**3. The types of fluids**

of Henle. Besides these mechanisms, the renin release is also controlled by renal sympa-

Renin as an enzyme will then catalyze the conversion of angiotensinogen, a large protein produced in the liver, to angiotensin I, a decapeptide. This is the rate-limiting step of the RAAS pathway (**Figure 3**). Angiotensin I has little biologic activity apart from being the precursor to angiotensin II. Its conversion to angiotensin II involves the removal of two amino acid moieties by the angiotensin-converting enzyme (ACE). ACE is primarily located in the

The ultimate objective of the RAAS, through the activities of angiotensin II and aldosterone as summarized in **Figure 3**, is the preservation of effective fluid volume and pressure. The RAAS demonstrates the strong interconnection between the body fluid and electrolytes in maintaining the fluid homeostasis. In the acute setting, this interconnection is very relevant given the frequent alterations of the electrolyte contents of the body in the acute phase of illness. The assessment of electrolytes in the acute patients should, therefore, be comprehensive and extend beyond the laboratory results. For example, the assessment should also consider the potential electrolyte losses from the gastrointestinal tract, a common organ affected in acute illnesses [7].

The classic microcirculation model, based on the semipermeability of the capillary and postcapillary venule walls, and the presence of hydrostatic and oncotic pressure gradients across these walls had for long described the flux of fluids and electrolytes between the plasma and the interstitial fluid [8, 9]. The identification of the endothelial glycocalyx layer, a web of membrane-bound glycoproteins and proteoglycans on the luminal side of endothelial cells, has now challenged the classic model [10, 11]. The colloid oncotic pressure from the sub-glycocalyx space is a key determinant of the trans-capillary flow. The disruption to the integrity of the glycocalyx layer, or the "leakiness," in a number of acute situations like sepsis [12], trauma, and postsurgery, has been attributed to the development of interstitial edema

pulmonary capillaries, but it is also found in the kidney epithelial cells.

thetic nerves and angiotensin II.

42 Essentials of Accident and Emergency Medicine

**2.3. The microcirculation model**

**Figure 3.** The renin-angiotensin II-aldosterone-system (RAAS).

The history of intravenous fluids began during the cholera pandemic in Europe in the 1830s. The success of Thomas Latta in using a saline solution to resuscitate dying cholera patients paved the way for the widespread use of intravenous fluids and the research to refine their contents [15]. The early milestones in intravenous fluid therapy included the first experiment with albumin in 1834 [16] and the attempt by Sydney Ringer to develop a physiological solution for cardiac contractility with his Ringer's solution in 1876 [17]. Ringer's solution was modified by Alexis Hartmann in 1932 by including lactate to help overcome the acidosis in dehydrated pediatric patients [18]. The gelatins and other solutions with larger molecules only broke into the scene during the Second World War [19], although the first study in humans was performed in 1915 [20]. It is interesting that the history behind the most common type of fluids used, the 0.9% saline, is unclear. The present-day 0.9% saline, often called the "normal saline," has far higher sodium and chloride concentrations than Latta's 1832 saline solution. The only possible connection to 0.9% saline in the history was the in vitro studies of Hamburger in the 1890s that described 0.9% NaCl as an "indifferent solution" in which erythrocytes were least likely to lyse [21, 22].

From the above breakthroughs, the science of intravenous fluids has grown progressively, especially in the last couple of decades. Whether medicine will find an answer to the ideal intravenous fluid will be debatable, but more evidence has emerged in the comparison between the different types of fluids available.

#### **3.1. Crystalloids**

Crystalloids are solutions containing salts in the form of electrolytes and small molecules. The composition of commonly available crystalloids is given in **Table 1**.


[33–35]. Among the explanations suggested for the higher AKI incidence with the chloride-rich fluids like saline is the renal vasoconstrictive response to the high chloride delivery to the macula densa of JGA, a mechanism similar to the regulatory tubuloglomerular feedback [36, 37]. Similar trends of results implicating saline with AKI have been repeated in large retrospective trials [38, 39]. However, the only three large randomized trials comparing saline with balanced solutions to date have shown inconsistent results. These cluster randomized trials either showed no difference in renal outcomes [40] or a significant increase in major adverse kidney events within 30 days in the saline group for both the intensive care and emergency department populations [41, 42].

While large multicenter randomized controlled trials are ongoing to provide stronger evidence on the issue of saline [43, 44], there has been a notable shift in clinical practice with an increasing use of the balanced solutions [45]. 0.9% saline, nonetheless, remains the fluid of choice for patients with metabolic acidosis, hyponatremia, and traumatic brain injury, the

Colloid solutions are characterized by the large molecules suspended in carrier solutions that would also contain electrolytes. The colloid osmotic pressure or oncotic pressure generated by these large molecules helps to retain fluid in the intravascular space longer. The composi-

The volume effect of colloid, when compared to crystalloid, has traditionally been thought to be at a 1:3 ratio. This gives colloid a perceived advantage in reducing the volume of fluid

HES: hydroxyethyl starch. Gelofusine®: B Braun, Melsungen, Germany; Albumex®: CSL Limited, Victoria, Australia;

Voluven®: Fresenius-Kabi, Bad Homburg, German. All concentrations in mmol/L; osmolality in mosmol/kg.

Sodium 140 154 140 48-100 154 Potassium 5 0 0 0 0 Chloride 100 125 128 19 154 Calcium 2.2 0 0 0 0 Magnesium 1 0 0 0 0 Bicarbonate 24 0 0 0 0 Lactate 1 0 0 0 0 Acetate 0 0 0 0 0 Malate 0 0 0 0 0 Octanoate 0 0 6.4 32 0 Real osmolality 287 271 260 130 298

**Plasma Gelofusine® Albumex®4 Albumex®20 Voluven® (HES 6%** 

**130/0.4)**

Approach to Fluid Therapy in the Acute Setting http://dx.doi.org/10.5772/intechopen.74458 45

latter attributed to its relatively high osmolality.

tion of the commonly available colloids is in **Table 2**.

**Table 2.** The composition of commonly used colloids.

**3.2. Colloids**

Plasma-Lyte 148®: Baxter International, Deerfield, IL, USA; Sterofundin®: B Braun, Melsungen, Germany. All concentrations in mmol/L; osmolality in mosmol/kg.

**Table 1.** The composition of commonly used crystalloids.

Based on their differing compositions, crystalloids have been divided into saline solutions and balanced solutions. Saline solutions, chiefly the 0.9% NaCl solutions, are differentiated from the rest of crystalloids by their high contents of sodium and chloride. These concentrations of 150 mmol/L, especially for chloride, are much higher than the plasma concentrations. The 0.9% saline has thus been described as supra-physiological, and the name "normal saline" has been put to question [23, 24]. Balanced solutions, on the other hand, are other solutions like Hartmann's, Plasmalyte 148®, and Sterofundin® that contains more closely resemble human plasma concentrations. These solutions achieve lower sodium and chloride concentrations through the addition of other electrolytes and buffers like lactate and acetate.

The debate is ongoing as to which will be the better choice for the acute population of patients, saline or balanced solutions. While saline is cheap and is still the most commonly used crystalloid in the world, there are significant concerns with its effect on acid-base balance and kidney function. The high chloride contents of saline contribute to the hyperchloremic or strong ion acidosis [25–27], and this has been well shown in different studies in different acute populations [28–30]. Given that acidosis is a common biochemical presentation in the acute setting, such acidosis could confuse patients' assessment. This has made a case for suggesting balanced solutions as the fluid of choice, even when saline has always been the conventional prescription like in diabetic ketoacidosis [31, 32].

On the other hand, the potential risk of acute kidney injury (AKI) from the use of saline is a main research agenda. Changing the intravenous fluid practice from chloride-rich fluids (0.9% saline, 4% succinylated gelatin, or 4% albumin) to chloride-restrictive fluids (Hartmann's solution, Plasma-Lyte 148, and 20% albumin) had been shown to reduce the incidence of AKI in the intensive care and emergency department populations in a single-center, open label sequential trial [33–35]. Among the explanations suggested for the higher AKI incidence with the chloride-rich fluids like saline is the renal vasoconstrictive response to the high chloride delivery to the macula densa of JGA, a mechanism similar to the regulatory tubuloglomerular feedback [36, 37]. Similar trends of results implicating saline with AKI have been repeated in large retrospective trials [38, 39]. However, the only three large randomized trials comparing saline with balanced solutions to date have shown inconsistent results. These cluster randomized trials either showed no difference in renal outcomes [40] or a significant increase in major adverse kidney events within 30 days in the saline group for both the intensive care and emergency department populations [41, 42].

While large multicenter randomized controlled trials are ongoing to provide stronger evidence on the issue of saline [43, 44], there has been a notable shift in clinical practice with an increasing use of the balanced solutions [45]. 0.9% saline, nonetheless, remains the fluid of choice for patients with metabolic acidosis, hyponatremia, and traumatic brain injury, the latter attributed to its relatively high osmolality.

#### **3.2. Colloids**

Based on their differing compositions, crystalloids have been divided into saline solutions and balanced solutions. Saline solutions, chiefly the 0.9% NaCl solutions, are differentiated from the rest of crystalloids by their high contents of sodium and chloride. These concentrations of 150 mmol/L, especially for chloride, are much higher than the plasma concentrations. The 0.9% saline has thus been described as supra-physiological, and the name "normal saline" has been put to question [23, 24]. Balanced solutions, on the other hand, are other solutions like Hartmann's, Plasmalyte 148®, and Sterofundin® that contains more closely resemble human plasma concentrations. These solutions achieve lower sodium and chloride concentrations

Plasma-Lyte 148®: Baxter International, Deerfield, IL, USA; Sterofundin®: B Braun, Melsungen, Germany. All concen-

**Plasma 0.9% NaCl Hartmann's Plasmalyte 148® Sterofundin®**

Sodium 140 150 131 140 140 Potassium 5 0 5 5 4 Chloride 100 150 111 98 127 Calcium 2.2 0 2 0 2.5 Magnesium 1 0 1 1.5 1 Bicarbonate 24 0 0 0 0 Lactate 1 0 29 0 0 Acetate 0 0 0 27 24 Gluconate 0 0 0 23 0 Maleate 0 0 0 0 5 Real osmolality 287 286 254 273 287

The debate is ongoing as to which will be the better choice for the acute population of patients, saline or balanced solutions. While saline is cheap and is still the most commonly used crystalloid in the world, there are significant concerns with its effect on acid-base balance and kidney function. The high chloride contents of saline contribute to the hyperchloremic or strong ion acidosis [25–27], and this has been well shown in different studies in different acute populations [28–30]. Given that acidosis is a common biochemical presentation in the acute setting, such acidosis could confuse patients' assessment. This has made a case for suggesting balanced solutions as the fluid of choice, even when saline has always been the conventional

On the other hand, the potential risk of acute kidney injury (AKI) from the use of saline is a main research agenda. Changing the intravenous fluid practice from chloride-rich fluids (0.9% saline, 4% succinylated gelatin, or 4% albumin) to chloride-restrictive fluids (Hartmann's solution, Plasma-Lyte 148, and 20% albumin) had been shown to reduce the incidence of AKI in the intensive care and emergency department populations in a single-center, open label sequential trial

through the addition of other electrolytes and buffers like lactate and acetate.

prescription like in diabetic ketoacidosis [31, 32].

trations in mmol/L; osmolality in mosmol/kg.

44 Essentials of Accident and Emergency Medicine

**Table 1.** The composition of commonly used crystalloids.

Colloid solutions are characterized by the large molecules suspended in carrier solutions that would also contain electrolytes. The colloid osmotic pressure or oncotic pressure generated by these large molecules helps to retain fluid in the intravascular space longer. The composition of the commonly available colloids is in **Table 2**.

The volume effect of colloid, when compared to crystalloid, has traditionally been thought to be at a 1:3 ratio. This gives colloid a perceived advantage in reducing the volume of fluid


HES: hydroxyethyl starch. Gelofusine®: B Braun, Melsungen, Germany; Albumex®: CSL Limited, Victoria, Australia; Voluven®: Fresenius-Kabi, Bad Homburg, German. All concentrations in mmol/L; osmolality in mosmol/kg.

**Table 2.** The composition of commonly used colloids.

infused during resuscitation. However, data from recent large multicenter trials on the use of different types of colloids suggested a smaller colloid: crystalloid ratio, between 1:1.1 and 1:1.6 [46–49]. The finding of smaller volume effect advantage from colloid than previously thought adds to the predominant concern on the use of colloid—its effects on the kidney.

defined the fluid bolus therapy as delivery of more than 250 mL of either colloid or crystalloid fluid over less than 30 minutes, with crystalloids the most acceptable [61]. These numbers only reflect the majority views on the fluid challenge and must be interpreted in the context of the other aspects of an acute fluid strategy—the fluid responsiveness and the fluid balance.

Approach to Fluid Therapy in the Acute Setting http://dx.doi.org/10.5772/intechopen.74458 47

Clinical assessment is always an integral component of any fluid therapy approach. Identifying body volume repletion and the likelihood to respond to fluid resuscitation should begin with the background history and elicitation of signs of volume deficits, from the peripheral temperature gradient and capillary refill time [62] to the tachycardia, decreased mean arterial pressure, and oliguria. However, reliance on these clinical signs alone for assessment of volume status and responsiveness could be misleading [63–65]. For instance, an increase in the mean arterial pressure following a fluid challenge could be a result of the changes in the

Beyond clinical signs, the indices of fluid responsiveness—both static and dynamic—have been extensively studied. The static index of central venous pressure (CVP), arguably the most commonly used measure of fluid responsiveness, has long been shown to have no meaningful relationship to fluid volume and should be abandoned [66]. Similarly, the more invasive static index measurement of pulmonary artery occlusion pressure (PAOP) has its limitations and

The dynamic indices of fluid responsiveness work on the basis of inducing a change in preload and following up the effects on stroke volume and cardiac output [69]. There are different versions of these dynamic measurements with many evolving around the respiratory variation of hemodynamic indices. Examples include the pulse pressure variation (PPV), the pulse contour-derived stroke volume, the inferior vena cava (IVC) parameters assessed by ultrasonography, and the descending aortic blood flow assessed by esophageal Doppler [70–75]. There are, however, limitations to the observations of these respiratory variations. Some of these are of practical significance, like the need for tidal volumes of >7 ml/kg, the absence of

An approach to assessment of fluid responsiveness that is not affected by the practical ventilatory limitations above is the passive leg raising, PLR [76]. The postural change in PLR transfers around 300 mL of venous blood from the lower body to the heart. The advantage of this is it is an endogenous fluid challenge that is rapidly reversible [77]. To date, the PLR has been deemed as the most reliable measure of fluid responsiveness [78], although an increase in the

It is important to recognize that fluid responsiveness does not necessarily mean that fluid challenges must be given. It also does not mean that patients should be receiving fluid challenges until they are no longer fluid responsive. The hemodynamic benefits of the fluid boluses should be weighed against the risks of accumulating positive fluid balance, with a strong consideration of the use of vasopressors like noradrenaline to improve

arterial vascular tone rather than a true increase in cardiac output.

spontaneous ventilatory efforts, and the absence of arrhythmia.

intra-abdominal pressure or pain could give a false-negative result [79].

does not predict fluid responsiveness [67, 68].

**4.2. Fluid responsiveness**

organ perfusion [80].

Strong evidence emerged in the last decade demonstrating a significant association between the risk of renal dysfunction, measured as AKI, and the need for renal replacement therapy, with the use of hydroxyethyl starch in the acute population of sepsis and intensive care [46, 47]. There are also doubts from observational data on the renal safety of another choice of colloid, the gelatins, in the septic population [50, 51]. The hyperoncotic albumin solutions (20–25%), on the other hand, have been associated with increased risk of renal events when used in cardiac surgery [52] and in patients in shock [53].

Besides these renal effects, colloids are more expensive than crystalloids, and there has been an absence of their clinical superiority over crystalloids in the mortality outcome of studies on different acute populations [49, 54, 55]. All these lead to the call for caution in the use of colloids. The recent Surviving Sepsis Guidelines, for example, strongly recommend against the use of hydroxyethyl starches and place albumin and gelatins as a second choice to crystalloids in sepsis fluid resuscitation [56].
