Fluid Physiology Part 2: Regulation of Body Fluids and the Distribution of Infusion Fluids

Abstract

The regulation of body fluids and infusion fluid distribution is a critical aspect of intensive care management. In this chapter, we explore the various control systems that maintain fluid balance in the body, including the kidneys, nervous system, and hormones. We also discuss the impact of disease and medical treatments on these control systems and the resulting fluid derangements, such as hypovolemia, volume depletion, and dehydration. The use of infusion fluids to distribute into the different body fluid spaces is analyzed, including the plasma, extracellular fluid, and total body water. Hemodynamic responses and signs of organ dysfunction are the main clinical guides for fluid management, while electrolyte disturbances induced by disease and medication are also discussed. Volume kinetic analysis is utilized to compare the efficacy of crystalloid and colloid solutions, and the limitations of body fluid volume measurements are also examined. This chapter provides essential insights for intensivists and other medical professionals involved in the management of critically ill patients.

FormalPara IFA Commentary (MLNGM)

We continue a similar but also different deep dive in the second part on fluid physiology. Are colloids and crystalloids really different with respect to their plasma volume-increasing or volume-expanding effects? In conditions of low blood pressure and hypoperfusion (e.g., postoperative or shock state, after anesthesia induction, and trauma), it seems that as long as they are infused crystalloids and colloids have similar effects compared to healthy volunteers where colloids have a greater effect on effective plasma volume. Can we talk about the pharmacokinetics and pharmacodynamics of fluids in analogy to antibiotics or other drugs? Volume kinetics is an adaptation of the pharmacokinetic theory that makes it possible to analyze and simulate the distribution and elimination following an infusion of intravenous fluids. Applying this concept, it is possible, by simulation, to determine the infusion rate that is required to reach a predetermined plasma volume expansion. Fluid pharmacokinetics describes how the body affects a drug, resulting in a particular plasma and effect site concentration. The pharmacokinetics of intravenous fluids depends on distribution volume, osmolality, tonicity, oncoticity, and kidney function. Eventually, the half-time depends not only on the type of fluid, but also on the patient’s condition, comorbidities, and the clinical context. Fluid pharmacodynamics relates drug concentrations to their specific effect. For fluids, the Frank–Starling relationship between cardiac output and cardiac preload is the equivalent of the dose–effect curve for standard medications. Because of the shape of the Frank–Starling relationship, the response of cardiac output to the fluid-induced increase in cardiac preload is not constant. This chapter will give a concise overview of fluid kinetics and dynamics with a focus on fluid intake and fluid loss and the important role of the cell and capillary membrane. It will discuss the Starling equation and edema formation and how organ dysfunction (e.g., kidney, neurologic, cardiovascular, and endocrine) may alter fluid homeostasis. An overview will be given on daily electrolyte needs (Table 3.1) the different crystalloid and colloid solutions and how they may have different impacts on fluid efficiency (Fig. 3.1).

Table 3.1 Daily electrolyte requirements

Fig. 3.1

Different volume expansion effects in stable (not critically ill) conditions after 1 h of administration of 1 L of IV solution

FormalPara Learning Objectives

After reading this chapter, you will:

• 1. Know what the normal need for fluid is in a human and what might cause this need to change.

• 2. Understand how osmotic and colloid osmotic pressure in an infusion fluid alters its distribution between body fluid compartments.

• 3. Comprehend the traditional Starling equation.

• 4. Identify how fast glucose can be administered by intravenous infusion without causing harm and how this can be monitored.

• 5. Learn the cardiac and renal responses to dehydration and fluid loading.

Introduction

The turnover of fluid is fairly slow in humans, with a basic need of 1.0 mL/kg/h. The body has limited tolerance for losses of body fluid, so the intensivist has to deal with derangements such as hypovolemia, volume depletion, and dehydration. An infusion fluid can be tailored to distribute into any of the body fluid spaces, including the plasma, the extracellular fluid space, or the total body water. The fluid balance is controlled by the kidneys, the nervous system, and hormones; however, these control systems may be dysfunctional during intensive care due to the disease and the medical treatment. The key clinical guides to fluid management are the hemodynamic responses to fluid and the signs of organ dysfunction, such as lowered pH, plasma lactate, and plasma creatinine. Volume expansion is often needed during the initial treatment phase due to vasodilatation and disturbances of the adrenergic system. Judicious fluid administration is recommended later in the course of disease, because fluid underload and overload are both problematic. Electrolyte derangements may be induced by disease and/or medication. The most essential electrolyte disturbances to consider involve sodium, potassium, calcium, and bicarbonate. Volume kinetic analysis shows a pronounced distribution phase for bolus doses of crystalloid fluid. Colloid fluid provides a two to three times stronger plasma volume expansion, but the difference between colloid and crystalloid solutions disappears after 6–12 h, depending on arterial pressure. Measurements of body fluid volumes can be performed but have limited applicability due to the complex methodology. See also Chap. 2 for the first part on fluid physiology.

Fluid Balance

Fluid Intake

Water constitutes between 50% and 60% of the body weight in adult females and males, respectively, with some decrease over the lifespan. The water volume is distributed over two compartments, the intra- and extracellular fluid spaces (ICF and ECF, respectively); the ECF is further divided into plasma and interstitial fluid. These volumes are tightly controlled by hormonal, neurological, and cardiovascular mechanisms.

The turnover of fluid in the body is fairly slow. The basic need for fluid is 1.0 mL/kg/h, i.e., 1.2 L/day in a patient weighing 50 kg and 2.4 L in a patient weighing 100 kg. To obtain a reasonable margin, the basic need is usually set 25% higher.

The so-called 4/2/1 rule provides a recommendation for suitable water intake for children. This rule suggests 4 mL/kg/h for infants weighing 3–10 kg; 40 mL/kg plus 2 mL/kg/h for each kg over 10 kg for children weighing 10–20 kg; and 60 mL/h plus 1 mL/kg/h for each kg over 20 kg in children weighing >20 kg.

Fluid Losses

Fluid losses from the body consist primarily of insensible water losses (i.e., evaporation, which is mostly derived from the airways) and baseline diuresis. These two sources each account for half of the water loss in a fasting individual. A small amount of water, approximately 300 mL/day, is created in the body as a result of the metabolism of glucose. Water losses by sweating are normally quite small, but these increase in fever conditions and during physical exercise.

The body has a limited tolerance for losses of body fluid. The blood volume, which is a part of both the ICF and ECF, is particularly sensitive. A loss of blood volume below normal is called hypovolemia. The arterial pressure is maintained by catecholamine release during blood losses of up to 20% of the blood volume (approximately 1 L in the adult) although cardiac output falls. The body then changes strategy to vasodilatation, which creates an abrupt drop in pressure. The reason for this changeover is unclear from a physiological point of view; however, a low flow and low blood pressure more effectively allow blood clots to form, which is beneficial in uncontrolled hemorrhage.

Loss of extracellular fluid is called volume depletion and occurs in patients experiencing diarrhea and vomiting. Finally, loss of total body water is due to insufficient intake of water and is common in the elderly. The hallmark of insufficient water intake is a rise in serum osmolality to 300 mosmol/kg or more. This condition is often called dehydration in daily language, but it is more specifically hyperosmotic dehydration or else intracellular volume depletion and occurs in patients experiencing diarrhea and vomiting. Finally, loss of total body water is due to insufficient intake of water and is common in the elderly. The hallmark of insufficient water intake is a rise in serum osmolality dehydration. In conscious humans, dehydration quickly leads to poor mental and physical performance.

Table 3.2 shows the effect of fluid loss and gain on interstitial, plasma, and intracellular volume and plasma tonicity.

Table 3.2 Effect of fluid loss and gain on interstitial, plasma, and intracellular volume and plasma tonicity

Fluid Movement and Edema Formation

Cell Membrane

Movements of fluid between the body fluid volumes are determined by specific factors. The distribution across the cell membrane, i.e., the separation between the ICF and ECF, is governed by osmolality and the permeability of the cell membrane for the molecules that contribute to the osmolality. For example, sodium is important for fluid distribution because only small amounts of this ion enter the cells, and whatever amount enters is quickly expelled via the sodium–potassium pump. By contrast, ethanol markedly raises the osmolality but does not redistribute water because ethanol easily passes through the cell membrane. Many molecules, such as amino acids, have intermediate characteristics and may, like glucose, be actively pumped into the cells, and water then follows by virtue of osmosis. Therefore, the influence of a glucose solution on the fluid distribution is time-dependent. The ability of a solution to redistribute water across the cell membrane is called its tonicity. A saline solution with a concentration higher than 0.9% withdraws fluid from the ICF to the ECF and is therefore called hypertonic. By contrast, pure water is strongly hypotonic, as it distributes across the cell membrane in proportion to the sizes of the ICF and ECF. An ethanol solution can be hyperosmotic while still being hypotonic.

Capillary Membrane

The capillary membrane separates the blood from the interstitial fluid. This membrane allows the filtration of fluid from the plasma to the interstitium through pores and fenestrations over a very short distance of the length of the capillary. The pores are either small (40–45 Å) and allow small ions to pass with ease, or they are large (250 Å) and allow proteins to pass. The proteins follow the flow of fluid through the large pores, in a process called convection, and leave the plasma at a rate of 5–8% per hour. This means that small molecules, such as electrolytes and glucose, are filtered freely in both the small and large pores, while macromolecules (such as albumin) pass slowly through the large ones only. Filtered fluid is mostly returned to the plasma by lymphatic flow, while absorption from the interstitium to the plasma occurs in the gastrointestinal canal and lymphatic glands. Absorption also occurs from other body areas in hypovolemic states.

In healthy humans, the hydrostatic pressure in the capillaries is 17–25 mmHg, whereas it is slightly negative, at about −3 mmHg, in the interstitial fluid. The interstitial fluid space is filled with proteoglycan filaments and collagen fibrils that bind the tissues together. The connective tissue has an initial low compliance for volume expansion, which counteracts fluid accumulation. The jelly-like consistency of the interstitium restricts the rapid movement of fluid, whereas electrolytes and metabolic products diffuse almost freely.

The interstitial fluid volume corresponds to 15% of the body weight; of this, only two-thirds becomes expanded by an infusion of crystalloid fluid. Very dense areas of the interstitial fluid space, such as bone tissue, might even be difficult to expand by fluid at all.

The osmolality created by the macromolecules is called the colloid osmotic pressure. It accounts for only a small fraction of the total osmolality in the body fluids but is still, together with the hydrostatic pressure, the pressure that determines the distribution of fluid between the plasma and the interstitium. A colloid infusion fluid that expands the plasma volume by its own volume is considered iso-oncotic.

The difficulty for macromolecules to pass the endothelium is partly explained by the existence of a layer on the luminal side of the endothelium called the glycocalyx. This layer might be degraded in inflammatory states and ischemia, which then accelerates the passage of macromolecules. The functions of the glycocalyx layer have been mostly disclosed during the past 25 years, and many details of its physiological role probably remain to be established.

The integrity of the glycocalyx layer in living humans can be explored by filming the microcirculation with a camera placed on the nail bed or below the tongue. Alternatively, molecular constituents of the glycocalyx layer, such as syndecan-1, heparan sulfate, and hyaluronic acid, are found in increasing concentrations in plasma and urine. However, so far, linking increasing plasma levels to a physiological effect in humans has been challenging.

The Starling Equation

Fluid exchange across the capillary membrane was investigated by the English physiologist Ernest Starling (1866–1927) who, in 1896, formulated his Starling Equation, which is still considered to be valid. The “traditional” equation summarizes the factors that determine the transcapillary exchange in the following way:

$$ \mathrm{Fluid}\ \mathrm{exchange}={K}_{\mathrm{f}}\;\left[\left({P}_{\mathrm{c}}-{P}_{\mathrm{i}}\right)-\sigma\;\left({\pi}_{\mathrm{p}}-{\pi}_{\mathrm{i}}\right)\right] $$

where K_f is a proportionality constant, P_c and P_i are the hydrostatic fluid pressure in the capillary and interstitium, respectively, and π_p and π_i are the colloid osmotic pressure in the plasma and interstitial fluid, respectively. The symbol σ is the reflection coefficient, which explains how easily macromolecules pass through the capillary wall. A reflection coefficient of 1.0 means that the membrane is impermeable, and 0 means that the molecule passes without any difficulty. The value of σ greatly varies between vascular beds.

Recent microcirculatory research suggests that the principles behind the Starling equation need to be revised due to the active role played by the endothelial glycocalyx layer in forming the transcapillary fluid equilibrium. These alternations are discussed in detail by Tom Woodcock in the first chapter of this book.

Edema Formation

Edema develops in response to the rapid infusion of crystalloid fluid, which overwhelms the capacity of the lymphatic system to return the infused volume. Edema can also occur due to the blunted return of fluid from the interstitial fluid space to the plasma, as in the case of acute burns, toxicosis of pregnancy, and sepsis. A gradual loss of the elastic properties of the interstitial meshwork of proteoglycans occurs if volume expansion progresses. Massive expansion of the interstitial fluid space, corresponding to a crystalloid fluid infusion of approximately 7–8 L, finally overcomes the negative pressure. The tissue then breaks up, and fluid accumulates in small pools or lacunae in the skin and certain organs, such as the heart.

The brain is not subject to edema by fluid overload with isotonic fluid. Instead, brain edema arises due to metabolic or physical damage or reductions in serum osmolality. Edema is particularly critical in this organ as the skull provides the brain with only a limited capacity to swell.

The Importance of Organ Function

The Kidneys

Approximately 20% of the renal plasma flow is filtered in the glomeruli and creates the primary urine. The renal blood flow and the glomerular filtration rate are affected by the arterial pressure, but they are autoregulated between 80 and 160 mmHg. The primary urine is refined within the kidneys with regard to volume and the composition of small molecules. The kidneys have a remarkable capacity to match variability in the intake of water with urinary excretion. Proteins are not excreted in healthy humans.

Normal urinary excretion in an adult is 1.0–1.5 L per 24 h. Excretion of less than 400 mL is called oliguria and less than 100 mL is called anuria. The reasons for anuria can be pre-renal (low arterial pressure), intra-renal (kidney injury), or post-renal (renal stones and outflow obstruction).

Poor urinary excretion is often treated with a bolus infusion of 500 mL of crystalloid fluid in case the patient is hypovolemic. A second treatment is an injection of loop diuretics, which increase sodium excretion and urine volume. A third method is to boost urinary excretion with 100–200 mL of hyperosmotic 10–20% mannitol, which is not metabolized and only eliminated by osmotic diuresis.

Nervous Control

The autonomic nervous system maintains a balance between parasympathetic and sympathetic nervous impulses. The sympathetic impulses are of particular interest for fluid balance, as they constrict arterioles, which raises peripheral resistance. Sympathetic impulses also constrict large veins, which increases cardiac output, and stimulates the release of noradrenaline and adrenaline from the adrenals into the blood. These are short-acting hormones that cause vasoconstriction, although adrenaline causes vasodilatation in muscle tissue.

Urinary excretion is reduced by beta-1-receptor stimulation, which can be created by providing the drug isoprenaline, while diuresis is increased by alpha-1-stimulation, which is achieved by phenylephrine.

Hormones

Besides the two hormones excreted from the adrenal medulla, which are under the control of sympathetic nerves, a number of other agents also affect the fluid balance. Cortisol is excreted from the adrenal cortex. This stress hormone has profound effects on metabolism, but it also promotes fluid retention by increasing the reabsorption of sodium in the kidneys. Cortisol excretion is elevated by surgical stress.

Renin is excreted by the kidneys in response to low arterial pressure. Renin activates a vasoconstrictor and angiotensin and further stimulates the secretion of aldosterone, which is another hormone that reduces sodium excretion and thereby promotes water retention in the body.

Vasopressin (antidiuretic hormone) is excreted from the brain in response to high serum osmolality. This hormone acts on the kidneys to increase the reabsorption of water. Vasopressin is important for the long-term correction of the body’s fluid balance in plasma concentrations between 1 and 6 pg/mL. Very high plasma concentrations, up to several hundred pg/mL, occur in response to any short period of hemorrhagic hypotension. In this range, the hormone also has a vasoconstrictive effect. Despite the short half-life of vasopressin, the elevation of its plasma concentration is sufficient to cause renal fluid retention that lasts for several hours.

Atrial natriuretic peptide (ANP) is excreted in response to the distention of the atrial muscle cells of the heart. The key effect of ANP is to decrease the blood volume by increasing sodium excretion and capillary leakage of proteins. A structurally similar hormone, brain natriuretic peptide (BNP), is released from the cardiac ventricles in response to distention. These hormones act on the same receptors, but ANP exerts a stronger effect.

Vasopressin, ANP, noradrenaline, and adrenaline exert immediate effects and have short half-lives, whereas the steroid hormones cortisol and aldosterone act more slowly.

Cardiac Response to Fluid

The typical hemodynamic response to volume loading with an infusion fluid is an increase in cardiac output, with no change in arterial pressure, while peripheral resistance decreases. The rise in cardiac output requires a sufficient venous return and the ability of the heart to pump more fluid. Cardiac output does not increase if the vascular system is already adequately filled with volume. The ability of the heart to pump more volume in response to fluid loading is called fluid responsiveness. This can be tested in many ways, both by infusing a bolus volume of fluid (during general anesthesia) or by recording the response in cardiac stroke volume to leg lifting (“passive leg raising test” in the conscious patient). Providing infusion fluid to a patient who is not fluid-responsive is hardly meaningful, as it impairs oxygen delivery and raises the central venous pressure. However, a patient can be made more fluid-responsive by the administration of adrenergic drugs.

Monitoring of the central hemodynamic response to volume loading has a key role in guiding fluid therapy and will be reviewed in greater detail elsewhere in this book.

Electrolytes

Sodium

This ion is essential to nerve function and is the most abundant positively charged ion in the ECF. Sodium is essential for maintaining fluid balance across the cell membrane. Sodium enters the cells, but, as already mentioned, intracellular sodium is actively pumped out to the ECF again. The normal plasma sodium concentration is 133–146 mmol/L. A drop in concentration below 130 mmol/L triggers the appearance of nervous system symptoms, consisting of confusion and various degrees of muscular weakness and depressed consciousness [1, 2]. Severe forms of hyponatremia, involving brain damage, correspond to plasma concentrations below 120 mmol/L.

Hyponatremia can be acute (excessive water ingestion), subacute (2–3 days after surgery), or chronic (unhealthy diet, kidney injury, and diuretics). The chronic form is most commonly seen in intensive care. The speed at which hyponatremia is restored must match the rate at which it has developed because the brain adapts slowly to a new ionic environment [3]. Hypernatremia also blurs consciousness, and the cause is usually iatrogenic.

Chloride

This is the negatively charged ion that balances the sodium ion in the ECF. Elevated concentrations, which are usually iatrogenic, reduce urinary excretion by local vasoconstriction and are associated with acidosis. Hypochloremia arises as a result of vomiting and causes metabolic alkalosis.

Calcium

Half of the calcium in plasma is abound to albumin and the other half is the biologically active free ionized fraction, which is important for muscle and nerve function and serves as a co-factor for coagulation proteins.

Infusion of approximately 4 L of fluid that lacks calcium (0.9% saline and PlasmaLyte) dilutes the calcium concentration enough to impair muscle function. The deterioration also includes the heart, whereby cardiac output decreases. Blood transfusions having citrate as a preservative have the same effect, but they work by binding calcium rather than diluting the concentration. Intravenous calcium is an effective treatment.

Injections of large amounts of calcium stop the heart in systole; however, in a clinical setting, plasma calcium is rarely high enough to disturb heart function.

Bicarbonate

This ion has a profound importance for the acid–base balance due to its capacity to buffer hydrogen ions; however, perhaps even more importantly, it increases the strong ion difference to create a neutral blood pH. Sodium bicarbonate is marketed as a hypertonic infusion fluid and might be considered for temporary relief in severe metabolic acidosis (pH < 7.0). Instead, the chief therapeutic effort should be directed toward treating the cause of the acidosis.

Potassium

This is the most abundant positively charged ion within the cells, whereas its concentration in the ECF is quite low (3.6–5.1 mmol/L). A deviation of 50% from the upper or lower border of the normal range may have a fatal outcome on the heart. The effect of potassium on the heart is opposite that of potassium, but arrhythmia is the most typical sign of abnormal values.

Acute stress causes a temporary shift of potassium from the ECF to the ICF and is often seen after trauma and surgery. The mechanism is adrenergic beta-2-receptor stimulation. Therefore, hyperkalemia can be treated with adrenaline. Chronic hypokalemia is usually the result of diuretic therapy or an aberrant diet.

Potassium should be added to infusion fluids used for maintenance therapy (20–40 mmol/L). Due to the risk of cardiac arrhythmias, it should be provided no faster than 10 mmol//h unless the electrocardiograph is monitored continuously. Hence, infusions with a higher potassium concentration than the plasma cannot be administered at a high rate.

Crystalloid Fluid Solutions

Ringer’s Solution

Ringer’s solutions are aimed to resemble the composition of the ECF fluid. However, the sodium concentration is 130 mmol/L, which is lower than in the plasma (mean 138 mmol/L). A buffer (lactate or acetate) is usually added to maintain a normal pH. These fluids still exert a slight acidifying effect. Both lactate and acetate also have some vasodilating properties. These solutions are slightly hypotonic (270 mosmol/kg).

Ringer’s solutions are distributed from the plasma across the ECF volume in a process that requires approximately 30 min for completion. However, very small amounts (5 mL/kg) undergo barely any distribution and almost exclusively fill up the plasma volume [4]. Larger volumes infused over 30 min expand the plasma volume by approximately half its volume. When the infusion is turned off, the plasma volume expansion rapidly falls until full equilibration in the ECF volume has been achieved. Thereafter, the fluid is eliminated by voiding with a half-life of between 20 and 40 min (volunteers) to several hundred minutes (arterial hypotension, anesthetized patients).

The suitable rates of infusion of Ringer’s solutions are often said to be limited only by the patient’s hemodynamic capacity. However, large-scale infusions (75–100 mL/kg over 30 min) change the integrity of the interstitial meshwork of the interstitial fluid space and thereby promote edema [4]. Body areas that are particularly susceptible to crystalloid fluid overload, such as the skin, lungs, and gastrointestinal wall, have a high compliance for volume expansion. Volume loading might also cause degradation of the endothelial glycocalyx layer. However, infusing 25 mL/kg seems to be innocuous in this respect [5].

Ringer’s solutions are used to expand the ECF volume, which is needed to combat fluid and blood losses during surgery and intensive care. ECF volume expansion also compensates the blood flow for disturbances of the autonomic nervous system, which occur due to general anesthesia and severe disease.

Other Crystalloid Fluids

Normal (0.9%) saline is an isotonic fluid that contains only sodium and chloride in equal amounts. The fluid causes slight metabolic acidosis when the infused volume is 2 L or more. The half-life in volunteers is twice as long as for Ringer’s solutions and amounts to approximately 90 min [6]. The indication for isotonic saline is restricted to hyponatremia and volume replacement after vomiting.

Saline may also be used in a 3% or 7.5% solution to combat brain edema or severe hyponatremia, and for fluid resuscitation in acute trauma care. These hypertonic fluids should not be infused together with erythrocytes.

Mannitol is a sugar isomer that can only be eliminated by urinary excretion. The half-life is almost the same as for isotonic saline. Mannitol is iso-osmotic in a 5% concentration but is used in a 10–20% preparation to treat brain edema and to stimulate diuresis. Hypertonic mannitol contains no electrolytes, which are therefore excreted along with the osmotic diuresis. The resulting decrease in the electrolyte concentrations in the ECF causes post-infusion cellular swelling (rebound effect).

Glucose (dextrose) fluids are maintenance solutions. They cannot be infused as liberally as the previous crystalloid solutions due to an accompanying rise in plasma glucose. A glucose solution is iso-osmotic at a 5% concentration, which only contains 200 kcal/L. This small amount of calories can only prevent starvation and does not provide adequate nutrition. The chief indication for its use is to prevent hypoglycemia and severe muscle wasting and to provide water for hydration of the ICF space.

The main problem with glucose solutions is that intravenous administration trespasses the gastrointestinal hormones that aid the glucose metabolism. Hence, the hyperglycemic effect of an intravenous infusion is much greater when compared to oral intake of glucose. Even worse, the trauma associated with intensive care causes resistance to the effects of insulin. Therefore, plasma glucose should be measured often and not allowed to rise above 9–10 mmol/L. This is usually achieved by not allowing 1 L of glucose 5% to be infused over a shorter time period than 6 h [7].

The use of glucose solutions of concentrations higher than 5% should be monitored carefully with measurements of plasma glucose. Insulin administration is often needed. The aim is then to increase the administration of calories and/or to restrict the administration of fluid volume.

Allowing very high plasma concentrations of glucose (>12 mmol/L) is discouraged, not only because they promote bacterial growth, but also because osmotic diuresis develops. If cardiac arrest develops, any brain damage will be greater in the hyperglycemic compared to the normoglycemic patient [8].

Colloid Fluid Solutions

Colloid fluids contain water, electrolytes, and a macromolecule that contributes to the intravascular colloid osmotic pressure. Large volumes improve the microcirculation and slightly impair coagulation. In contrast to crystalloids, colloids all share an allergic potential. Hence, colloid fluids should only be given if drugs to combat allergic reactions are at hand.

Albumin is the chief plasma protein and is marketed for plasma volume expansion in iso-oncotic or nearly iso-oncotic preparations (3–5%) and in a hyper-oncotic concentration (20%). Albumin also serves as an antioxidant.

The 4% albumin preparation expands the plasma volume by approximately the same amount as the infused volume. The half-life of its plasma volume expansion is several hours, which is closely related to the intravascular persistence of the albumin [9]. The intravascular persistence is probably shorter in septic patients due to increased capillary leakage of albumin [10].

The 20% preparation increases the circulating plasma volume by twice the infused volume [11].

Repeated infusions of large amounts of albumin put a burden on protein metabolism and urea excretion, which can be an issue in intensive care patient.

There is no evidence that albumin promotes kidney injury in septic patients [12].

Hydroxyethyl starch (HES) is a colloid solution prepared from plants. HES preparations are colloids intended for plasma volume expansion. The most widely used, Voluven (Fresenius Kabi), expands the plasma volume by as much as the infused amount. The elimination is complex and involves a mixture of urinary excretion, molecular cleavage, and phagocytosis.

Impairment of kidney function has been associated with the use of HES in septic patients. Therefore, HES has only limited importance as a plasma volume expander in intensive care.

Gelatin contains small colloid molecules prepared from animals. Elimination is by renal excretion. Therefore, the volume expansion is claimed to be short-lived (2 h). Allergic reactions are fairly common but are mostly limited to fever reactions.

Plasma expands the plasma volume by as much as is observed with 5% albumin [9]. However, plasma should not be used for volume expansion because plasma contains coagulation proteins and has a greater allergic potential than 5% albumin.

Measurement of Body Fluid Volumes

Many techniques can be used to assess the body fluid volumes. These were of greatest importance in the 1950s and 1960s but are considered too cumbersome for clinical use today. However, these methods are still used in research and have contributed much knowledge about macroscopic fluid physiology.

The leading principle is the dilution concept. A substance that distributes in one body fluid space only is injected and allowed to equilibrate. A blood sample is taken, and the volume occupied by the injected substance is calculated as the dose divided by the plasma concentration. This principle is most attractive if the turnover of the injected substance is slow. If not, several samples must be taken into account for substance elimination.

Tracers for the measurement of the ECF volume include bromide, which has a slow turnover, and iohexol, which also yields the glomerular filtration rate. To use iohexol, several samples must be taken into account for urinary excretion of the tracer [13].

Tracers for the measurement of total body water are tritium (radioactive) and deuterium (not radioactive). Several hours are required for equilibration. Ethanol has been proposed for this purpose, as ethanol is a solvent and distributes evenly in water alone [14].

The plasma volume has frequently been measured with radioiodinated albumin, which is radioactive. Several blood samples are usually taken. Evans blue is a dye that colors albumin in the plasma. Plasma tracers overestimate the plasma volume by almost 10% [15]. Indocyanine green (ICG) is also a dye that binds to plasma albumin. The half-life is only 3 min, due to rapid uptake by the liver [16]. The transit time from injection in the central circulation to the liver is approximately 1 min. Whether ICG overestimates the plasma volume is not known.

The red cell mass can be measured with labeling techniques, such as chromium, technetium, and carbon monoxide.

Bioimpedance (BIA) uses the fact that water volumes oppose electrical currents and that the opposition is different inside and outside the cells. BIA is measured by running a series of electrical currents through the body, usually from the arm to one leg, and then evaluating the impedance pattern in relationship with the quantification of the body fluid volumes by tracer techniques [17]. The measurement requires about 1 min to complete and is painless, but it is disturbed by body movements.

Anthropometric equations are created based on tracer measurements. They point out typical correlations between body fluid volumes and characteristics of the individual, such as gender, height, and weight [18, 19]. The most common assumptions are that the blood volume constitutes 7%, the interstitial fluid 15%, the ECF volume 20%, the ICF volume 35–40%, and the total body water 55–60% of the body weight. Albeit crude, these assumptions are quite useful in everyday clinical work.

Fluid Efficiency

The intravascular volume expansion resulting from infusing a fluid is often related to the amount infused. The concept of fluid efficiency has two characteristics: the degree and the duration of volume expansion relative to the infused volume. Tracer methods have been used to assess fluid efficiency, and physiological endpoints are also useful.

A widely used approach is to use hemodilution for this purpose. The hemodilution tells us over how large a space the infused fluid volume has distributed. The hemodilution will be quite large if a colloid fluid distributes only over the plasma volume (Fig. 3.2).

Fig. 3.2

Plasma dilution in ten volunteers (thin lines) and the simulated average (thick) during and after a 30-min infusion of 10 mL/kg hydroxyethyl starch (Voluven). (From Ref. 22)

The volume of distribution of a fluid that spreads across the total body of water can also be estimated using the dilution concept, although the hemodilution will be much smaller. If we specifically want to estimate how much the blood volume has increased, we must assume a blood volume at baseline, which may or may not be correct.

Commonly used equations assume that the hemoglobin concentration is measured before (Hb) and after (Hb(t)) the infusion. Here, BV denotes the blood volume at baseline.

$$ {\displaystyle \begin{array}{c}\varDelta BV=\mathrm{BV}\left(\mathrm{Hb}/\mathrm{Hb}(t)\right)-\mathrm{BV}\\ {}\mathrm{Fluid}\kern0.17em \mathrm{efficiency}=\varDelta BV/\mathrm{infused}\kern0.17em \mathrm{volume}\end{array}} $$

These relationships assume that no bleeding occurs. If this is the case, then the intensivist can estimate the total hemoglobin mass as BV × Hb, from which losses of Hb are subtracted. The new Hb mass is then divided by Hb(t) to yield the new BV [20]. This calculation is very useful clinically.

A key insight is that hemodilution should ideally parallel the relationship between bleeding and BV. The patient is hypervolemic if the hemodilution is greater than the blood loss divided by BV, whereas the patient is hypovolemic if the hemodilution is small in relation to the bled volume.

Volume Kinetics, Basic Concepts

The hemodilution concept can be elaborated upon to capture flows of fluid between body fluid compartments over time. This approach is called volume kinetics and has similarities to pharmacokinetics. One important difference is that the walls of the body fluid compartments are expandable [21]. Another difference is the choice of input variable. In conventional pharmacokinetics, the plasma concentration of the drug to be studied serves as the input. For volume kinetics, hemodilution is used to capture the distribution of the infused water volume. With regard to volume, the blood contains almost exclusively Hb and water. If Hb is decreased, the water component of the blood is increased. The increase in the blood water concentration then seems to yield the same concept as a drug concentration in conventional pharmacokinetics. Sadly, though, this is an illusion, because the rise in blood water concentration that occurs when a fluid is infused represents a dilution of administered water in a much larger water volume. This fact adds some requirements to the calculations.

The blood volume is not important to the calculations, but volume kinetics is still based on serial analysis of the blood Hb concentration and, at best, the urine volume as well, during and after infusion of a fluid in a controlled setting. The results have shown that the interstitial fluid space after expansion by a crystalloid fluid is only twice as large as the plasma volume, i.e., less than commonly assumed. The distribution of crystalloid fluid occurs with a half-life of 8 min, except in association with an abrupt drop in arterial pressure, when distribution is temporarily arrested. Hence, when the blood pressure drops, it does not matter if one infuses a crystalloid or a colloid fluid.

The simple experiment shown in Fig. 3.2 illustrates the basic thoughts on volume kinetics. Serial measurements of Hb in ten volunteers are performed during and after a 30-min infusion of 10 mL/kg of hydroxyethyl starch in ten male volunteers weighing 80 kg. The hemodilution is corrected for baseline hematocrit to express the plasma dilution. Extrapolation to time 0 of the exponential elimination curve yields a plasma dilution of 0.3. If we divide the infused volume (800 mL) by the plasma dilution at time 0 (i.e., 0.3), we obtain the volume of distribution for the infused starch volume. This is almost precisely 3.0 L, which is the expected plasma volume in these volunteers [22]. From this estimation, we can conclude that the starch preparation only distributes in the plasma volume.

We can also obtain the half-life of the intravascular persistence from Fig. 3.2. By plotting the curve on a logarithmic paper, it becomes apparent to the naked eye that half of the plasma volume expansion has subsided after 120 min. The volume expansion of the starch preparation lasts for 4 half-lives, i.e., 480 min.

The volume kinetic calculations become more complicated, necessitating the use of a computer, when crystalloid electrolyte fluids and glucose solutions are studied. Here, the infused fluid is assumed to distribute between a central fluid space, which is the plasma, and a peripheral fluid space, which is the interstitial fluid. Fluid distributed from the plasma to the interstitium is governed by a rate parameter k₁₂ and the return of fluid by another rate parameter k₂₁. The elimination of fluid, mostly by urinary excretion, is determined by a rate parameter k₁₀. Figure 3.3 shows how volume kinetics can reveal that the edema and hypovolemia in toxicosis of pregnancy are due to poor return of distributed fluid, whereas the diuretic response to infused fluid is well maintained [21].

Fig. 3.3

Output of volume kinetic analysis of an infusion of 10 mL/kg Ringer’s acetate in eight women with mild–moderate degree of toxicosis of pregnant and eight pregnant controls matched for a gestational week. Three rate parameters determine the distribution of infusion fluid. Edema is caused by poor return of fluid after distribution to interstitial fluid space (low k₂₁). (From Ref. 21)

Crystalloids Versus Colloids

The difference in fluid efficiency (sometimes called potency) between crystalloid and colloid fluids can be disclosed over time using volume kinetics. The colloid is more efficient during infusion and during the distribution phase of the crystalloid (Fig. 3.3), which can be more precisely quantified by plotting the ratio between the plasma volume expansion yielded by the two infusions (Fig. 3.4).

Fig. 3.4

(a) Plasma volume expansion resulting from infusing 1 L of 5% albumin and Ringer’s acetate in volunteers. (b) The ratio between the plasma volume expansion during and after infusion of 1 L of hydroxyethyl starch and Ringer’s acetate over 1 h. (Simulations based on volume kinetic data taken from Ref. 9 and 22)

Using typical kinetic data for conscious volunteers, the colloid is twice as effective as a crystalloid during infusion and is three times more effective during the distribution phase of the crystalloid, while the difference between the two types of infusion disappears at 12 h (ratio = 1.0).

The elimination of crystalloid fluid is greatly retarded during general anesthesia due to the reduction in arterial pressure [21]. By contrast, the intravascular persistence of a colloid fluid does not seem to be affected by the arterial pressure. Therefore, the ratio between a colloid and a crystalloid infusion will reach 1.0 by 5–6 h after a 60-min infusion and by 10 h during continuous infusions. These calculations do not assume any injury to the endothelial glycocalyx layer. The fact that the better plasma volume expansion from a colloid fluid is only temporary has caused much confusion in intensive care [23].

The finding of a transient 50% plasma volume expansion of crystalloid electrolyte fluid is worrying in the presence of a hemorrhage that has not been stopped surgically. The recommendation that three times the bled volume should be infused leads to hypervolemia, with a high risk of rebleeding if a major vein is injured. Moreover, urinary excretion is almost normal, despite hypovolemia, at least as long as the arterial pressure is unchanged, and this leads to a later rebound hypovolemia. One would think that the body would retain a sufficient amount of the infused fluid to restore and maintain normovolemia, but this is not the case. Therefore, optimal handling is to infuse 1.5 times the bled volume over 30 min and not to stop the infusion, but to gradually reduce the rate of infusion by 50% every 30 min. This practice restores the blood volume while avoiding both hyper- and hypovolemia [24].

Goals of Fluid Therapy

A primary goal of fluid therapy in intensive care is to safeguard cardiovascular sufficiency to ensure normal tissue perfusion and oxygenation of the body organs. For this purpose, the response of cardiac output to fluid administration is a useful guide. However, it might be questioned whether striving toward a high cardiac output is needed in the absence of signs of organ dysfunction (normal plasma lactate, creatinine, low pH, etc.). Using repeated fluid boluses to achieve this goal might lead to overhydration and problems with edema later in the disease process.

Both fluid underload and overload are problematic; hypovolemia causes a convection limitation because too little blood and oxygen reach the capillaries. Fluid overload creates another problem, diffusion limitation, because interstitial edema increases the distance that oxygen and metabolic products must travel between the capillaries and the cells [25]. To avoid mistakes, combinations of fluids and vasopressors/inotropes are titrated carefully to find an optimal fluid balance situation where organ function is preserved.

Systemic vasodilatation and disturbance of adrenergic function are the main reasons why fluid therapy should be aggressive in the early stages of severe disease. To avoid fluid-associated complications, early deliberate fluid overload must later be reversed by applying a dehydrating strategy (de-escalation). More about fluid management during these stages is discussed in other chapters of this book.

Arterial pressure, central venous pressure, and urinary excretion only give vague signals about inappropriate fluid therapy. Central venous pressure rises when the volume of administered fluid has passed the flat portion of the Frank–Starling curve, but this pressure might be affected by other stimuli as well. Arterial pressure and urinary excretion do indicate underhydration, but only at a very late stage. Clinical judgment is blurred by the release of a host of hormones and cytokines, as well as drug effects and therapeutic interventions, such as mechanical ventilation, which affect fluid physiology.

The management of fluid therapy during intensive care is a difficult task that requires skill, knowledge, and good clinical judgment to ensure normal tissue perfusion and oxygenation of the body organs. The tools are given in this book, but it takes a good doctor to use them successfully.

Take Home Messages

• Plasma volume expansion is needed during the initial treatment phase of acute disease due to vasodilatation and disturbances of the adrenergic system.

• The “traditional Starling equation” summarizes the factors that determine the transcapillary exchange in a way that is sufficient in most practical settings.

• Fluid accumulation and fluid overload cause edema by, in part, a gradual loss of the elastic properties of the interstitial meshwork of proteoglycans.

• A drop in plasma sodium to below 130 mmol/L triggers the appearance of nervous system symptoms, consisting of confusion and various degrees of muscular weakness and depressed consciousness.

• Infusion of approximately 4 L of fluid that lacks calcium (0.9% saline and PlasmaLyte) dilutes the calcium concentration enough to impair muscle function. The deterioration also includes the heart, whereby cardiac output decreases.

• The fluid efficiency is the plasma volume expansion divided by the infused fluid volume. This is 0.5 for a crystalloid fluid infused over 30 min, approximately 0.8 for 5% albumin, 1.0 for hydroxyethyl starch 130/0.4, and 2.0 for 20% albumin.

• The blood volume expansion during infusion of crystalloid fluid is at least 50% as long as the infusion is continued. The reason for this is the slow distribution. After infusion this fraction drops to 20% within 30 min.

• If mean arterial pressure decreases by 20% (e.g., after induction of anesthesia, during surgery, in case of hypovolemic shock), crystalloid distribution stops and 100% of the infused fluid then remains in the blood. The explanation for this is the Starling mechanism.

• Excretion of a crystalloid fluid is very slow during anesthesia. The reason for this observation is mainly the reduced arterial pressure, while the pressure hardly affects the intravascular persistence of colloid fluids. This helps us to understand why crystalloids and colloids in this setting may have similar volume expansion effects.