade of events that similarly results in organ dysfunction. From an evolutionary point of view we have evolved to deal with hypovolemia and not hypervolemia. The argument is no longer “wet or dry” but “just the right amount of fluid”. This is not an easy determination and requires an evaluation of the patient’s hemodynamics, organ perfusion, cardiac function and an assessment of “fluid responsiveness” in addition to understanding the patients’ clinical condition. It is no longer acceptable to pour in liters of fluid and “see what happens”. In addition to understanding that we need to precisely titrate fluid volumes we have also gained much better insight into which fluid to give. It is also import to note that at 3 h only 15 % of a crystalloid bolus remains intravascular in normal health volunteers, while in experimental sepsis models almost 100 % of the fluid bolus filters into the interstitium [11–13]. This can’t be a good thing. It would therefore appear that clinicians are required to unlearn the traditional methods of fluid resuscitation and embrace the new approach.

The first step in the hemodynamic management of critically ill patients is to determine the adequacy of tissue/organ perfusion. While the signs of shock may be obvious, those of sub-clinical hypoperfusion may be more subtle. The signs of hypoperfusion include:

It should be noted that hypotension and tachycardia reflect significant volume depletion. A blood loss of about 1 l is required before a patient develops a tachycardia and about 1.5 l before the blood pressure begins to drop. In those patients with hypotension or evidence inadequate tissue perfusion, fluid resuscitation is generally regarded as the first step in resuscitation. Clinical studies have, however, demonstrated that only about 50 % of hemodynamically unstable critically ill patients (In ER, ICU or OR) are volume responsive [14].

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 (and is likely 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 (Fig. 9.1). 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 [15]. 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 [16].

An analysis of the overlapping Frank-Starling and extra-vascular lung water (EVLW) curves demonstrate that as patients’ become less fluid responsive EVLW (and tissue edema) increase markedly (see Fig. 9.1) due to increased cardiac filling pressures and transmitted hydrostatic pressures [17]. This process is accentuated in patients with endothelial damage (sepsis, ARDS, pancreatitis, burns) [18]. It should be noted that as “one” climbs up the Frank-Starling Curve “one” get diminishing returns; a smaller increase in SV with greater propensity to develop tissue edema. Increased cardiac filling pressures trigger the release of natriuretic peptides, presumably to assist in fluid removal. What is most disturbing about this sequence of events is that natriuretic peptides cleave membrane-bound proteoglycans and glycoproteins (most notably syndecan-1 and hyaluronic acid) off the endothelial glycocalyx (see below) [19, 20]. The endothelial glycocalyx plays a major role in regulating endothelial permeability [21]. Therefore, excessive volume expansion increases the release of natriuretic peptides which in turn damages the endothelial glycocalyx and this is followed by a rapid shift of intravascular fluid into the interstitial space leading to a marked increase in EVLW and tissue edema [19, 20]. To make matters even worse, natriuretic peptides inhibit the lymphatic propulsive mechanism and the return of lymph into the vascular system further aggravating tissue edema [22, 23].

Only patients who are likely to show a significant increase in SV with a fluid challenge and in whom the increased SV is considered to be beneficial should be given a fluid challenge. Furthermore, all attempts should be made to limit the volume of fluid administered. This begets the question of how to predict fluid responsiveness? After Hughes and Magovern described the technique of central venous pressure (CVP) monitoring in 1959 this method became a standard tool for guiding fluid therapy [28]. It has now been clearly established that there is a poor relationship between the CVP and intravascular volume status and no relationship between the CVP and fluid responsiveness [29]. In 1970 the flow-directed pulmonary artery catheter (PAC) was developed by Swan and Ganz allowing measurement of the pulmonary artery occlusion pressure (PAOP). However, the PAOP suffers from the same limitation as the CVP and multiple studies have demonstrated that, like the CVP, the PAOP is unable to predict fluid responsiveness [30, 31].

While there is a poor relationship between blood volume and CVP and while there is no relationship between fluid responsiveness and the CVP (or change in CVP following a fluid bolus) in any individual patient the CVP tends to increase with fluid loading. In some patients however, the CVP may fall with fluid loading due to decreased sympathetic tone and decreased venoconstriction. The change in the CVP following a fluid challenge is frequently used to guide further fluid management. This strategy was described several decades ago by Weil and Henning who proposed the 2–5 CVP Rule [32]. According to this scheme, the CVP is measured at 10 min intervals. If the change in CVP was < 2 mmHg, the infusion was continued, if it was in the 2–5 mmHg the infusion was interrupted and reevaluated after a 10 min wait. If the change was > 5 mmHg the infusion was stopped [32, 33]. However the 2–5 CVP rule is unable to predict fluid responsiveness in patients with both a low CVP (< 12 mmHg) or a high (> 12 mmHg) CVP. EGDT and the Surviving Sepsis Campaign recommend targeting a CVP > 8 mmHg (8–12 mmHg on mechanical ventilation [1, 34]. This is likely a very bad idea. It is important to recall that a normal CVP is close to ZERO. Furthermore, a rapid fluid bolus is likely to distend the cardiac chambers with the release of BNP; also a very bad thing. Apart from resulting in gross fluid overload a high CVP in itself is a very bad thing.

WHY a High CVP is a Very VERY Bad Thing (see Chap. 12 )

Following the “widespread” recognition that the CVP/PAOP had no utility in guiding fluid resuscitation [30], the idea that heart-lung interactions during mechanical ventilation could be used to predict fluid responsiveness gained some popularity [38, 39]. The principles underlying this technique are based on simple physiology (see Fig. 9.4) [17, 40]. Intermittent positive-pressure ventilation induces cyclic changes in the loading conditions of the left and right ventricles. Mechanical insufflation decreases preload and increases afterload of the right ventricle (RV). The reduction in RV preload and increase in RV afterload both lead to a decrease in RV stroke volume, which is at a minimum at the end of the inspiratory period. The inspiratory reduction in RV ejection leads to a decrease in left ventricular (LV) filling after a phase lag of two or three heart beats. The cyclic changes in RV and LV stroke volume are greater when the ventricles operate on the steep rather than the flat portion of the Frank-Starling curve [17, 40]. A pulse pressure variation (PPV) or stoke volume variation (SVV) of greater than 13 % were shown to be predictive of fluid responsiveness (see Fig. 9.5) [38, 39]. In a meta-analysis published in 2009 it was demonstrated that the PPV was highly predictive of fluid responsiveness (ROC of 0.94) [14]. Due to its sound physiological basis, good predictive ability and apparent simplicity this technique was met with great enthusiasm and algorithms based on this principle were developed for use in the OR and ICU [42, 43]. However, what was not fully appreciated when the meta-analysis was published was that almost all the studies were performed in a highly controlled environment (usually the OR) in a highly select group of patients [14]. It soon became apparent that a large number of clinical factors interacted to limit the accuracy of the PPV/SVV in predicting fluid responsiveness [44, 45].

Conditions which need to be met (ALL) to ensure accuracy of PPV/SVV:

In a cohort of cardiac surgical patients Lansdorp and colleagues demonstrated that PPV/SVV did not predict volume responsiveness in routine clinical practice [46]. Multiple studies have now confirmed these findings [47, 48]. In the largest study to date, Canneson and colleagues demonstrated that despite a strong predictive value, the PPV was inconclusive in predicting fluid responsiveness in 25 % of patients during general anesthesia [49]. The utility of the PPV/SVV in the ICU appears significantly worse [47, 48]. In a multicenter, point prevalence study Mahjoub and colleagues demonstrate that only 2 % of ICU patients met the validity criteria for using the PPV to assess fluid responsiveness [50]. Furthermore, only 3 % of patients with an arterial line in place satisfied all the validly criteria. These data suggest that due to the frequency of confounding factors the PPV/SVV should not be used as the primary technique for directing fluid management in the OR and ICU. Nevertheless intravascular volume depletion should be suspected in patients who demonstrate marked PPV evident on either an arterial pressure waveform or pulse oximetric waveform. However, in these situations other tests should be performed to confirm fluid responsiveness (see below).