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CASE 20
A 19-year-old woman with a history of depression is found by her college
roommate lying on the floor, vomiting and having seizures, with an empty bottle of aspirin beside her. The roommate states that she has not been taking her
depression medications and has been overwhelmed by the upcoming final
examinations. The roommate bought the bottle of aspirin earlier that morning.
In the emergency center, the patient is lethargic and confused with a low-grade
fever and is hyperventilating. Her urine drug screen is negative, but the arterial blood gases reveal an anion gap metabolic acidosis, probably as a result of
the aspirin overdose.
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What is the anion gap and what is its significance?
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What effect does metabolic acidosis have on the respiratory system?
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What chemoreceptors are involved in the response to an acid–base
disturbance?
Are the lung stretch receptors fast- or slow-acting reflexes?
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ANSWERS TO CASE 20: CONTROL OF BREATHING
Summary: A 19-year-old college student with a history of depression presents
to the emergency center with salicylate poisoning and an anion gap acidosis.
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Significance of the anion gap: Anion gap = [Na+] − ([Cl−] + [HCO3-]).
An increase in the rate of production (eg, lactic acid or ketoacids) or
ingestion of noncarbonic acids or substances that increase lactic acid or
ketoacid production will cause a decrease in the plasma concentration
of bicarbonate. The anion gap helps identify the type of acidosis and
estimate the magnitude of the acid load to the system.
Effect of metabolic acidosis on the respiratory system: Increases
ventilation to lower the arterial [CO2] to compensate for the fall in
plasma pH.
Chemoreceptors involved in response to an acid–base disturbance:
Two groups of chemoreceptors respond to a metabolic acidosis:
1. Peripheral chemoreceptors located in the carotid bodies detect
changes in arterial [H+], [CO2], and [O2].
2. Central chemoreceptors located on the medulla (reticular segment).
They are separated from the blood by the blood–brain barrier and
detect changes in the arterial [CO2].
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Lung stretch receptors: Slow-acting reflexes.
CLINICAL CORRELATION
Overdosing on over-the-counter medications is a commonly seen problem in
emergency centers. A thorough history and physical examination often will
reveal clues necessary to make the diagnosis. In this case, the history of
depression with stressful final examinations coming up and an empty bottle of
recently purchased aspirin make one think of the possibility of salicylate poisoning. Salicylate poisoning may cause clinical symptoms of vomiting, sweating, tachycardia, fever, lethargy confusion, coma, seizures, cardiovascular
collapse, and possibly pulmonary or cerebral edema. Salicylate ingestion can
cause a multitude of effects, depending on the magnitude of the ingestion. A
complication is that salicylates can alter metabolic processes, causing an
increase in lactic acid production, and directly stimulate central respiratory
centers, causing hyperventilation and a fall in arterial PCO2. Symptoms usually occur 3 to 6 hours after an overdose. Abnormal laboratory findings may
include anion gap metabolic acidosis, hypokalemia, hypoglycemia, and a positive
urine ferric chloride test. Other agents are also possible, including acetaminophen, alcohol, and illicit drugs. Treatment of salicylate toxicity includes activated
charcoal to decontaminate the stomach (possibly gastric lavage), correction of
CLINICAL CASES
165
electrolyte abnormalities, supportive care with intravenous (IV) fluids, and
alkalization of urine (promotes excretion of salicylates). Elevated levels of salicylates increase the sensitivity of the respiratory center in the brain. The metabolic acidosis results in hyperventilation and a compensatory respiratory
alkalosis.
APPROACH TO CONTROL OF BREATHING
Objectives
1.
2.
3.
Know the central and peripheral centers for control of breathing.
Describe the different types of chemoreceptors.
Know the different types of receptors (lung stretch, irritant, etc.).
Definitions
Respiratory center: Located in the reticular formation of the medulla it is
responsible for maintaining a rhythmical cycle of breathing and integrating neural input from a variety of receptors (e.g. central and peripheral chemoreceptors) to adjust the rate and depth of breathing in
response to perturbations in environmental or physical conditions.
Central chemoreceptors: Located in the ventrolateral surface of the
medulla directly respond to a change in the pH of the CSF, however,
since the blood brain barrier is impermeable to either H+ or HCO3-, these
receptors detect changes in the arterial PCO2.
Peripheral chemoreceptors: Located on the carotid and aortic bodies
these receptors respond directly to changes in the arterial pH, PCO2, and
PO2.
CO2 / HCO3- buffering system: The central buffering system in the body
for maintaining H+ homeostasis. The importance of this buffering system is the ability to control the arterial PCO2 by pulmonary function and
[HCO3-] through renal function to compensate for acid-base
disturbances.
DISCUSSION
The pH of the arterial blood is normally 7.4 and is dependent mainly on the
CO2 / HCO3- buffering system in the blood:
CO2 + H2O Æ H2CO3 Æ H+ + HCO3The control of the pH, or hydrogen ion homeostasis is dependent on an
interaction of the respiratory control of arterial PCO2 and renal control of
arterial HCO3- and H+ excretion. Acid–base disturbances are generally identified as being of respiratory or metabolic origin. Respiratory acid–base disorders are a consequence of a respiratory disturbance that results in a change
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CASE FILES: PHYSIOLOGY
in the arterial PCO2. Until the disturbance is corrected, renal function will
compensate the disruption. Metabolic disturbances are the consequence of a
change in the arterial pH caused by initial changes in [H+] or [HCO3-]. The
respiratory system serves to compensate for metabolic disturbances. The
respiratory system is finely tuned to and highly sensitive to changes in CO2
and H+. The O2 concentration is an important regulator, but has a minimal role
until the arterial PO2 falls to less than 55 to 60 mm Hg. Acid–base disturbances
have immediate effects on respiration caused by specific chemoreceptors that
are sensitive to changes in CO2, H+, and O2.
This case involves a metabolic acidosis caused by the ingestion of an
acidic substance. The respiratory system can compensate for this disturbance
only by controlling the CO2 concentration and shifting the equilibrium of the
CO2/HCO3- buffering system and maintaining hydrogen ion homeostasis.
Acid–base balance is markedly disturbed, as indicated by the anion gap.
Acid–base balance can be restored only by renal excretion of the acid and
reabsorption of HCO3- (see Case 27 for the renal response to an acid–base disturbance).
Respiration is spontaneously and rhythmically initiated by the respiratory center located in the reticular formation of the medulla. Neural signaling to the inspiratory and expiratory muscle groups maintains the cycle of
breathing. Numerous mechanisms are capable of modifying the signal to alter
the frequency and depth of breathing in response to voluntary stimuli, reflexes
and other neural stimuli, and a variety of chemical or mechanical stimuli.
Acid–base disturbances are characteristically identified by their effects on
plasma pH, PCO2, and [HCO3-]. Chemoreceptors located centrally and in the
periphery respond to changes in arterial pH and PCO2 with input to the respiratory center that causes compensatory changes in breathing. Peripheral
chemoreceptors are located in the carotid bodies and the aortic bodies and
detect changes in pH, O2, and to a lesser extent PCO2. Under normal conditions, O2 has little role in the control of ventilation. However, under hypoxic
conditions in which the PO2 begins to approach 50 mm Hg or lower, O2 stimulates ventilation directly and increases sensitivity to H+ and CO2. Impulses
from the peripheral chemoreceptors are carried by the glossopharyngeal
nerve to the respiratory center. Stimulation of the peripheral chemoreceptors
causes an increase in ventilatory rate. Central chemoreceptors located on the
medulla are separated from the blood by the blood–brain barrier. These receptors are bathed by the cerebrospinal fluid (CSF), which is essentially a pure
bicarbonate buffer. Because the blood–brain barrier is impermeable to H+ and
HCO3- but freely permeable to CO2, a change in the arterial CO2 will cause
a change in the CSF CO2 with a concomitant change in the CSF pH. Thus,
although directly sensing a change in CSF pH, central chemoreceptors respond
to changes in the arterial PCO2. A fall in the arterial PCO2 (hypocapnia) will
increase the CSF pH and slow respiration. An increase in the arterial PCO2
(hypercapnia) will decrease the CSF pH and stimulate respiration.
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167
Physiologically, a metabolic acidosis or an initial decrease in pH (an
increase in H+) stimulates the peripheral chemoreceptors, resulting in
hyperventilation. The hyperventilation leads to a compensatory fall in PCO2.
Normally, the magnitude of the hyperventilation is limited and controlled by a
negative feedback from the central chemoreceptors, which detect only a
decrease in PCO2. This important control mechanism serves to dampen the
respiratory response to an acid–base disturbance. In the present case of salicylate intoxication, there also may be a direct stimulation of the respiratory
center that will cause a further increase in the respiratory rate with a resultant respiratory alkalosis (hypocapnia) superimposed on the metabolic
acidosis. This example emphasizes the importance of the interactions between
the central and peripheral chemoreceptors. A metabolic alkalosis will have
exactly the opposite response. The peripheral chemoreceptors respond to an
increased pH (a fall in H+) by slowing ventilation with a compensatory rise in
PCO2. The rise in arterial PCO2 is sensed by central chemoreceptors, which
respond with an increase in the ventilatory rate to dampen the response. In disorders in which one or the other chemoreceptor is blocked or nonfunctional,
severe aberrations in breathing patterns are observed.
In addition to the chemoreceptors outlined above, there are three receptor
groups that are located in the lungs. J-receptors (juxtapulmonary capillary
receptors) are located in the interstitium near alveoli and blood capillaries.
Increasing pressure in the interstitium by edema or capillary engorgement
stimulates J-receptors, causing bronchoconstriction and tachypnea. Irritant
receptors are located in the airways between epithelial cells. They are located
in such a way that they have immediate contact with inhaled air and are stimulated by cigarette smoke, dust, fumes, and cold air. Stimulation of irritant
receptors leads to bronchoconstriction, hyperpnea, coughing, and sneezing.
Pulmonary stretch receptors are located in airway smooth muscle and are
stimulated by distention of the lung and serve to protect the lungs against
being overinflated.
COMPREHENSION QUESTIONS
[20.1]
A 17-year-old male develops pneumonia, diabetic ketoacidosis, and
metabolic acidosis. Respiratory compensation to a metabolic acidosis
consists of hyperventilation to lower the arterial PCO2. The cause of
the hyperventilation is described by which of the following
statements?
A. CO2 produced from the reaction of the acid with bicarbonate stimulates central chemoreceptors.
B. A decrease in the bicarbonate concentration stimulates ventilation.
C. H+ stimulates central chemoreceptors.
D. H+ stimulates peripheral chemoreceptors.
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[20.2]
CASE FILES: PHYSIOLOGY
A 21-year-old woman is admitted to the intensive care unit for an opiate drug overdose that probably has suppressed her central chemoreceptor response to CO2, diminishing the drive for ventilation. Her
respiratory rate is diminished at eight breaths per minute. Which of
the following is the best course of action for this patient?
A.
B.
C.
D.
[20.3]
Administration of oxygen by mask
Administration of benzodiazepine for possible alcohol withdrawal
Leaving the patient on room air
Placing the patient on a low opiate infusion to prevent opiate
withdrawal
A 29-year-old man who lives at sea level drives up a mountain to a
high altitude (17,000 feet) for over 3 hours. Which of the following
statements best describes his condition after the elevation climb?
A.
B.
C.
D.
Increased arterial PO2
Decreased arterial PCO2
Decreased arterial pH
Decreased respiratory rate
Answers
[20.1]
D. A common mistake is thinking that elevated CO2 produced by the
reaction of the acid with bicarbonate is the stimulus for ventilation. To
the contrary, as soon as the peripheral chemoreceptors sense an
increase in the H+, there will be an immediate increase in the rate of
ventilation. The hyperventilation lowers the alveolar PCO2, which lowers the arterial PCO2. This is the appropriate compensatory response
because the initial perturbation was a decrease in the bicarbonate concentration from the acid insult. From the Henderson-Hasselbalch equation, it is apparent that a fall in the bicarbonate concentration can be
compensated most rapidly by a proportionate fall in CO2.
[20.2]
C. Because of the narcotic effect, the central receptors are insensitive to
CO2; therefore, CO2 exerts no ventilatory drive. The only drive for ventilation is the fall in O2 resulting from the near cessation of breathing.
Applying oxygen will remove the remaining drive for ventilation, and
breathing will stop. Thus, room air with oxygen saturation monitoring
is the best action. Medications that further suppress respirations, such as
sedatives (benzodiazepines, opiates, hypnotics), are contraindicated.
[20.3]
B. The partial pressure of oxygen decreases with increasing altitude.
Rapid ascent to high altitude can result in hypoxia. The hypoxia stimulates pulmonary ventilation to increase alveolar PO2. A consequence
of the hyperventilation is to decrease the PCO2, or hypocapnia. The
fall in CO2 shifts the equilibrium of the CO2/HCO3- buffer system to
decrease the H+, resulting in a respiratory alkalosis.
CLINICAL CASES
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PHYSIOLOGY PEARLS
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The rate and depth of respiration are controlled by a neural feedback
loop that involves central chemoreceptors in the medulla and
peripheral chemoreceptors in the aortic and carotid bodies.
Central chemoreceptors are separated from the blood by the
blood–brain barrier and detect changes in arterial [CO2].
Peripheral chemoreceptors respond directly to [H+], CO2, and O2.
The concentration of CO2 in the blood is controlled by the alveolar
PCO2. Hyperventilation decreases the PCO2, and hypoventilation
increases the PCO2. Raising the arterial [CO2] causes a hyperventilation with a compensatory decrease, and lowering the [CO2]
causes a hypoventilation.
The main buffer system in the body is the CO2/HCO3− buffering system.
One of its components, CO2, is controlled by the ventilatory rate;
therefore, one of the most effective ways of compensating for an acid
or base disturbance is to alter the [CO2] in the blood. Increasing H+
stimulates ventilation, which lowers CO2. Conversely, a fall in [H+]
slows ventilation, resulting in a rise in [CO2].
REFERENCE
Powell FL. Structure and function of the respiratory system. In: Johnson LR, ed.
Essential Medical Physiology. 3rd ed. San Diego, CA: Elsevier Academic Press;
2003:259-276.
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