Acid-Base Disturbances and the Central Nervous System

www.nephrologyrounds.org
JANUARY 2005
Vo l u m e 3 , I s s u e 1
NEPHROLOGY Rounds
TM
AS
PRESENTED IN THE ROUNDS OF
Acid-Base Disturbances and
the Central Nervous System
B RIGHAM
By JULIAN L. SEIFTER, M.D.
B OSTON, M ASSACHUSETTS
Neurologic dysfunction is a common sequela of both systemic and cerebral acidbase disturbances. The central nervous system (CNS) plays a pivotal role in determining the nature and extent of systemic compensation for both respiratory and metabolic
disturbances. Although the CNS is well-equipped to guard against systemic acid-base
imbalances, neurologic symptoms are common in these disorders. Manipulation of
systemic acid-base status has been shown to be therapeutically effective in certain neurologic and systemic conditions. Understanding the basis of both systemic and cerebral
changes in these disorders permits physicians to assess and treat them appropriately.
Cerebral acid-base disorders are commonly seen in response to primary CNS
lesions. In addition to producing profound changes within the CNS, these imbalances
affect systemic acid-base status. This issue of Nephrology Rounds addresses the effects
of systemic acid-base disturbances on the CNS, as well as the effects of primary CNS
lesions on both cerebral and systemic acid-base status.
The blood-brain barrier, choroid plexus, and cerebrospinal fluid (CSF)
Much of the CNS is separated from the systemic circulation by the blood-brain barrier,
which permits neurons, the brain’s interstitial fluid, and the CSF to maintain an environment
distinct from the rest of the body. Specific carrier systems in the brain’s endothelial cells are
responsible for controlled exchange between the blood and the CNS.1 There is relatively
unrestricted exchange of substances between the CSF and the brain extracellular space. The
choroid plexus in the lateral ventricles secretes most of the CSF. Choroid epithelial cells
contain transporters that generate the unique environment of CSF (Figure 1).
Acid-base status of the brain and CSF
Although in a steady state, the acid-base components of the CSF and arterial blood differ
significantly (Table 1).1,2 Important to this finding is that permeability to CO2 exceeds that of
bicarbonate. The greater acidity is, in part, the result of higher pCO2 in the CSF. Despite readily diffusing across the blood-brain barrier, CO2 is maintained at increased partial pressures by
continuous metabolic generation and release by brain cells. The bicarbonate concentration of
CSF is slightly less than that of blood, although it is the primary buffer in CSF. Levels of lactate
are higher in the CSF. The intracellular environment of brain cells is distinct from that of the
CSF and less well-studied.2,3
CNS control of ventilation
The CNS is responsible for the total body content of CO2, achieved because of the modulation of both voluntary and involuntary respiration. Voluntary respiration and the hyperventilation seen in anxiety and certain primary CNS lesions are determined by higher cortical
centers. Involuntary respiration is controlled by areas in the brainstem and is dependent upon
input from both central and peripheral sensory receptors that respond to the concentrations of
hydrogen, pCO2, and pO2 of the blood and CSF.
The central component in involuntary ventilatory control is the respiratory control center
in the medulla oblongata. The medullary centers, consisting of dorsal and ventral groups of
neurons, are responsible for the basic respiratory pattern integrating input from higher brain
centers as well as central and peripheral chemoreceptors.
Input from these peripheral and central sensors allows this center to modify respiration
based on the acid-base status of the blood and CSF. Central chemoreceptors are distinct from
the respiratory control center, but are located adjacent to it at the ventrolateral surface of the
THE
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TEACHING AFFILIATE
Co-Editors
Joseph V. Bonventre, M.D., Ph.D.,
(Division Director)
Barry M. Brenner, M.D., F.R.C.P.,
(Director Emeritus)
Nephrology Division
Brigham and Women’s Hospital
Reza Abdi, M.D.
Joseph V. Bonventre, M.D., Ph.D.
Barry M. Brenner, M.D.
Charles B. Carpenter, M.D.
Anil Chandraker, M.B., M.R.C.P.
Michael Clarkson, M.D.
Gary C. Curhan, M.D.,Sc.D.
Bradley M. Denker, M.D.
Markus Frank, M.D.
Won Han, M.D.
Matthias A. Hediger, Ph.D.
Li-Li Hsiao, M.D., Ph.D.
Takaharu Ichimura, Ph.D.
Vicki Rubin Kelley, Ph.D.
Julie Lin, M.D.
Valerie A. Luyckx, M.D.
Colm C. Magee, M.D.
Edgar L. Milford, M.D.
David B. Mount, M.D.
Nader Najafian, M.D.
David L. Perkins, M.D., Ph.D.
Martin R. Pollak, M.D.
Stephen T. Reeders, M.D.
Mohamed H. Sayegh, M.D.
Julian L. Seifter, M.D.
Alice Sheridan, M.D.
Ajay K. Singh, M.B., M.R.C.P.(U.K.)
John Kevin Tucker, M.D.
Wolfgang C.Winkelmayer. M.D., Sc.D.
Jing Zhou, M.D., Ph.D.
Brigham and Women’s Hospital
Website: www.brighamandwomens.org/renal
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Figure 1: Choroid plexus cell
Table 1: Composition of CSF
Transporters in the choroid plexus are responsible for the composition of the CSF, which differs significantly from that of
blood. Some of the identified transporters include an apical
Na-K-ATPase pump that exchanges potassium from the CSF for
sodium. Carbonic anhydrase within the cell generates bicarbonate that enters the CSF; the hydrogen ion is exchanged for
sodium on the basolateral membrane. A chloride(C l )-bicarbonate exchanger on the basolateral membrane extrudes Cl in
exchange for bicarbonate.
H2O, Na+, HCO3¯, C l ¯
CSF
K+
Na+
3Na+
HCO3-
CSF
Osmolarity (mosm/L)
295
pH
7.31
48
pCO2 (mm Hg)
Bicarbonate (mEq/L)
23.0
Chloride (mEq/L)
124.0
Sodium (mEq/L)
138.0
Potassium (mEq/L)
2.8
Calcium (mEq/L)
2.4
Phosphorus (mg/dL)
1.6
Total Protein
15-50(mg/dL)
Lactate (mEq/L)
1.6
Plasma
295
7.41 (art)
38 (art)
23.0
101.0
138.0
4.1
1.9
4.0
6.5-8.4g/100/dL
1.0
ATPase
Cl-
2K+
Respiratory acidosis
Na+
The effect of acute respiratory acidosis on the CSF pH
and the intracellular pH of brain cells is almost instantaneous, reflecting the ability of CO2 to cross the blood-brain
barrier.3 However, the initial acidosis caused by elevated
pCO2 levels is compensated for more quickly in the CNS
than in the periphery. Within 1 day of sustained hypercarbia, the CSF pH returns to normal, with an elevated bicarbonate level, while the arterial pH remains acidotic.4
The intracellular pH of brain cells returns to normal even
more quickly than the pH of CSF. Both the CSF and brain
cells return to a normal pH significantly before systemic
compensation is evident.5
The primary mechanism by which the brain and CSF
compensate for acute hypercapnia is by increasing bicarbonate concentration. Two mechanisms are thought
responsible (dual contribution theory). The first is an
increase in carbonic anhydrase activity in the cells of the
choroid plexus, producing bicarbonate that is then transported into the CSF. Acetazolamide is capable of blocking
the increase in bicarbonate seen in the CSF in acute hypercapnia. Second, bicarbonate diffuses into CSF from plasma
because of the electrochemical gradient existing between
CSF and capillary blood. Other mechanisms that may
contribute to increased CSF bicarbonate concentrations
include decreased lactic acid production, with an increase in
cerebral blood flow secondary to CO2 vasodilatory effects.
Intracellular bicarbonate could be released into the extracellular environment by exchange with chloride. Increased
ammonia production via the glutamine-alpha-ketoglutarate
pathway during acute respiratory acidosis could buffer
hydrogen ions via the creation of ammonium.6 Decarboxylation reactions produce CO2, including those involving
glucose metabolism and the conversion of glutamic acid to
γ-aminobutyric acid (GABA).7,8
Permissive hypercapnia has been utilized clinically in
patients with respiratory failure to limit pulmonary damage
secondary to mechanical ventilation. By decreasing tidal
volume and pressures, pulmonary injury is limited. This
technique has been associated with improved survival in
acute respiratory distress syndrome (ARDS) patients.
When the pCO2 is allowed to rise precipitously, increased
intracranial pressure may occur. The procedure is usually
avoided in patients with CNS diseases.9
2Cl-
HCO3-
K+
Na+
H+
ClHCO3H2O
medulla; they sense changes in the pH and pCO2 of the
brainstem interstitial fluid and CSF.2 The central chemoreceptors are exquisitely sensitive to changes in hydrogen
ion concentration and pCO2, an effect that diminishes with
age;4 however, they are relatively insensitive to changes in
pO2 except in cases of severe hypoxia.
Pulmonary stretch receptors and carotid sinus and aortic arch chemo- and baroreceptors contribute to peripheral
sensory input. The carotid chemoreceptor is the most
important for maintenance of systemic acid-base balance.
The carotid bodies, surrounded by a capillary plexus, afford
close proximity to systemic blood. They respond to pCO2
and hydrogen ion concentration and pO2 at values < 60 mm
Hg. The carotid chemoreceptor sensitivity to combined
hypoxia and hypercapnia exceeds the additive effect of
each individually; hypoxia renders chemoreceptors more
sensitive to hypercapnia, and vice-versa. The hydrogen ion
concentration increases chemoreceptor sensitivity to hypercapnia, as does a sudden change in pCO2.
Respiratory acid-base disturbances
Respiratory acid-base disturbances have a profound
effect on the CNS (Table 2). This phenomenon stems from
the fact that the CNS must respond to changes in systemic
pCO2, reflected immediately in the CNS as a result of the
permeability of the blood-brain barrier to CO2, as well as to
changes in the peripheral concentration of hydrogen ions.
However, despite these changes, the CNS is able to maintain a remarkably constant pH in the face of even significant
respiratory acid-base disturbances.
Table 2: Neurologic findings in acid-base
disorders
Respiratory acidosis
• Confusion
• Myoclonus
• Anxiety
• Depression
• Psychosis
• Coma
• Asterixis
• Cerebral edema,
• Seizures
headaches, papilledema
Respiratory alkalosis
• Dizziness
• Seizures
• Paresthesia
• Coma
• Asterixis
• Decreased cerebral blood
• Confusion
flow at pCO2 <25 mm Hg
Metabolic acidosis
• Headache
• Depressed sensorium
• Seizures
Metabolic alkalosis
• Cerebral hypoxia
• Confusion
• Delirium
• Coma
• Specific cause important
• Coma
• Seizures
• Tetany
Chronic hypercapnia is generally seen in patients with
chronic disease. Patients exhibit a decreased ventilatory
response to increased pCO2, decreased pO2, and increased
hydrogen ion concentration. In time, renal compensation
occurs, including excretion of acid as ammonium chloride
and the generation and reabsorption of bicarbonate, that
restores systemic pH towards normal values. This compensation allows the normal balance of bicarbonate between
CSF and plasma, with CSF bicarbonate slightly lower.
Effects of respiratory acidosis on respiratory drive
In acute respiratory acidosis, the peripheral and central
chemoreceptors work in concert, both responding to
increases in hydrogen ion concentrations to increase ventilation. The observed pCO2 results from the balance between
the initial hypoventilatory stimulus and the offsetting, compensatory efforts of the chemosensors.
With the rapid restoration of CSF pH to normal
values, the stimulus for ventilation becomes entirely dependent upon the peripheral chemoreceptors, sustaining an
increase in ventilation until renal compensation is complete, a process that may take 3 -5 days
Respiratory alkalosis
As in respiratory acidosis, the CNS is immediately
affected by decreases in systemic pCO2 because of bloodbrain barrier permeability to CO2. The CSF and intracellular pH show an initial short-lived response that parallels the
systemic increase in pH.
Acute hypocapnia results in an initial increase in the pH
of both the CSF and the brain intracellular environment; it
is quickly offset by a decrease in bicarbonate levels10 and an
increase in lactate that promptly returns intracellular pH to
normal. The increase in lactate in both the CSF and brain
cells is thought to arise from tissue hypoxia secondary to
cerebral vasoconstriction and increased hemoglobin affinity
for oxygen. Alkalosis produces a transient left shift in the
hemoglobin-oxygen dissociation curve via its effects on
2,3-diphosphoglycerate (DPG) in red blood cells, decreasing delivery of oxygen to brain cells and favoring anaerobic glycolysis. Increased phosphofructokinase-1 activity in
brain cells caused by the initial increase in cell pH also
contributes to increased lactate production.
Chronic respiratory alkalosis is observed in patients
with chronic conditions, although CNS compensation for
respiratory alkalosis occurs within hours. Chronic respiratory
alkalosis does not appear to have a distinct symptomatology.
Renal compensation for sustained hypocapnia is
complete in 36 to 72 hours, via a net reduction in renal
hydrogen ion excretion, accomplished largely by decreased
ammonium and titratable acid excretion. The threshold for
bicarbonate excretion is lowered, resulting in bicarbonaturia. As a result, systemic bicarbonate levels decrease and
arterial pH returns toward normal values.
Primary neurologic diseases have been shown to stimulate alveolar hyperventilation. The causes include stroke,
infection, trauma, and tumors. Two patterns of respiration
are seen: central hyperventilation (regular, but with increased
rate and tidal volume) and Cheyne-Stokes breathing (characterized by periods of hyperventilation alternating with
apnea). The pattern appears to depend on the location of
the lesion rather than etiology.11
Central hyperventilation is associated with lesions
at the pontine-midbrain level and does not seem to correlate with changes in pCO2 or pO2, and may be associated
with increased CSF lactate.12 Cheyne-Stokes respiration is
seen in patients with bilateral cortical and upper pontine
lesions and may be related to increased sensitivity of
the respiratory center to pCO2.11 Both altered respiratory
patterns are associated with a poor prognosis.
Acute exposure to high altitude results in hypoxiainduced hyperventilation. Compensation requires several
days to take effect and is characterized by a gradual increase
in hyperventilation. The result is a steadily decreasing
pCO2 and increasing pO2.13 This phenomenon may be the
result of conflicting signals from peripheral and central
chemoreceptors. The effect of the hypoxic stimulus to
ventilate on the peripheral chemoreceptors is initially
modulated by the effects of alkalosis, both peripherally and
centrally. However, as bicarbonate in the CSF falls, inhibition of the central stimulus to ventilate decreases. Therefore, the changing balance between hypoxemia, alkalosis,
and CSF pH in adaptation to high altitude may be responsible for this gradual increase in hyperventilation over time.
Once a steady state is achieved, the drive to ventilate is
determined by the effects of hypoxemia and alkalemia on
the peripheral chemoreceptors.10
Effects of respiratory alkalosis on respiratory drive
Because of the many causes of respiratory alkalosis, the
responses of the central and peripheral chemoreceptors are
variable. Primary stimulation of the central chemoreceptor
is a common cause of respiratory alkalosis, as seen in cortical
hyperventilation, endotoxemia, and pregnancy. In these
cases, the signals from central and peripheral chemoreceptors will oppose each other, with central signals overriding
peripheral input until the primary stimulus is removed.
However, in cases where the primary stimulus is the
result of systemic conditions such as hypoxia secondary to pulmonary disease or anemia, the peripheral
and central chemoreceptors initially receive similar
signals to reduce ventilation appropriate to increases in
peripheral and CSF pH. However, the CSF pH returns
quickly to normal values, at which point the stimulus is
derived solely from the peripheral chemoreceptors
that act to reduce hyperventilation until renal compensation is complete. The observed hypocapnia results
from the balance of the initial hyperventilatory stimulus and the offsetting, compensatory efforts of the
chemosensors.
Metabolic acid-base disturbances
In contrast to respiratory acid-base disturbances,
in metabolic acidosis and alkalosis, the CNS is confronted initially with systemic changes in hydrogen ion
and bicarbonate concentrations.14,15 The CNS is able
to protect its unique environment by regulating bicarbonate levels using the blood-brain barrier. Brain
intracellular pH in animals and CSF in humans have
shown only minimal changes in response to sustained
metabolic acidosis or alkalosis. Neurologic sequelae
may be due to the etiology itself, respiratory compensation, or treatment.
Metabolic acidosis
The changes in CNS acid-base status that result
from metabolic acidosis appear to be primarily in
response to respiratory compensation rather than the
underlying acid-base disturbance. Because of peripheral
chemoreceptor stimuli, alveolar ventilation increases,
leading to a decrease in pCO2 and an increase in arterial pH. The CSF response to metabolic acidosis is
transient and paradoxical, resulting in a period of CSF
alkalosis as CO2 diffuses from the CNS, increasing the
bicarbonate/pCO2 ratio. The central response is to
decrease the degree of hyperventilation until brain pH
normalizes. The transient CNS alkalosis may account
for the delay in full respiratory response to metabolic
acidosis. The eventual degree of compensatory hypocapnia seen in metabolic acidosis appears to be the
point where brain pH is normalized and the stimulus
comes entirely from the periphery. Once a new respiratory steady-state has been achieved, the pH of the
CSF and brain cells remains remarkably constant. This
is due to the brain’s ability to generate bicarbonate to
offset bicarbonate losses to plasma and, to a lesser
extent, the relative impermeability of the blood-brain
barrier to bicarbonate. An increase in cerebral blood
flow, secondary to vasodilatation in response to any
local acidosis, contributes by increasing CO2 transport
out of brain cells and decreasing lactic acid production.15 The ventilatory response to sustained metabolic
acidosis is highly predictable.16
In addition to affecting the time course of respiratory compensation to acute metabolic acidosis, the
CSF pH may account for the “respiratory overshoot”
observed during the rapid correction of metabolic acidosis. Patients whose blood pH has been corrected
may continue to hyperventilate as a result of a transiently acidotic CSF stimulating the central chemoreceptors. The sudden increase in pCO2 resulting from
decreased peripheral stimulation to ventilate creates an
acidic CNS environment that perpetuates hyperventilation and may result in cerebral edema.17,18
Neurologic changes, including depression of the
sensorium in diabetic ketoacidosis (DKA), may be due
to hyperosmolality, cerebral hypoxia, ketonemia, and
metabolic acidosis. As in other cases of metabolic acidosis, the acid-base disturbance per se does not appear
to have a significant effect on the acid-base status of
the CNS unless it is severe.19
Treatment of DKA may precipitate acid-base
disturbances in the CNS. The administration of
bicarbonate occasionally results in cerebral edema that
is significant enough to cause a loss of consciousness
and even death. Some degree of elevated CSF pressure
is believed to be present in most patients during
recovery. Intracellular acidosis may develop due to
decreased oxygen delivery to brain tissue resulting
from the withdrawal of the compensatory effect of
acidemia on hemoglobin’s affinity for oxygen. The
affinity of hemoglobin for oxygen is generally in the
normal range in metabolic acidosis despite a decrease
in 2,3-DPG activity since acidemia counteracts this
effect. With the removal of acidemia, oxygen delivery
to tissues decreases.
Lactic acidosis results from increased production
of lactate, the final product in the anaerobic pathway of
glucose metabolism. It is usually the result of tissue
hypoxia, drug and toxin ingestion, ethanol intoxication, sepsis, diabetes mellitus, and liver failure. Lactic
acidosis can result from seizure activity when lactate is
quickly metabolized by the liver, kidneys, and other
sites, and often the acidosis rapidly resolves. Administration of bicarbonate is usually unnecessary and may
precipitate a rebound acute metabolic alkalosis. This is
of concern in a patient with seizures since it lowers the
seizure threshold.
Salicylate intoxication produces a complex acidbase picture. Manifestations include hyperventilation,
an anion-gap metabolic acidosis and, in severe cases,
seizures, respiratory depression, and coma. The effects
of salicylates are age-dependent. Respiratory alkalosis
is the result of a direct stimulatory effect of salicylates
on the medullary respiratory control center and often
presents with breathlessness.6 Salicylates increase
metabolic rate due to their function as an uncoupler
of oxidative phosphorylation, resulting in increased O2
consumption and CO2 production. However, the
increase in alveolar ventilation resulting from stimulation of central chemoreceptors overcomes this
increase in pCO2. Although urinary alkalinization
favors salicylate excretion, it may impair tissue-toblood CO2 transport and, therefore, worsen acidosis in
the respiratory center.
Metabolic alkalosis
The compensatory response to metabolic alkalosis
is respiratory: alveolar ventilation is decreased in order
NEPHROLOGY Rounds
to increase pCO2 and, thereby, decrease pH. However,
compensation is generally less effective in metabolic
alkalosis than in metabolic acidosis. One reason may
be that hypoventilation also decreases pO2, a potent
stimulus for the peripheral chemoreceptors to increase
alveolar ventilation. Hypokalemia may blunt respiratory compensation due to intracellular acidosis in the
brain. The ventilatory response to metabolic alkalosis
is highly varied and unpredictable. Patients with metabolic alkalosis rarely attain a pCO2 > 60 mm Hg.
The effects of metabolic alkalosis on the CNS,
caused by the alkalosis itself and by compensatory
hypoventilation, are largely due to changes in blood flow
and oxygenation. In addition to producing systemic
hypoxia from hypoventilation, metabolic alkalosis is a
potent cerebral vasoconstrictor that can lead to tissue
hypoxia in the brain. This response is amplified by the
increased affinity of hemoglobin for oxygen in alkalemia,
resulting in less effective delivery of oxygen to tissues
than the arterial pO2 may suggest. However, despite
these findings, the CSF and intracellular pH of brain
cells remain relatively constant in metabolic alkalosis.
In acute metabolic alkalosis, an initial paradoxical
acidotic shift in CSF pH occurs secondary to a sudden
increase in pCO2. This phenomenon, similar to the
alkaline shift in CSF pH seen in acute metabolic acidosis, may contribute to the unpredictable respiratory
response to metabolic alkalosis by activating central
chemoreceptors and increasing ventilatory drive in the
face of peripheral stimulation to decrease alveolar ventilation. Lactate production in the brain has been
shown to increase at pH values >7.5, possibly reflecting increased anaerobic glycolysis secondary to the
increased affinity of hemoglobin for oxygen.3,15
In chronic metabolic alkalosis, the CSF returns
toward normal values. This normal brain pH would
result in respiratory drive deriving entirely from the
peripheral chemoreceptors.
Posthypercapnic alkalosis is an acute condition in
which ventilated patients with compensated, chronic
hypercapnia experience a sudden decrease in pCO2,
without prompt renal excretion of the elevated bicarbonate. This condition may persist, since the kidney
continues to reabsorb bicarbonate due to low chloride
levels. Consequences include arrhythmias, seizures,
coma, and even death, in some patients. To manage
this condition, pCO2 should be allowed to rise as
slowly as possible to avoid hypoxemia and allow the
chloride stores to be repleted.
Cerebral acidosis
Cerebral acidosis is most commonly the result of
cerebral hypoxia. It can be secondary to generalized or
focal cerebral ischemia, tumor, or head injury. Grand
mal seizures have been associated with cerebral, as
well as systemic metabolic acidosis, although they are
apparently secondary to increased cerebral metabolic
activity as opposed to hypoxia. Acidosis seen in these
conditions is primarily the result of increased tissue
lactate production and cell catabolism.20,21
In cerebral ischemia, lactate has been shown to rise
rapidly. Brain cell swelling may involve activation of
membrane transporters (eg, the Na/H-antiporter, the
Na/HCO3-cotransporter, and the Cl/HCO3 exchanger)
in an attempt to correct the intracellular acidosis. Subsequent intracellular accumulation of Na and Cl results
in osmotic entry of water into the cells. In addition,
lactate itself has been implicated in abnormalities of
neurotransmitter release and calcium homeostasis in
brain cells.
Effects of cerebral acidosis on respiratory drive
The intra- and extracellular acidity resulting from
these conditions might be expected to increase ventilatory drive via its effects on the medullary respiratory
center. However, cerebral hypoxia produces respiratory depression.
Cerebral acidosis and seizures
In contrast to the systemic lactic acidosis seen in
seizure patients, the cerebral lactic acidosis in such
patients does not reflect systemic or cerebral hypoxia.
Levels of lactate in CSF and brain tissue of patients
with status epilepticus are found to be elevated to levels
that are apparently independent of systemic lactate
levels, reflecting the inability of lactate to readily cross
the blood-brain barrier.22 The production of lactate
may be secondary to increased metabolic activity that
results in the utilization of all available pathways to
generate adenosine triphosphate (ATP).
Conclusions and discussion
The brain plays an integral part in the normal
maintenance of acid-base balance. Regulation of body
fluid pH depends on negative feedback systems. Thus
the brain maintains its own acid-base homeostasis,
mediated through the effects of acid-base parameters
on peripheral and central chemoreceptors. Metabolic
processes within the brain and its special permeability
properties determine the time-course and extent of
these compensations. Acute disturbances – both respiratory and metabolic – are rapidly compensated for in
the CNS to near complete correction. This is in contrast to the degree of expected compensation in the
periphery that generally falls short of full correction.
The consequences of acute changes in brain pH are
abnormalities in neurologic function.
The idea that compensations for acid-base disorders are not complete because the driving forces for
such compensations would be removed with a complete correction of the primary disorder is not true if
one considers the brain’s acid-base status. In all four
primary disturbances, acute processes do perturb CNS
acidity but, in the chronic state, normalization is possible. However, in the peripheral blood, full compensations do not appear to occur. It is true that renal
adaptations to metabolic acidosis or alkalosis may not
afford complete correction, but that is because the
primary metabolic disturbance overwhelms the renal
capacity to correct it by altering renal net acid excretion, or because there are confounding effects on acid
excretion. Metabolic alkalosis requires factors such as
hypokalemia or volume depletion to sustain it, while
metabolic acidosis will develop when the renal capacity
NEPHROLOGY Rounds
to reabsorb bicarbonate is impaired or the ability to excrete
ammonium is exceeded. The degree of pulmonary compensation in the chronic state of metabolic disturbances is
largely due to limitations imposed by peripheral chemosensors and brain acid-base regulation. Limitations of
metabolic compensation for respiratory acidosis are set by
renal function, capacity for ammoniagenesis, acid secretion,
and the increased bicarbonate reabsorptive capacity due to
high pCO2. The intrinsic function of the lung and the compromise between peripheral and central chemosensors at
which brain homeostasis is best preserved determine the
pCO2 that will reach a new steady state of production and
pulmonary clearance of CO2.
It is notable that chronic respiratory alkalosis is the
disorder most likely to approach normal pH with compensation. It is possible that this observation is due to the enormous capacity of the kidney to excrete bicarbonate and
decrease acid excretion. However, the pCO2 level where
this occurs is determined by a balance between pulmonary
function and a compromise between peripheral and central
chemosensors. Acid-base disorders should be considered as
acute and chronic, not only because that knowledge helps
determine mixed disturbances, but also because acute
processes may be more symptomatic, reflect brain acid-base
changes, and call for different approaches to treatment
than used in the chronic state. Further, when approaching
management of an acid-base problem, the impact on brain
function should be considered. Attention to other electrolyte
or metabolic abnormalities such as hypophosphatemia or
hyponatremia should be considered together with acidbase. For example, a patient with cerebral edema from
hyponatremia may have an acute respiratory alkalosis causing an extreme elevation of blood pH, but the cerebral
vasoconstrictive effect may be important for the brain.
This model of adaptation by the brain to metabolic acidosis is analogous to the response in hyponatremic states. In
the latter, there is an initial swelling of brain cells that
results in adaptive volume-regulatory mechanisms allowing
brain cells to recover volume despite continued systemic
abnormalities. Management of hyponatremia requires
understanding of this adaptation to avoid paradoxical cell
shrinkage with rapid correction. An understanding of brain
responses in acid-base disturbances is also necessary.
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