Regulation of Acids, Bases, and Electrolytes

Regulation of Acids, Bases, and Electrolytes


The prominent roles of the lungs and the kidneys in acid-base homeostasis were described in Chapter 8. In this chapter, we take a more in-depth look at precisely how the lungs and the kidneys perform these functions. Regarding the regulation of volatile acid, some of the major factors that control and regulate ventilation in health and disease are reviewed.

This is followed by a review of kidney (renal) function. Processes used by the kidneys to excrete wastes and to maintain fluid and electrolyte balance are examined. In particular, sodium regulation and its effect on blood bicarbonate are explored.

The effects of certain therapeutic interventions, such as diuretics and steroids, are also considered. In addition, the value of the serum electrolyte profile in evaluating acid-base disturbances is discussed.


As described earlier, the volume of carbon dioxide (and, therefore, volatile acid) excretion varies directly with the quantity of alveolar ventilation. The amount of alveolar ventilation, in turn, depends on the mechanisms responsible for the control and regulation of ventilation. Thus, a brief review of the major factors that regulate ventilation in health and disease is in order.

The control of ventilation is a complex physiologic process. The major factors that play a role in the regulation of ventilation are shown in Figure 12-1. The primary respiratory center (generator) is located in the medulla of the brain (medullary center). Output of the medullary center is influenced by several other centers in the brain that affect respiration. The apneustic and pneumotaxic centers in the pons tend to modify the ventilatory pattern, and the cerebral cortex may participate in voluntary input into the system.

Reflexes and chemoreceptors serve to measure the output of the system and provide feedback loops back to the medulla. As such, reflexes and chemoreceptors play a vital role in the regulation of ventilation. Although a detailed analysis of all the factors that mediate ventilation is beyond the scope of this text, a basic review of the chemoreceptors and a few prominent reflexes is important to understand arterial blood gas application.


The chemoreceptors are probably the single most important mechanism by which ventilation is regulated. Two basic groups of chemo- receptors influence ventilation: (1) the central chemoreceptors, located within the central nervous system; and (2) the peripheral chemoreceptors, located within the cardiovascular system.

Central Chemoreceptors

Blood-Brain Barrier

The CSF is separated from the blood by the blood-brain barrier, which is readily permeable to gases but relatively impermeable to ions. Gases equilibrate quickly across the blood-brain barrier. Some ions, such as bicarbonate, may tend to equilibrate across the barrier, but the exchange process is active transport rather than simple diffusion. The active transport of ions across the blood-brain barrier may take a considerable time (i.e., hours to days)81 compared with the immediate diffusion of gases.

Thus, when the PaCO2 increases, PCO2 in the CSF immediately follows suit. This, in turn, lowers the pH of the CSF, and the ventilatory drive is augmented within minutes. In metabolic acidosis, however, the bicarbonate ion is transported slowly out of the CSF. Therefore, it takes longer for the pH of the CSF to decrease, and consequently the ventilatory response is delayed.

Cheyne-Stokes Ventilation

It is noteworthy that even with respiratory (i.e., PCO2) gas changes, there is some delay from the time when the alveolar PCO2 changes until this change is reflected in the CSF. This time delay explains why the ventilatory response to increased or decreased alveolar PCO2, although highly sensitive, is not instantaneous. Furthermore, if circulation is impaired, such as in congestive heart failure, this delay may be exaggerated because it takes longer for blood from the lungs to reach the medulla. In theory, this circulatory delay may explain the Cheyne- Stokes breathing that is sometimes observed in congestive heart failure.

Cheyne-Stokes breathing is a recurrent pattern of ventilation characterized by a progressive rise and fall of tidal volume (Fig. 12-2). A period of apnea may sometimes occur between cycles. The related alveolar and central chemoreceptor PCO2 levels at different points in the breathing cycle are also shown in Figure 12-2.

Peripheral Chemoreceptors


The second group of chemosensitive cells (chemoreceptors) that affects ventilation is located adjacent to the walls of certain arterial blood vessels. These peripheral chemoreceptors are located in two distinct anatomic areas: the carotid and aortic bodies.

The carotid bodies are a group of cells located near the bifurcation of the common carotid artery into the internal and external carotid arteries. They appear as small, pink nodules, approximately 3 to 5 mm in diameter.81 The aortic bodies are located within the arch of the aorta.

The two sets of cells, which are referred to collectively as the peripheral chemoreceptors, serve to chemically monitor the blood passing by them. To perform this function, the peripheral chemoreceptors receive a relatively large blood flow in proportion to their size.


Although both the peripheral and central chemoreceptors respond to increased PaCO2 and decreased pH, they are not equally sensitive to these stimuli. Specifically, a relatively large increase in PaCO2 or a decrease in pH (e.g., PaCO2 increase = 10 mm Hg; pH decrease = 0.1)81 is necessary before a notable increase in ventilation will be triggered via the peripheral chemoreceptors. Conversely, the central chemoreceptors respond to very slight changes in PaCO2. In a normal young man, minute ventilation increases approximately 2.5 L with only a 1-mm Hg increase in PaCO2.81


The response of the peripheral chemoreceptors to a low PaO2 sets them apart from the central chemoreceptors and is their most important mechanism clinically. Even in normal humans, some, albeit few, impulses are sent to the brain from the peripheral chemoreceptors stimulating ventilation. PaCO2 and the central chemoreceptors are the primary mechanisms of ventilatory control during normal ventilation.

Regulation of ventilation in pulmonary disease is often in marked contrast. Here, the peripheral chemoreceptors often play the dominant role in determining the ventilatory pattern. The number of peripheral chemoreceptor impulses sent to the brain to stimulate ventilation in hypoxemia may increase greatly. Initially, ventilatory impulses increase only slightly as PaO2 falls slightly below the normal range. When PaO2 falls below 60 mm Hg, however, there is a dramatic increase in impulse production and ventilation.

Not only do the peripheral chemoreceptors greatly stimulate ventilation when PaO2 falls below this critical point; they also stimulate the cardiovascular system. Clinically, this is manifested by a rise in heart rate and arterial blood pressure. Restoration of PaO2 to normal, however, allows ventilation, heart rate, and blood pressure to return to normal levels.

Chemoreceptor Interactions

The breathing pattern observed at any given time is the net result of the integration of various different inputs. As stated earlier, messages may originate from brain centers, chemoreceptors, reflexes, or even voluntary commands. Notwithstanding, the chemoreceptors are often the most dominant forces that control ventilation. In some situations, the peripheral and central chemoreceptors work together for a potentiated response. In other circumstances, they tend to antagonize each other and blunt individual responses. A few examples of chemoreceptor interactions follow.

Acute Hypoxemia

In the presence of disease, the peripheral chemoreceptors may take the dominant role in the regulation of ventilation. For example, in acute, severe hypoxemia, the peripheral chemoreceptors send a powerful message to the brain to increase ventilation and generally will override the central chemoreceptors. Subsequently, the increased ventilation that accompanies severe, acute hypoxemia lowers PaCO2. The decreased PaCO2, in turn, has the effect of making the CSF alkalotic and depressing ventilation via the central chemoreceptors.

Thus, in acute hypoxemia, two conflicting messages are sent to the brain. The severe hypoxemia requires an increase in ventilation via the peripheral chemoreceptors, whereas the low PaCO2 depresses the central chemoreceptors. Because the number of impulses resulting from severe hypoxemia is large and the decrease in impulses resulting from the falling PaCO2 is small, the individual will display a net increase in ventilation. It is important to recognize, however, that the central chemoreceptors tend slightly to blunt the hyperventilation.

Mild Disease

The initial blood gas abnormality associated with mild pulmonary disease is mild hypoxemia with a normal PaCO2 (see Table 12-1). In this early stage, the increase in peripheral chemoreceptor stimulation is so minute that it is not clinically detectable. The central chemoreceptors maintain primary control over ventilation.

Moderate Disease

As deterioration in external respiration continues, PaO2 continues to decline. At a PaO2 level of approximately 60 mm Hg (although there may be considerable individual variation with regard to the specific PaO2 when this occurs), a dramatic increase in peripheral chemoreceptor stimulation is seen, and the peripheral chemoreceptors assume primary control of ventilation. The strong peripheral chemoreceptor drive usually results in an increase in alveolar ventilation and a fall in the PaCO2 (see Table 12-1).

It is important to note that, during this phase, the cardiovascular system is also required to increase the heart rate and to elevate the blood pressure. From a teleologic perspective, because O2 levels are falling to a critical point on the oxyhemoglobin curve, the cardiovascular system appears to be trying to ensure sufficient tissue O2 delivery.

Severe Disease

If external respiration continues to deteriorate, CO2 excretion is ultimately impaired and PaCO2 levels begin to increase. Furthermore, PaO2 levels continue to fall (see Table 12-1). Indeed, the classic definition of acute respiratory failure is a PaCO2 greater than 50 mm Hg and/or a PaO2 less than 50 mm Hg.

The same pattern of progressive pulmonary deterioration can also occur over a short time (days or hours) in acute pulmonary disease. This pattern may be observed in pneumonia, postoperative respiratory failure, or acute asthma. It is always important to identify patients with moderate impairment (i.e., moderate disease as described in Table 12-1), because further deterioration leads to hypercarbia. The classic example of this is the patient in status asthmaticus (sustained unresponsive asthma) whose condition deteriorates progressively over a period of days, leading ultimately to exhaustion and to the abrupt onset of respiratory acidemia.

In patients with severe chronic lung disease, administration of oxygen may lead to progressive hypercapnia and occasionally even to apnea. For years, it was believed that this occurred because these patients were breathing exclusively in response to the so-called hypoxic drive of the peripheral chemoreceptors. It was assumed that the central chemoreceptors had become dulled because of the chronic hypercarbia; it followed, then, that oxygen therapy increased the PaO2 and knocked out the drive to breathe.

Other studies have shown that the worsening hypercarbia associated with oxygen therapy in these patients is more likely a result of ventilation-perfusion alterations than a result of a decrease in ventilatory drive.463 Furthermore, the Haldane effect (release of CO2 from Hb into the blood in the presence of increased oxygen) may be responsible for some of the ensuing hypercarbia.464 The precise mechanism responsible for this hypoventilation remains a controversial issue and multiple factors may be influencing ventilation simultaneously. Regardless of the exact mechanism, worsening hypercarbia must be recognized as a possible consequence of oxygen therapy in chronic lung disease.


At least six different reflexes have been described in relation to the regulation of ventilation.81 The precise role of many of these reflexes must still be defined. Nevertheless, two reflexes may be useful in helping the clinician to understand the origin of respiratory alkalosis in certain pulmonary conditions.

Hering-Breuer Reflex

The Hering-Breuer reflex, or stretch reflex, is probably the most widely known of the reflexes involved in the regulation of ventilation. This reflex appears to regulate tidal volume and respiratory rate to minimize the muscular work of breathing.

The Hering-Breuer reflex is not usually active during normal breathing. Rather, it is activated when the lung is overinflated or underinflated. The Hering-Breuer reflex is often described as two separate reflexes: an inflation reflex, which inhibits inspiration, and a deflation reflex, which stimulates inspiration when the lung volume is low.

The deflation reflex may be responsible, at least in part, for the hyperventilation observed in restrictive lung diseases. The ventilatory pattern commonly observed in these patients is characterized by a rapid respiratory rate and a low tidal volume. This pattern, although beneficial in terms of the work of breathing, may lead to respiratory alkalosis.


The renal system has essentially three primary functions. First, the kidneys are responsible for excreting nonvolatile waste products, including fixed acids. Second, the kidneys are responsible for the regulation of blood volume. Third, the kidneys must regulate blood concentrations of various electrolytes (e.g., HCO3) and other blood constituents.

Macroscopic Anatomy and Physiology

The gross anatomy of the kidney is shown in Figure 12-3. Each of the two kidneys consists of an outer cortex and an inner medulla. Urine formed in the functional units of the kidney gathers in the renal pelvis and then flows through the ureters down to the urinary bladder, where it is stored. Ultimately, urine is excreted through the urethra.

Microscopic Anatomy and Physiology

The functional unit of the kidney is the nephron. Each kidney contains approximately 1 million nephrons. A schematic drawing of the functional nephron is shown in Figure 12-4. Blood enters the nephron through the afferent arteriole, which in turn enters an enclosed capsule. This capsule, called Bowman’s capsule, is actually the first portion of the renal tubular system.

Encased within the capsule, the afferent arteriole branches into a capillary network and then leaves Bowman’s capsule through the efferent arteriole. The capillary tuft or network within the capsule is called the glomerulus. The capillaries that make up the glomerulus are very porous, and much of the plasma is filtered into Bowman’s capsule. The fluid that accumulates within the capsule is called the glomerular filtrate, which begins its journey through the nephron.

The tubule that the glomerular filtrate passes through immediately upon leaving Bowman’s capsule is called the proximal tubule, because it is close (proximal) to the capsule. Actually, this tubule follows a very convoluted path, and it is sometimes referred to as the proximal convoluted tubule. The glomerular filtrate then travels through the loop of Henle, the distal convoluted tubule, and, ultimately, the collecting duct. The fluid that accumulates in the collecting duct is essentially urine, which then flows to the renal pelvis en route to be excreted.

Urine Formation

Three processes are involved in the formation of urine: (1) glomerular filtration, (2) tubular reabsorption, and (3) tubular secretion. Through these processes, the kidney can accomplish its functions, which are described at the beginning of this section.

Glomerular Filtration

The glomerulus functions as a semi-permeable membrane that allows for the diffusion of fluid similar in ionic concentration to plasma into the filtrate. Cells and proteins do not normally pass through the glomerulus into the filtrate. In fact, proteinuria (protein in the urine) and hematuria (blood in the urine) may be important findings that suggest renal disease.

The volume of glomerular filtrate formed depends on the volume of renal perfusion. Normally, the kidneys receive approximately 20% of the cardiac output. The amount of this volume that is filtered out into the glomerular filtrate is also large. A volume roughly equivalent to the entire extracellular fluid volume (i.e., 15 L) passes through the glomeruli every 2 hours.465 In the patient with reduced volume and metabolic alkalosis, glomerular filtration is likewise reduced. This perpetuates the syndrome of metabolic alkalosis as excess [HCO3] cannot be excreted.480 Thus, correction of metabolic alkalosis is dependent on adequate renal perfusion and glomerular filtration.

Any drug that increases cardiac output (e.g., epinephrine, digitalis) or preferentially increases renal perfusion (e.g., aminophylline) tends to increase urine formation. A diuretic is any substance that increases urine flow. Therefore, in a broad sense, these drugs may be considered to be mild diuretics, although they are not generally administered primarily for this purpose. An increase in the amount of urine excreted is called polyuria; a decreased urine output is called oliguria.

Tubular Reabsorption

Approximately 99% of all the fluid that passes into the glomerular filtrate is reabsorbed. As the filtrate passes through the nephron, various electrolytes and substances are reabsorbed in proportion to the body’s needs. As shown in Figure 12-4, a rich supply of capillaries (i.e., peritubular capillaries and vasa recta) is immediately adjacent to the renal tubules that facilitate reabsorption of many of these electrolytes back into the bloodstream.

Stay updated, free articles. Join our Telegram channel

Jul 10, 2016 | Posted by in RESPIRATORY | Comments Off on Regulation of Acids, Bases, and Electrolytes

Full access? Get Clinical Tree

Get Clinical Tree app for offline access