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result in changes in the frequency of signal output from these receptors. Increases in atrial distention

cause decreased nerve signal traffic, which ultimately causes increased sympathetic tone to the heart,

which results in tachycardia and inhibition of sympathetic tone to the kidney. This leads to increased

renal blood flow and decreased tubular sodium reabsorption. Conversely, low volume in the

intrathoracic vessels results in increased sympathetic tone to the kidneys, decreased renal blood flow,

and increased sodium reabsorption.

The effects of sympathetic activity on renal sodium reabsorption are probably mediated both by

direct tubular innervation and by β-adrenergic stimulation of renin production. Whether this effect is

crucial to fine regulation of sodium balance under normal physiologic conditions is unclear. Renal

denervation in conscious, unstressed animals results in minimal alteration of either blood flow or

sodium reabsorption. The effects of renal denervation become much more marked with anesthesia

administration or hypotension, suggesting that sympathetic effects on renal function may be important

during periods of physiologic stress.

Arterial baroreceptors are located in the aortic arch and carotid arteries. They respond to changes in

heart rate, arterial pressure, and the rate of rise in the arterial pressure. Arterial baroreceptors are

important during periods in which there are extremes in the changes in arterial pressure characteristics,

as occur during hemorrhage. They are probably not involved in controlling subtle volume or pressure

changes. In addition to large-vessel baroreceptors, there are arterial baroreceptors in the afferent

arterioles of the kidneys. These baroreceptors modulate renin secretion. Increases in transmural

pressure cause suppression of renin release, and decreases in transmural pressure stimulate renin

release.

Hormonal Mediators of Volume Control

Renin–Angiotensin System. Renin is a proteolytic enzyme that is released from the juxtaglomerular

cells of afferent arterioles in the kidney in response to several stimuli. These include changes in arterial

pressure, changes in sodium chloride delivery to the macula densa of the distal convoluted tubule,

increases in β-adrenergic activity, and increases in cellular cyclic adenosine monophosphate.

Renin cleaves angiotensin I from circulating angiotensinogen, produced by the liver. Angiotensin I is

cleaved to the octapeptide angiotensin II by angiotensin-converting enzyme (ACE), which is produced

by vascular endothelial cells. One pass through the pulmonary microvasculature converts most

angiotensin I to angiotensin II. Angiotensin II acts both locally and systemically to increase vascular

tone. It also stimulates catecholamine release from the adrenal medulla, increases sympathetic tone

through central effects, and stimulates catecholamine release from sympathetic nerve terminals.

Angiotensin II affects sodium reabsorption by decreasing renal blood flow and glomerular filtration.

This results in altered tubuloglomerular feedback, the mechanism by which changes in distal tubular

NaCl delivery alter glomerular blood flow. Finally, angiotensin II increases sodium reabsorption by

direct tubular action as well as by stimulation of aldosterone release from the adrenal cortex. The

multiplicity of actions of angiotensin is depicted in Figure 11-5.

Aldosterone. Aldosterone is a mineralocorticoid produced in the zona glomerulosa of the adrenal cortex.

Aldosterone increases renal tubular reabsorption of sodium. Aldosterone acts directly on the distal

tubule cells by modifying gene expression and stabilizing the epithelial Na+ channel in the open state

and by increasing the number of channels in the apical membrane of these cells.5 By increasing protein

production in these tubular cells, aldosterone induces an influx of sodium, which causes an increase in

cellular Na+-K+-adenosine triphosphatase activity. The net result is increased sodium reabsorption and

the obligate loss of potassium via the renal outer medullary potassium (ROMK) channel. Although the

primary regulator of aldosterone secretion is angiotensin II, aldosterone release is also stimulated by

increased potassium levels, adrenocorticotropic hormone, endothelins, and prostaglandins.10

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Figure 11-5. Multiple effects of increased angiotensin II release in response to the stimulus of decreased extracellular volume.

Atrial and Renal Natriuretic Peptides. ANP is synthesized and released by atrial myocytes in

response to atrial wall distention. As mentioned previously, small changes in right atrial pressure

produce large increases in plasma levels of ANP.7,8 There is evidence that ANP has a direct inhibitory

effect on renal sodium reabsorption, which is probably maximal at the level of the medullary collecting

tubules. Although pharmacologic doses of ANP can cause changes in both renal blood flow and

glomerular filtration rate (GFR), physiologic levels do not appear to have any major effect on these

parameters. Other active fragments of the ANP prohormone have been found to have natriuretic

activity. The best described is urodilatin, also known as renal natriuretic peptide. Urodilatin is a peptide

with ANP-like activity that was first isolated from human urine. It is synthesized and luminally secreted

by cortical collecting tubule cells. Like ANP, it is released in the kidney tubules in response to atrial

distention and saline loading. It is at least twice as potent as ANP, acting in the distal nephron to cause a

rise in intracellular cyclic guanosine monophosphate, leading to sodium, chloride, and water diuresis.

ANP and other peptides may play an important role in controlling intravascular volume and water and

electrolyte secretion.

Renal Prostaglandins. Renal prostaglandins appear to play a role in volume control, although under

normal physiologic conditions, this role may be minimal. Disease states such as sepsis and jaundice, or

the induction of anesthesia, may make the contribution of the prostaglandins more pronounced.9

Prostaglandin E2

(PGE2

) and prostaglandin I2

(PGI2

) appear to be the predominant prostaglandins

produced in the kidney. PGE2

is produced primarily by the interstitial cells of the renal medulla. The

release of PGE2 has been shown to depend on increases in interstitial pressure, which can be induced by

changes in renal perfusion, ureteral obstruction, or alterations in oncotic pressure. Under these

conditions, PGE2

increases sodium excretion in the absence of changes in GFR. PGE2 antagonizes the

action of vasopressin (ADH) and inhibits ADH-induced sodium reabsorption along the medullary

collecting duct and thick ascending limb. PGI2

is produced by the glomeruli and endothelial cells of the

kidney and is present in the greatest concentrations in the renal cortex. PGI2

is a vasodilator, and its

effects on renal vascular resistance increase both renal blood flow and GFR. PGI2 production is

augmented by increases in angiotensin, catecholamines, and sympathetic tone and may act to

counterbalance their vasoconstricting effects. Although under normal physiologic conditions inhibition

of prostaglandin production has little effect on renal function, administration of nonsteroidal antiinflammatory agents, which inhibit cyclooxygenase, to patients with conditions known to cause renal

dysfunction (e.g., cirrhosis) can precipitate renal failure, presumably because of loss of the protective

effects of the renal prostaglandins.

Endothelins. Endothelins are peptide vasoconstrictors that are involved in volume and pressure

regulation.10 Endothelin is produced and released by endothelial and other cells to act on adjacent

smooth muscle cells. In addition to increasing peripheral resistance, endothelin infusion has a direct

inotropic effect on the myocardium. In contrast to its vasoconstrictive effects, endothelin stimulates the

release of other vasoactive mediators, particularly endogenous vasodilators like nitric oxide, which act

to limit its intense vasoconstrictor effect.

Endothelin exerts a complex influence on sodium and water exchange through varied interactions

with many other hormones that govern fluid and electrolyte balance. One net effect of endothelin is a

decrease in the filtered load of sodium in the kidney. This results in inhibition of water reabsorption and

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decreased sodium excretion. Endothelin increases ANP secretion, activates ACE, and inhibits renin

release by the juxtaglomerular apparatus. At low doses, endothelin-1 produces natriuresis and diuresis.

Endothelin also modulates the biosynthesis of aldosterone, thereby inhibiting water reabsorption

through aldosterone-controlled mechanisms. Vasopressin-mediated water reabsorption is also inhibited.

Endothelin appears to have complex interactions with other regulators of renal perfusion and handling

of water and electrolytes, which has stimulated research to evaluate the contribution of endothelin to

the pathophysiology of various renal diseases.11

Nitric Oxide. Nitric oxide is a short-lived free radical produced from l-arginine by nitric oxide

synthases.11 This substance has numerous biologic functions, including regulation of vascular tone and

tissue blood flow. Nitric oxide is produced in renal smooth muscle cells, mesangial cells, tubules, and

endothelial cells and participates in the regulation of renal hemodynamics and renal handling of water

and electrolytes. Nitric oxide and PGI2 each independently cause renal vasodilation in response to a

variety of stimuli. Nitric oxide contributes to tubuloglomerular feedback, which modulates the delivery

and reabsorption of sodium and chloride in the renal tubules. Nitric oxide also regulates renin release by

the juxtaglomerular apparatus. Nitric oxide produced in the proximal tubule may mediate the effects of

angiotensin on tubular reabsorption.11

Normal Water and Electrolyte Exchange

Surgical patients are prone to fluid and electrolyte abnormalities. It is important to recognize that

disease states, trauma, and stress-related abnormalities – especially those caused by a surgical procedure

– alter many of the body’s fundamental homeostatic mechanisms. It is therefore important to

understand normal fluid and electrolyte balance to avoid additional iatrogenic perturbations of these

mechanisms.

Normal Water Exchange

6 Water losses are both sensible (measurable) and insensible (unmeasurable). Measurable losses include

urinary and intestinal. Table 11-3 summarizes the normal sensible and insensible losses encountered in a

24-hour period. The volumes of these losses may vary considerably especially in disease states. Under

normal conditions, the minimal amount of water needed to excrete normal metabolic waste products is

approximately 300 to 500 mL/day.

The GI tract has a net secretory action down to the level of the jejunum. After that, the resorptive

capacity of the remainder of the small and large bowel acts to keep further water loss to a minimum.

Fecal water loss is usually trivial: ∼150 mL/day. In disease conditions like bowel obstruction, severe

diarrhea, and enterocutaneous fistulas, GI losses of water and electrolytes can be significant causing

secondary pathophysiologic conditions.

Table 11-3 Body Fluid Compartments

Sweating and diaphoresis are active processes involving the secretion of a hypotonic mixture of

electrolytes and water. Sweating functions to allow the convective dissipation of heat. Diaphoresis is a

similar effect, but is a pathophysiologic state stemming from a disease process.

These aforementioned conditions are distinct from the immeasurable, evaporative loss of water from

the skin under normal conditions (Table 11-3). Evaporative skin losses are increased with an increase in

body surface area (especially infants and small children), patient temperature, and the relative humidity

of the environment. Evaporation through the skin functions through convective heat loss and is

proportional to calories expended. Approximately 30 mL of water is lost for every 100 kcal expended.

Respiratory exchange depends on ambient temperature, relative humidity, and on the amount of air

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flow. Overall, normal insensible water losses average approximately 8 to 12 mL/kg/day. Insensible

water loss increases 10% for each degree of body temperature above 37.2°C (99°F). In addition, patients

who breathe unhumidified air lose additional free water. Conversely, patients who are on respirators or

who breathe air that is 100% humidified have no respiratory losses and may gain free water.

FLUID AND ELECTROLYTE THERAPY

Parenteral Solutions

Crystalloids

7 The most widely used parenteral solutions are composed most commonly of sodium and chloride.

They are collectively referred to as crystalloids (based on the solid, room temperature form of the

primary ingredient sodium chloride). Crystalloids are inexpensive and highly effective for fluid

maintenance and rapid volume replacement. They also have excellent safety profiles. Although

crystalloid-induced hypercoagulability has been reported, its causes are multifactorial and poorly

understood.12–15 Clinically, this does not represent a significant problem.

The most commonly used crystalloid solutions available for parenteral administration are found in

Table 11-4. Selection of the appropriate fluid requires assessment of the patient’s maintenance fluid

needs, existing fluid deficits and anticipated ongoing fluid losses. When a single solution does not

accurately replace the required electrolyte components, bolus administration of specific replacement

solutions is commonly performed. It is commonplace to use more than one type of crystalloid solution.

This is commonly seen with parenteral medication formulations that may have specific carrier-fluid

requirements. Ions such as potassium, magnesium, or calcium may be necessary and can be added to

parenteral solutions to suit the patient’s requirements.

Table 11-4 Electrolyte Content of Commonly Used Intravenous Crystalloid

Solutions

Isotonic saline (0.9% sodium chloride or normal saline) contains 154 mEq of both sodium and chloride.

Although this solution can be useful in patients with hyponatremia or hypochloremia, the excess of both

sodium and chloride can lead to acid–base disturbances. For example, infusion of large volumes of 0.9%

saline can lead to a hyperchloremic metabolic acidosis. In addition, the pH of normal saline and of the

related solutions (0.45%, 0.33%, and 0.2% saline) is 4.0 to 5.0 further decreasing the blood pH.

Lactated Ringer solution is a buffered solution composed of the conjugate-base lactate. It was created

in the 1930s by an American pediatrician, Alexis Hartmann, as a treatment for metabolic acidosis. The

solution has a lower sodium and chloride content (130 mEq/L) and adds a very small amount of

potassium and calcium (4 mEq/L each). It is ideal for the replacement of acute fluid losses where serum

electrolyte concentrations are initially normal. Normal renal function usually ensures that any extra free

water from this solution is excreted. Hyponatremia can occur with extended use of lactated Ringer

solution. Furthermore, the presence of potassium in lactated Ringer solution has been a concern when

used in patients with acute kidney injury, although more recent data has suggested that normal saline

(with no potassium in solution) may actually be more likely to cause hyperkalemia in this population

due to metabolic acidosis-induced cellular shifts of potassium from the cell. Although the lactate anion

in lactated Ringer solution is metabolized to bicarbonate in the liver, this does not appear to contribute

to acidosis in normal hepatic function. Work comparing the D,L-racemic mixture of lactate has implicated

the D-isomer in leukocyte activation.16 There are no compelling data to suggest that resuscitation with

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this solution increases the inflammatory response. Utilization of only the L-isomer is presumed to

eliminate this concern.16 Ringer solution is not used as a diluent in blood transfusions given the concern

of calcium being chelated by citrate (an anticoagulant in blood products), which may promote clotting

in donor blood.

For maintenance fluid therapy especially prior to an operation with nil per os status or following

correction of any existing deficits, less concentrated saline solutions are more appropriate to replace

ongoing fluid losses (e.g., nasogastric tube losses). The specific crystalloid selected is best determined

by calculated requirements. These fluids are hypoosmotic and hypotonic with respect to plasma. In

theory, rapid infusion of very hypotonic solutions can result in red blood cell lysis. For this reason, 5%

dextrose (50 g of dextrose per liter) has traditionally been added to these solutions to increase tonicity.

The addition of dextrose is beneficial in pediatric patients who are unable to adequately control glucose

homeostasis due to immature livers. A 5% dextrose solution represents 200 kcal per liter of solution.

Hypertonic saline solutions (HTSs) (3% NaCl and 5% NaCl) are generally used to replace sodium

deficits in patients with symptomatic hyponatremia. These and even more concentrated (7.5% and 23%

NaCl) solutions have also been used for resuscitation of hemorrhagic shock, head trauma, and burn

patients.17–19 Hypertonic saline appears to increase intravascular volume in these patients more quickly

than isotonic solutions. It is believed that the osmotic gradient produced redistributes fluids from the

perivascular and intracellular spaces to the intravascular space with consequent plasma volume

expansion (up to fourfold). This, in turn, may decrease the total resuscitation volume requirement.

When HTS is used for resuscitation of patients with severe sepsis, it has been shown to result in

improvements in oxygen transport, cardiac output, and pulmonary capillary wedge pressure.17 The

systemic and mesenteric oxygen extraction coefficient improves without worsening of other markers of

perfusion. This is achieved by rapid mobilization of fluids from the intracellular compartment to the

extracellular compartment. These cardiovascular and hemodynamic effects are short-lived, in general

lasting from 60 to 120 minutes.

The osmotic effect of hypertonic saline may benefit patients with acute severe brain injury.19 By

reducing the water content of the brain, HTS can help to control intracerebral pressure after injury. In

addition, HTS has immunomodulatory effects, which are well documented.20 HTS reduces the systemic

inflammatory response syndrome and may attenuate multiple organ dysfunction syndrome. HTSs are

not without adverse effects, however. Patients are at risk for electrolyte abnormalities such as

hypernatremia, hyperchloremia, and consequent metabolic acidosis. Extravasation into the soft tissues

can produce significant soft tissue edema and even necrosis.

Colloids

Colloids are composed of large molecules (e.g., albumin) that have a greater tendency to stay in the

intravascular space. They appear to be more effective at enhancing the plasma volume than do

crystalloid fluids. Colloid solutions offer the potential benefits of promoting fluid retention in the

intravascular space and reducing excess interstitial fluid (edema). Worldwide, albumin and artificial

colloids are relied on to a varying degree in fluid management of the surgical patient. In the United

States, concerns regarding the effectiveness, cost, and potential complications of colloid administration

have limited their use to specific clinical situations.

Albumin

Albumin (69 kD) is the primary protein in plasma responsible for oncotic pressure. Exogenous human

albumin is derived from human plasma and heat-treated to reduce the risk of infection. It is available in

a 5% (50 g/L) and a 25% solution (250 g/L) in isotonic saline. These act by increasing plasma oncotic

pressures and theoretically slowing or even reversing movement of water into the interstitial space.

Albumin has an approximate intravascular half-life of 4 hours in conditions of normal physiological

capillary permeability. However, many of the conditions associated with edema are also associated with

abnormalities in microvascular permeability (e.g., systemic inflammatory disease). For example, the

pulmonary circulation in the adult respiratory distress syndrome, regional circulatory beds in

postoperative patients, burns or infections, and the systemic circulation in sepsis all lead to conditions

resulting in increased microvascular permeability. It is, therefore, believed that exogenously

administered protein in colloid solutions quickly extravasate into the interstitial space and paradoxically

intensify – rather than decrease – interstitial edema. The SAFE trial (Saline vs. Albumin Fluid

Evaluation) found no overall difference in organ dysfunction or survival when comparing saline

administration to albumin infusion.21 However, the SOAP trial (Sepsis Occurrence in Acutely Ill

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