Hemodynamic targets are conventionally aimed at the promotion of convective flow, on the assumption that hypovolemia is mainly associated with decreased blood flow. In daily practice, when hypovolemia and tissue hypoperfusion is suspected, fluids are given with the expectation that tissue perfusion and oxygenation will be restored. For this purpose, clinicians use various systemic hemodynamic parameters, such as heart rate, venous pressure, blood pressure, cardiac output, stroke volume variation, and pulse pressure variation to guide the amount of administered fluid. Recent randomized controlled trials suggest that goal-directed therapy aimed at optimizing systemic oxygen transport fails to improve survival.[5,6] Hence, simply correcting global systemic variables is ineffective in promoting microcirculatory and tissue oxygen perfusion. Pottecher and co-workers observed that changes in cardiac output and microvascular variables after fluid administration did not follow each other, suggesting that mechanisms other than changes in cardiac output may affect the microvascular perfusion.[7] Ospina-Tascon et al. [8] and Pranskunas et al. [9] reported similar results when analyzing simultaneously systemic and microcirculatory effects of fluid administration. Both studies showed that improvement of microcirculatory perfusion was not coherently related to increases in cardiac output. Similar results were reported by Silva and co-workers when using gastric mucosal pCO₂ as a surrogate for tissue perfusion.[10] De Backer et al. reported that the relation between systemic hemodynamics and the microcirculation is not fixed, even though cardiac output and blood pressure values may be within normal ranges.[11]

This shows that apparent adequate systemic hemodynamics may be accompanied by derangements in the microcirculation. The persistence of such a condition has been shown to be related to adverse outcome, especially in sepsis.[11] These studies suggest that organ function is more directly related to the success of perfusion and oxygenation of the microcirculation than simply the restoration of systemic hemodynamic variables. Achievement of good microcirculatory function can, in this context, be considered to be the primary target of cardiovascular resuscitation.

Administrating fluids to hypovolemic patients with the aim of achieving an increase in global flow by optimizing systemic hemodynamics can actually result in a decrease of oxygen availability at the cellular level, owing to several mechanisms. Firstly, important reductions in the oxygen-carrying capacity of blood due to hemodilution can cause a decrease in oxygen availability to the parenchymal cells. A second condition might occur in the presence of capillary leak. Tissue edema occurring in this manner can be aggravated when fluids are infused, greatly worsening the diffusive component of the oxygen transport to the tissue cells. A third condition is when fluid administration targeting elevated central venous pressure results in impaired microcirculatory blood flow because of venous tamponade.[12] This detrimental effect might be amplified when using fluid therapy strategies targeting raised venous pressures, as currently recommended in some international guidelines.[13] A fourth condition can be caused by heterogeneous microcirculatory blood flow alterations due, for example, to endothelial and red blood cell dysfunction and leukocyte activation as occurs in sepsis; this can result in the shunting of microcirculatory weak units and lead to regional tissue hypoxia.[14]

These issues indicate that the effects of fluid administration are indeed complex, and that improvement of the macrocirculatory perfusion does not necessarily result in a coherent optimization of the microcirculation. From a physiological point of view, the integration of microcirculatory parameters to hemodynamic monitoring would provide a helpful complement to conventional systemic hemodynamic monitoring. This could allow us to optimize tissue perfusion and to identify conditions where there is a loss of hemodynamic coherence between systemic and microcirculatory determinants of oxygen delivery during resuscitation. To this end, a functional microcirculatory approach has been proposed to optimize fluid administration based on the concept of microcirculatory fluid-responsiveness balancing convective flow to diffusive microcirculatory capacity with the aim of achieving optimal oxygen transport to the cells.[4]

The microcirculation consists of a complex network of small blood vessels (<100 µm diameter) such as arterioles (responsible for modulating local arterial tone to match local metabolic demands), capillaries (acting as the primary exchange place for supplying oxygen and transporting metabolic cell waste products), and the outflow venules (where leukocyte interactions take place and vascular permeability changes largely take place). This complex system consists of different cell types such as endothelial cells inside microvessels, smooth muscle cells (mostly in arterioles), red blood cells, leukocytes, and plasma components in blood. These cellular systems interact with each other and are regulated by different complex mechanisms to optimize microcirculatory perfusion with the aim of providing adequate oxygen transport to the tissue cells.[15]

Microvascular perfusion can be monitored directly by various methods. It can be evaluated indirectly by indices of tissue perfusion and oxygenation such as skin mottling/capillary refill time, mixed-venous and central-venous O₂ saturation, lactate, laser Doppler, tissue pCO₂, and near infrared spectros-copy.[16] Direct monitoring of the microcirculation can be accomplished by hand-held videomicroscopy. Several systems have been introduced. The first such device clinically introduced by us was orthogonal polarizing spectral (OPS) imaging, followed by its technical successor sidestream dark field (SDF) imaging. These first and second generations require video capture and storage of movies followed by off-line analysis of images to quantify abnormalities.[17,18] These devices emit green light with a wavelength (530 nm) which is absorbed by hemoglobin, thereby identifying erythrocytes as dark moving cells through the microcirculation. The area of visualization is about 1 mm².[19] Software-assisted analysis can be used to give several indices related to microcirculatory function. These include the microvascular flow index (MFI), providing information about convective flow of blood, functional capillary density (FCD; that portion of functional capillaries in which there is flow), and proportion of perfused vessels (PPV), which provides information on diffusion distance of oxygen from the capillary vessels to the tissue cells.[20,21]

The use of hand-held vital microscopy has gone through a number of technological developments with the ultimate aim of introducing these devices for routine clinical use. A third-generation device has recently been introduced, called Cytocam incident dark field (IDF) imaging, based on a computer-controlled imaging sensor which allows automatic quantification of images. This development has been made possible by a new hardware platform, consisting of a high-density pixel imaging sensor illuminated by short green light-emitting diode (LED) pulses. Computer-controlled synchronization of illumination and image acquisition allows semi-automatic image analysis. The device is a pen-like probe incorporating IDF illumination with a set of high-resolution microscope lenses projecting images on to the image sensor. The probe is covered by a sterilizable cap.

Cytocam-IDF imaging is based on IDF, a principle originally introduced by Sherman et al.[22] The recent study by Aykut et al. validated this device and showed that 30% more capillaries could be visualized with Cytocam-IDF imaging than with its predecessors.[23] Now that it has been validated, Cytocam-IDF imaging may provide a new improved imaging modality fit for routine use for clinical assessment of microcirculatory alterations in patients.[23] Results obtained from hand-held videomicroscopy has contributed to the understanding that microvascular dysfunction can occur despite optimization of systemic hemodynamic parameters. Several studies have in addition shown that the persistence of such microcirculatory alterations is associated with postoperative complications, increased length of ventilation, and even increased mortality.[24–26]

Besides the correct physiological compartment being targeted when monitoring the effects of fluid therapy, the composition of the type of fluid is also an essential component for optimizing fluid therapy. The chloride content of normal saline is 154 mmol/l, which is much higher than that found in plasma (101 to 110 mmol/l) and also higher than in the so-called balanced solutions such as (modified) Ringer’s or Hartmann’s solution which contain other anions than chloride (for instance, bicarbonate precursors such as lactate, acetate, or gluconate).[27] The difference in chloride concentrations accounts for strong ion difference of these latter solutions, which is closer to the value of plasma (−42 mEq/l). For this reason administration of balanced salt solutions causes less dilution acidosis than does administration of saline.

Saline, however, is still by far the most commonly used fluid for resuscitation. It has the lowest price of all fluids, is relatively safe, and clinicians have an extended experience with its use at the bedside. In a recent trial on the association between saline and postoperative complications associated with hyperchloremic acidosis, McCluskey et al. [28] found that about 35,000 liters of crystalloid solution was used at their institution per year, of which more than 55% was saline. Ince et al. [29] reported that 11,800 liters of saline was used for resuscitation during 12,857 treatment days in their 36-bed mixed intensive care department in 2012, in comparison to 1,630 liters of Ringer’s lactate (RL), the only balanced crystalloid solution used in their department. Unfortunately, over the past decade, evidence is accumulating concerning the deleterious effects of saline. One of the most important problems is thought to be the high chloride content of saline, resulting in hyperchloremic dilutional acidosis.[30]

Hyperchloremia has been shown to be the cause of various adverse effects including afferent renal arterial vasoconstriction in animal models and in volunteers, possibly contributing to kidney dysfunction.[31,32] Three separate studies in pigs comparing 0.9% saline with RL after 30 min of uncontrolled hemorrhage have been described.[33–35] All showed that 0.9% saline required significantly greater volumes to reach hemodynamic targets than RL (256±145 ml/kg saline vs. 126±67 ml/kg RL, p < 0.04).[35] Hyperchloremic acidosis and dilutional coagulopathy were also found with saline.[35] Hypercoagulability and low blood loss were noted with RL.[33] Extravascular lung water index increased with both fluid types, but this occurred earlier and to a greater degree in the saline group.[34] In a hemodilution study in pigs comparing colloids (0.6% hydroxyethyl starch [HES]) with crystalloids, using hematocrit as a target for hemodilution, Konrad et al. [36] showed that much less colloid than crystalloid was required to reach similar targets, demonstrating the effectiveness of colloids for volume expansion. Similarly in a rat hemorrhagic shock study, where blood pressure was targeted as a resuscitation endpoint, much less of a balanced crystalloid solution was required to reach target in comparison with the unbalanced crystalloid solution.[37]

In 30 patients undergoing major surgery, randomized to receive either 0.9% saline or Plasma-Lyte 148 at 15 ml/kg per hour, those receiving saline had significantly increased chloride concentrations (∆[Cl⁻] +6.9 vs. +0.6 mmol/l, p < 0.01), decreased bicarbonate concentrations (∆[HCO₃⁻] −4.0 vs. −0.7 mmol/l, p < 0.01), compared with those receiving Plasma-Lyte 148.[38] There are two randomized controlled double-blind trials (n = 66 and n = 51) comparing 0.9% saline with RL in the perioperative period, with both showing that the use of 0.9% saline resulted in more adverse events than RL.[39,40] In patients undergoing abdominal aortic aneurysm repair, those receiving saline needed significantly greater volumes of packed red blood cells (780 vs. 560 ml), platelets (392 vs. 223 ml), and bicarbonate therapy (30 vs. 4 ml) than those receiving RL.[39] Hyperchloremic acidosis was found in the saline group, but this did not result in a difference in outcome.[39]

Recent large observational studies [28, 41–43] have suggested that the high chloride content of 0.9% saline may cause adverse events, especially when renal outcomes are considered. Assessment of outcomes in a propensity-matched study of 2,788 adults undergoing major open abdominal surgery who received only 0.9% saline, and in 926 patients who received only a balanced crystalloid on the day of surgery, showed that unadjusted in-hospital mortality (5.6 vs. 2.9%) and the percentage of patients developing complications (33.7 vs. 23%) were significantly greater (p < 0.01) in those receiving 0.9% saline than in those receiving the balanced crystalloid.[41] Although mortality in the saline group remained higher after correction for confounding variables, the difference ceased to be significant. Patients in the 0.9% saline group also received an average of 316 ml more fluid (p < 0.001), had a greater need for blood transfusion (odds ratio [95% CI]: 11.5 [10.3 to 12.7] vs. 1.8 [1.2 to 2.9]%, p < 0.001), and had more infectious complications (p < 0.001), and were 4.8 times more likely to require dialysis (p < 0.001) than those in the balanced crystalloid group. Overall complications were fewer in the balanced crystalloid group (odds ratio [95% CI]: 0.79 [0.66 to 0.97]).

Another study on 22,851 surgical patients with normal preoperative serum chloride concentration and renal function showed that 22% incidence of acute postoperative hyperchloremia.[28] Of the 4,955 patients with hyperchloremia after surgery, 4,266 (85%) patients were propensity matched with an equal number of patients who had normochloremia postoperatively. Patients with hyperchloremia were at increased risk of 30-day postoperative mortality (3.0 vs. 1.9%; odds ratio [95% CI]: 1.58 [1.25 to 1.98]) and had a longer median hospital stay (7.0 days [interquartile range 4.1–12.3] vs. 6.3 days [interquartile range 4.0–11.3], p < 0.01) than those with normal postoperative serum chloride concentrations.[28] Patients with postoperative hyperchloremia were also more likely to have postoperative renal dysfunction as defined by a 25% decrease in glomerular filtration rate (12.9 vs. 9.2%, p < 0.01). All these studies have shown that hyperchloremic acidosis is not a benign, self-limiting metabolic disturbance. It can be stated that 0.9% saline is neither “normal” nor “physiological” and that its high chloride content can lead to many pathophysiological changes, especially in renal function. These negative changes were not seen after infusion of balanced crystalloids.

A further topic of controversy concerns the effect of balanced and unbalanced solutions on immune suppression and modulation of coagulation.[27] It has been assumed that normal, unbalanced saline has proinflammatory properties relating to neutrophil activation.[44,45] This could contribute to detrimental effects in trauma and sepsis resuscitation. Balanced solutions such as RL may also be proinflammatory, although it has been shown that the D-lactate form was responsible for such effects.[45,46] Nevertheless, on the basis of current literature there is adequate evidence to suggest that the effects of balanced crystalloids are less detrimental than those of 0.9% saline, especially in relation to renal function.

Although balanced solutions have some advantages over 0.9% saline, normal saline is a better choice of fluid than RL in certain clinical scenarios such as brain injury where its isotonicity is of benefit.[47,48] A subset analysis of the SAFE trial showed the superiority of saline over albumin for brain injury patients where the hypo-osmolality of the albumin solutions was thought to contribute to increased intracranial pressures.[49] The plasma osmolality of the albumin used in that study was in the range of 280–300 mosmol/kg H₂O whereas saline osmolality is 286 mosmol/kg H₂O, which can be considered isotonic. RL, on the other hand, is hypo-osmolar (257 mosmol/kg H₂O) and can potentially promote tissue edema and cause cells to swell, especially in conditions where there is a damaged vascular endothelial barrier such as can occur in brain injury.[50]. However, Roquilly et al., who used a balanced solution in head injury patients, found that its use was comparable to 0.9% saline, with patients showing no difference in intracranial pressure increases following fluid therapy.[51] Finally, some of the acetate-based solutions contain calcium, which is contraindicated for blood tranfusions where blood has been preserved in citrate-based solutions.[52]

The most important impact of fluid therapy is determined by the amount of fluid administered.[4] Although fluid therapy is essential in the treatment of hypovolemia and tissue hypoperfusion, overhydration and a positive fluid balance are considered harmful and contribute to organ dysfunction.[4,53–56] Fluids dilute blood and can decrease its oxygen-delivering capacity. Less than 3% of oxygen transported by blood is dissolved in plasma and fluids. Fluids transport hardly any oxygen in themselves and are only effective in promoting blood flow. This means that fluid therapy has a limited window of efficacy: excess fluids cause a reduction in the oxygen-carrying capacity of blood by causing too much hemodilution while having limited effects on cardiac output and microcirculatory blood flow.[4,36,57,58] In a clinical study, Arikan et al. showed that fluid overload causes a reduction in the oxygenation index associated with adverse outcomes in pediatric patients.[59] Crystalloid fluids can decrease mortality in hypovolemic patients, but optimal type and dose of fluids remain to be defined.

Colloids have three- to four-fold greater plasma volume-expanding and hemodynamic effects compared with crystalloids and are the fluid of choice when volume expansion is indicated as a result of hypovolemia.[60–63] The Colloids versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was designed to compare colloids and crystalloids in need of volume expansion due to hypovolemia. The trial included 1,443 patients in the crystalloid group and 1,414 patients in the colloid group. Hypovolemic shock was the primary diagnosis in each group. The trial showed that the use of colloids vs. crystalloids did not result in a significant difference in 28-day mortality, although 90-day mortality was lower among patients in the colloid group. Additionally, no evidence of an increased risk of renal replacement therapy was detected in the colloid group.[64] Another study, Crystalloid versus Hydroxyethyl Starch Trial (CHEST), involved 7,000 adults in the ICU. In that study, the use of 6% HES (130/0.4), as compared with saline, was not associated with a significant difference in 90-day mortality (relative risk, 1.06; 95% CI, 0.96 to 1.18; P = 0.26). Although not an endpoint, the use of HES was associated with a slight increase in the rate of renal replacement therapy in a subset of the initial included patient group. However, there was a lower vasopressor requirement for the patients with HES.[65] Even though starches have been brought into disrepute in two large randomized control trial studies (the CHEST and 6S trials), it is important to realize that these colloid fluids were administered to patients who were not hypovolemic and in need of volume expansion, and their results should be interpreted with reservation. Indeed, in the CRISTAL trial where patients were truly hypovolemic and in need of volume expansion, colloid, of which the majority was starches, resulted in an outcome benefit. In a microcirculation trial in septic shock patients, Edul and co-workers compared 6% HES 130/0.4 to saline solution targeting mean arterial pressure. They found that fluid resuscitation with 6% HES 130/0.4 needed less volume than saline solution to normalize sublingual microcirculation.[66]

Atasever et al. [67] compared red blood cell transfusion to gelatin solutions and to no infusion after cardiac surgery, and studied the effect on microvascular perfusion, vascular density, hemoglobin, and oxygen saturation. They found no difference in changes in systemic delivery O₂, O₂ uptake, and extraction between the groups. Relative to gelatin or control, however, red blood cell transfusion increased perfused microcirculatory vessel density, hemoglobin content, and saturation in the microcirculation, while microcirculatory blood flow remained unchanged. Restricted fluid policy (usually defined as <7 ml/kg per hour), on the other hand, has been suggested in randomized studies in surgical patients to result in fewer complications than standard or more liberal fluid strategy, regardless of the type of solution used.[53–55,68–71] From this point of view, colloid administration offers advantages since less volume is needed, although care should be taken to protect vulnerable organs such as the kidney.

Microcirculatory-guided fluid resuscitation would provide a more physiologically based approach and possibly avoid fluid overload.[4] Targeting the microcirculation in this way may provide an important complement to targeting systemic hemodynamic variables. Functional microcirculatory hemodynamics (FMH), in parallel to the concepts underlying functional hemodynamics, may provide a new approach because observing the microcirculation allows verification of whether administration of fluids is successful in promoting convective flow. It can also establish the presence of microcirculatory fluid responsiveness.[4,7,9] The conceptual framework underlying FMH for optimal administration of fluids, introduced by Ince [4], is shown in Figure 12.2. The diagram is adapted from the work by Bellamy [72] and Peng and Kellum [73] who demonstrated the dilemma over how to decide the optimal volume of fluid to be administered to a specific patient. Shown on the x-axis of Figure 12.2 is the amount of fluid administered, and on the y-axis the risk of developing complications. This figure illustrates that in states of hypovolemia both too little and too much fluid are associated with clinical complications. In the concept of FMH, position A in Figure 12.2 is defined as true hypovolemia where, in the presence of clinical signs of hypovolemia, there is slow microcirculatory convective flow. This situation in FMH indicates the need for fluid administration.

Figure 12.2

The conceptual framework of functional microcirculatory hemodynamics. The relation is shown between fluid volume administration on the x-axis and the chances of developing clinical complication on the y-axis (adapted from [72] and [73]). The left side of the diagram indicates hypovolemia, where position A defines the condition in which clinical indicators of organ hypoperfusion coincide with reduced convection, indicating the need for fluid administration. Microcirculatory fluid responsiveness is indicated by improvement in flow (from A to B). Optimal convection and optimal diffusion (conserved FCD) define the optimal amount of fluid volume administration shown in position B. A diffusive limitation, which signals that too much fluid has been administrated, develops as a result of prolonged diffusion distance when RBC-filled capillaries are lost.

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