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 N EPHROLOGY D IVISION AND OF WOMEN ’ S H OSPITAL HARVARD MEDICAL SCHOOL 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 The editorial content of Nephrology Rounds is determined solely by the Nephrology Division of Brigham and Women’s Hospital. Nephrology Rounds is approved by the Harvard Medical School Department of Continuing Education to offer continuing education credit 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. References 1. Rowland LP, Fink ME, Rubin L. Cerebrospinal Fluid: Blood-Brain Barrier, Brain Edema, and Hydrocephalus. In: Kandel ER, Schwartz JH, Jessell TM, Eds. Principles of Neural Science. Norwalk, CT: Appleton & Lange; 1991: 1051-1060. 2. Adams RD, Victor M, Ropper A. Principles of Neurology. 6th Ed. New York: McGraw-Hill; 1997:16. 3. Arieff A. Acid-base balance in specialized tissues: central nervous system. In: Seldin DW, Giebisch G. Eds. The Regulation of Acid-Base Balance. New York: Raven Press; 1989: 107-121. 4. Madias NE, Cohen JJ. Respiratory Acidosis. In: Cohen JJ, Kassirer JP, Eds. Acid-Base. Boston: Little, Brown & Co; 1982:307-348. 5. Kazemi H, Shannon DC, Carvallo-Gil E. Brain CO2 buffering capacity in respiratory acidosis and alkalosis. J Appl Physiol 1967;22:241-6. 6. Moloney DA, Schiess MC, Evanoff GV. Respiratory acid-base disturbances. In: Kokko JP, Tannen RL, Eds. Fluids and Electrolytes. Philadelphia: WB Saunders Co; 1990:391-484. 7. Arieff A, Schmidt RW. Fluid and electrolyte disorders and the central nervous system. In: Maxwell MH, Kleeman CR, Eds. Clinical Disorders of Fluid and Electrolyte Metabolism. New York: McGraw-Hill Book Co; 1980:14091480. 8. Arieff AI, Kerian A, Massry SG, DeLima J. Intracellular pH of brain: alterations in acute respiratory acidosis and alkalosis. Am J Physiol 1976; 230(3):804-812. 9. Cardenas VJ jr, Zwishenberger JB, Tao W, et al. Correction of blood pH attenuates changes in hemodynamics and organ blood ﬂow during permissive hypercapnia. Crit Care Med 1996;24(5):827-834. 10. Heffner JE, Sahn SA. Controlled hyperventilation in patients with intracranial hypertension. Arch Intern Med 1983; 143:765-769. 11. Gennari FJ, Kassirer JP. Respiratory Alkalosis. In: Cohen JJ, Kassirer JP, Eds. Acid-Base. Boston:Little, Brown & Co; 1982:349-376. 12. Van Vaerenbergh PJ, Demeester G, Leusen I. Lactate in cerebrospinal ﬂuid during hyperventilation. Arch Int Physiol Biochim 1965;73(5):738-747. 13. Lenfant C, Sullivan K. Adaptation to high altitude. N Engl J Med 1971; 284:1298-1309. 14. Siesjo BK. Ponten U. Acid-base changes in the brain in non-respiratory acidosis and alkalosis. Exp Brain Res 1966;2:176-190. 15. Irsigler GB, Stafford MJ, Severinghaus JW. Relationship of CSF pH, O2, and CO2 responses in metabolic acidosis and alkalosis in humans. J Appl Physiol 1980;48(2):355-361. 16. Albert MS, Dell RB, Winters RW. Quantitative displacement of acid-base equilibrium in metabolic acidosis. Ann Intern Med 1967;66(2):312-322. 17. Herrera L, Kazemi H. CSF bicarbonate regulation in metabolic acidosis: role of HCO3- formation in CNS. J Appl Physiol 1980;49(5):778-783. 18. Staub F, winkler A, Haberstok J, et al. Swelling, intracellular acidosis, and damage of glial cells. Acta Neurochir Suppl 1996;66:56-62. 19. Neubauer JA, Simone A, Edelman NH. Role of brain lactic acidosis in hypoxic depression of ventilation. J Appl Physiol 1988;65(3):1324-1331. 20. Calabrese VP, Gruemer HD, James K, Haranowsky N, DeLorenzo RJ. Cerebrospinal ﬂuid lactate levels and prognosis in status epilepticus. Epilepsia 1991;32(6):816-821. 21. Brivet F, Bernardin M, Cherin P, Chalas J, Galanaud P, Dormont J. Hyperchloremic acidosis during grand mal seizure lactic acidosis. Intensive Care Med 1994;20:27-31. 22. Paschen W, Djuricic B, Mies G, Schmidt-Kastner R, Linn F. Lactate and pH in the brain: association and dissociation in different pathophysiological states. J Neurochem 1987;48:154-159. Upcoming Scientific Meetings 10-12 March 2005 10th International Conference on CRRT San Diego, California CONTACT: Tel.: 619-299-6673 Fax: 617-299-6675 Email: [email protected] Website: www.crrtonline.com 8-13 November 2005 American Society of Nephrology Philadelphia, PA CONTACT: Tel.: (202) 659-0599 Fax: (202) 659-0709 Website: asn-online.org This publication is made possible by an educational grant from Amgen Inc. ©2005 Nephrology Division, Brigham and Women’s Hospital, Boston, Massachusetts, which is solely responsible for the contents. 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