Lee E. Morrow and Mark A. Malesker
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Define primary acid–base disturbances within the human body.
2. Apply simple formulas in order to determine the etiology of simple acid–base disturbances and the adequacy of compensation.
3. Integrate the supplemental concepts of the anion gap and the excess gap to help assess complex acid–base disturbances.
4. Discuss the most common causes of each primary acid–base irregularity.
5. Determine the appropriate management for patients with acid–base disorders.
KEY CONCEPTS
Acid–base homeostasis is tightly regulated by the complex, but predictable, interactions of the kidneys, the lungs, and various buffer systems. The kidneys control serum bicarbonate (
) concentration through the excretion or reabsorption of filtered , the excretion of metabolic acids, and synthesis of new 
. The lungs control the arterial carbon dioxide (CO2) concentration through changes in the depth and/or rate of respiration.
Respiratory acidosis and alkalosis result from primary disturbances in the arterial CO2 concentration. Metabolic compensation of respiratory disturbances is a slow process, requiring days for the serum to reach the steady state.
Respiratory acidosis is caused by respiratory insufficiency resulting in an increased arterial CO2 concentration. The compensation for respiratory acidosis (if present for prolonged periods) is an increase in serum .
Respiratory alkalosis is caused by hyperventilation resulting in a decreased arterial CO2 concentration. The compensation for respiratory alkalosis (if present for prolonged periods) is a decrease in serum .
Metabolic acidosis and alkalosis result from primary disturbances in the serum concentration. Respiratory compensation of metabolic disturbances begins within minutes and is complete within 12 hours.
Metabolic acidosis is characterized by a decrease in serum . The anion gap is used to narrow the differential diagnosis, as metabolic acidosis may be caused by addition of acids (increased anion gap) or loss of (normal anion gap). The compensation for metabolic acidosis is an increase in ventilation with a decrease in arterial CO2.
Metabolic alkalosis is characterized by an increase in serum . This disorder requires loss of fluid that is low in from the body or addition of to the body. The compensation for metabolic alkalosis is a decrease in ventilation with an increase in arterial CO2.
Arterial blood gases, serum electrolytes, physical examination findings, the clinical history, and the patient’s recent medications must be reviewed in order to establish the etiology of a given acid–base disturbance.
It is critical to treat the underlying causative process to effectively resolve most observed acid–base disorders. However, supportive treatment of the pH and electrolytes is often needed until the underlying disease state is improved.
Given its reputation for complexity and the need to memorize innumerable formulas, acid–base analysis intimidates many health care providers. In reality, acid–base disorders always obey well-defined biochemical and physiologic principles. The pH determines a patient’s acid–base status and an assessment of the bicarbonate () and arterial carbon dioxide (PaCO2) values identifies the underlying process. Rigorous use of a systematic approach to arterial blood gases increases the likelihood that derangements in acid–base physiology are recognized and correctly interpreted. This chapter will outline a clinically useful approach to acid–base abnormalities and then apply this approach in a series of increasingly complex clinical scenarios.
Disturbances of acid–base equilibrium occur in a wide variety of illnesses and are among the most frequently encountered disorders in critical care medicine. The importance of a thorough command of this content cannot be overstated given that acid–base disorders are remarkably common and may result in significant morbidity and mortality. Although severe derangements may affect virtually any organ system, the most serious clinical effects are cardiovascular (arrhythmias and impaired contractility), neurologic (coma and seizures), pulmonary (dyspnea, impaired oxygen delivery, respiratory fatigue, and respiratory failure), and/or renal (hypokalemia). Changes in acid–base status also affect multiple aspects of pharmacokinetics (clearance and protein binding) and pharmacodynamics.
ACID–BASE HOMEOSTASIS
Acid–base homeostasis is responsible for maintaining blood hydrogen ion concentration [H+] near normal despite the daily acidic and/or alkaline loads derived from the intake and metabolism of foods. Acid–base status is traditionally represented in terms of pH, the negative logarithm of [H+]. Because [H+] is equal to 24 times the ratio of PaCO2 to , the pH can be altered by a change in either the bicarbonate concentration or the dissolved carbon dioxide. A critically important concept is that [H+] is dependent only on the ratio of PaCO2 to and not the absolute amount of either. As such, a normal PaCO2 or alone does not guarantee that the pH will be normal. Conversely, a normal pH does not imply that either the PaCO2 or will be normal.1
Acid–base homeostasis is tightly regulated by the complex, but predictable, interactions of the kidneys, the lungs, and various buffer systems. The kidneys control serum bicarbonate () concentration through the excretion or reabsorption of filtered , the excretion of metabolic acids, and synthesis of new . The lungs control arterial carbon dioxide (CO2) concentrations through changes in the depth and/or rate of respiration. The net result is tight regulation of the blood pH by these three distinct mechanisms working in harmony: extracellular bicarbonate and intracellular protein buffering systems; pulmonary regulation of PaCO2, effectively allowing carbonic acid to be eliminated by the lungs as CO2; and renal reclamation or excretion of and excretion of acids such as ammonium.
Because the kidneys excrete less than 1% of the estimated 13,000 mEq of H+ions generated in an average day, renal failure can be present for prolonged periods before life-threatening imbalances occur. Conversely, cessation of breathing for minutes results in profound acid–base disturbances.1
The best way to assess a patient’s acid–base status is to review the results of an arterial blood gas (ABG) specimen. Blood gas analyzers directly measure the pH and PaCO2, while the value is calculated using the Henderson–Hasselbalch equation. A more direct measure of serum is obtained by measuring the total venous carbon dioxide (tCO2). Because dissolved carbon dioxide is almost exclusively in the form of , tCO2 is essentially equivalent to the measured serum concentration. This value () is routinely reported on basic chemistry panels. In the remainder of this chapter, the pH and PaCO2 values should be assumed to come from an ABG while values should be considered to be measured serum concentrations.
BASIC PATHOPHYSIOLOGY
Under normal circumstances, the arterial pH is tightly regulated between 7.35 and 7.45. Acidemia is an abnormally low arterial blood pH (less than 7.35) while acidosis is a pathologic process that acidifies body fluids. Similarly, alkalemia is an abnormally high arterial blood pH (greater than 7.45) while alkalosis is a pathologic process that alkalinizes body fluids. As such, although a patient can simultaneously have acidosis and alkalosis, the end result will be acidemia or alkalemia.
Changes in the arterial pH are driven by changes in the PaCO2 and/or the serum . Carbon dioxide is a volatile acid that is regulated by the depth and rate of respiration. Because CO2 can be either “blown off” or “retained” by the respiratory system, it is referred to as being under respiratory control. Respiratory acidosis and alkalosis result from primary disturbances in the arterial CO2concentration. Metabolic compensation of respiratory disturbances is a slow process, often requiring days for the serum to reach the steady state. Respiratory acidosis is caused by respiratory insufficiency resulting in an increased arterial CO2 concentration. The compensation for respiratory acidosis (if present for prolonged periods) is an increase in serum . Respiratory alkalosis is caused by hyperventilation resulting in a decreased arterial CO2 concentration. The compensation for respiratory alkalosis (if present for prolonged periods) is a decrease in serum .
A respiratory acid-base disorder is a pH disturbance caused by pathologic alterations of the respiratory system or its central nervous system control. Such an alteration may result in the accumulation of PaCO2beyond normal limits (greater than 45 mm Hg or 6 kPa), a situation termed respiratory acidosis, or it may result in the loss of PaCO2 beyond normal limits (less than 35 mm Hg or 4.7 kPa), a condition termed respiratory alkalosis. Variations in respiratory rate and/or depth allow the lungs to achieve changes in the PaCO2 very quickly (within minutes).
Bicarbonate is a base that is regulated by renal metabolism via the enzyme carbonic anhydrase. As such, bicarbonate is often referred to as being under metabolic control. Metabolic acidosis and alkalosis result from primary disturbances in the serum concentration. Respiratory compensation of metabolic disturbances begins within minutes and is complete within 12 hours. Metabolic acidosis is characterized by a decrease in serum . The anion gap is used to narrow the differential diagnosis, as metabolic acidosis may be caused by addition of acids (increased anion gap) or loss of (normal anion gap). The compensation for metabolic acidosis is an increase in ventilation with a decrease in arterial CO2. Metabolic alkalosis is characterized by an increase in serum . This disorder requires loss of fluid that is low in from the body or addition of to the body. The compensation for metabolic alkalosis is a decrease in ventilation with an increase in arterial CO2.
A metabolic acid–base disorder is a pH disturbance caused by derangement of the pathways responsible for maintaining a normal concentration. This may result in a pathologic accumulation of (greater than 26 mEq/L or mmol/L), a condition termed metabolic alkalosis, or it may result in the loss of beyond normal (less than 22 mEq/L or mmol/L), a condition termed metabolic acidosis. In contrast to the lungs’ rapid effects on CO2, the kidneys change the very slowly (hours to days).
Respiratory and metabolic derangements can occur in isolation or in combination. If a patient has an isolated primary acid–base disorder that is not accompanied by another primary acid–base disorder, a simple (uncomplicated) disorder is present. The most common clinical disturbances are simple acid–base disorders. If two or three primary acid–base disorders are simultaneously present, the patient has a mixed (complicated) disorder. More complex clinical situations lead to mixed acid–base disturbances. Because CO2 is a volatile acid, it can rapidly be changed by the respiratory system. If a respiratory acid–base disturbance is present for minutes to hours it is considered an acute disorder, while if it is present for days or longer it is considered a chronic disorder. By definition, the metabolic machinery that regulates results in slow changes and all metabolic disorders are chronic.
Changes that follow the primary disorder and attempt to restore the blood pH to normal are referred to as compensatory changes. It should be stressed that compensation never normalizes the pH. Because all metabolic acid–base disorders are chronic and the normal respiratory system can quickly alter the PaCO2, essentially all metabolic disorders are accompanied by some degree of respiratory compensation.2,3Similarly, chronic respiratory acid–base disorders are typically accompanied by attempts at metabolic compensation.4,5 However, with acute respiratory acid–base disorders there is insufficient time for the metabolic pathways to compensate significantly.6 As such, acute respiratory derangements are essentially uncompensated.
The amount of compensation (metabolic or respiratory) can be reliably predicted based on the degree of derangement in the primary disorder. Table 28–1 outlines the simple acid–base disorders and provides formulas for calculating the expected compensatory responses.7 Although it is not mandatory to memorize these formulas in order to interpret acid–base problems, they can be helpful tools. If the measured values differ markedly from the calculated values (the measured serum is greater than 2 mEq/L [2 mmol/L] from the calculated value or the measured PaCO2 is more than 4 mm Hg [0.54 kPa] from the calculated value), a second acid–base disorder is present as outlined in Table 28–2.
Table 28–1 The Six Simple Acid–Base Disorders
Table 28–2 Diagnosis of Concurrent Acid–Base Disturbances When Compensation Is Inappropriate
APPLICATION OF BASIC PATHOPHYSIOLOGY
When given an ABG for interpretation, it is essential to use an approach that is focused yet comprehensive.8 An algorithm illustrating this concept is shown in Figure 28–1. Using this algorithm, Step 1 is to identify all abnormalities in the pH, PaCO2, and/or and then decide which abnormal values are primary and which are compensatory. This is best done by initially looking at the pH. Whichever side of 7.40 the pH is on, the process that caused it to shift to that side is the primary abnormality. If the arterial pH is lower than 7.40 (acidemia), an elevated PaCO2 (greater than 45 mm Hg or 6 kPa, respiratory acidosis) or a lowered (less than 22 mEq/L or mmol/L, metabolic acidosis) would be the primary abnormality. If the arterial pH is higher than 7.40 (alkalemia), a decreased PaCO2 (less than 35 or 4.7 kPa, respiratory alkalosis) or an increased (greater than 25 mEq/L or mmol/L, metabolic alkalosis) would be the primary abnormality. Once the primary disorder is established, Step 2 is to apply the formulas from Table 28–1 to assess whether compensation is appropriate and to look for concurrent processes.7
FIGURE 28–1. An algorithmic approach to acid–base disorders. Normal values: pH 7.35 to 7.45, PaCO2 35 to 45 mm Hg (4.7–6 kPa), 22 to 26 mEq/L (mmol/L), anion gap less than 12 mEq/L (mmol/L). Note that PaCO2 should be in millimeters of mercury to use the equations in the figure. (Cl−, chloride ion; , bicarbonate; Na+, sodium ion; PaCO2, partial pressure of arterial carbon dioxide.)
An alternative to a diagnostic algorithm is use of a graphic nomogram.9 Nomograms are plots of the pH, PaCO2, and that allow the user to rapidly determine whether arterial blood gas values are consistent with one of the six simple primary acid–base disturbances. Although nomograms are commonly used to identify acid–base disturbances in clinical practice, only individuals who fully comprehend the fundamental concepts of acid–base assessment should use these tools. Also, appreciate that nomograms have limited utility when dealing with complex acid–base derangements.
Patient Encounters 1 Through 5: Application of Basic Pathophysiology
Case Study 1
An unconscious 23-year-old man is brought to the emergency department by several friends who quickly disappear without providing any clinical history. On exam the patient has prominent “track marks” consistent with chronic IV drug abuse. The initial ABG has a pH of 7.16, PaCO2 of 70 mm Hg (9.3 kPa), and of 27 mEq/L (mmol/L).
What is the primary acid-base disorder?
Has compensation occurred?
Given the clinical history, what is the most likely explanation for the ABG findings?
Case Study 2
The next patient is a 72-year-old man with advanced emphysema who requires chronic oxygen therapy. During a routine office visit, an ABG is checked to verify his ongoing need for supplemental oxygen. His blood gas sample has a pH of 7.34, PaCO2 of 60 mm Hg (8.0 kPa), and of 35 mEq/L (mmol/L).
What is the primary acid-base disorder?
Has compensation occurred?
Given the clinical history, what is the most likely explanation for the ABG findings?
Case Study 3
Now consider a healthy 20-year-old woman who is having labs drawn as part of a research protocol. Her ABG shows a pH of 7.50, PaCO2 of 29 mm Hg (3.86 kPa), and of 22 mEq/L (mmol/L).
What is the primary acid-base disorder?
Has compensation occurred?
Given the clinical history, what is the most likely explanation for the ABG findings?
Case Study 4
This 59-year-old woman has a long history of ischemic cardiomyopathy and congestive heart failure that requires daily furosemide (Lasix) therapy. An ABG has been drawn because of increasing dyspnea and shows the following: pH of 7.50, PaCO2 of 47 mm Hg (6.3 kPa), and of 36 mEq/L (mmol/L).
What is the primary acid-base disorder?
Has compensation occurred?
Given the clinical history, what is the most likely explanation for the ABG findings?
Case Study 5
The final patient in this section is a 46-year-old woman with chronic renal insufficiency who is being hospitalized for gastroenteritis with profound diarrhea. Her ABG shows a pH of 7.20, PaCO2, of 20 mm Hg (2.7 kPa), and of 8 mEq/L (mmol/L).
What is the primary acid-base disorder?
Has compensation occurred?
Given the clinical history, what is the most likely explanation for the ABG findings?
Acid–base disturbances are always manifestations of underlying clinical disorders. It is useful to specifically define the primary acid–base abnormality, as each disorder is caused by a limited number of disease processes. Establishing the specific disease process responsible for the observed acid–base disorder is clinically important because treatment of a given disorder will only be accomplished by correcting the underlying disease process.
ADVANCED PATHOPHYSIOLOGY
The concepts in this section will be used to further expand on Steps 3 and 4 of the diagnostic algorithm shown in Figure 28–1. Under normal circumstances the serum is in the isoelectric state. This means that the positively charged entities reported in a standard chemistry panel (cations: sodium and potassium) should be exactly balanced by the negatively charged entities (anions: chloride and bicarbonate). However, this relationship is consistently incorrect, as the measured cations are higher than the measured anions by 10 to 12 mEq/L (mmol/L). This discrepancy results from the presence of unmeasured anions (e.g., circulating proteins, phosphates, and sulfates). This apparent difference in charges, the serum anion gap, is calculated as follows:
Anion gap = Na+ − (Cl– + ).
Because the serum potassium content is relatively small and is very tightly regulated, it is generally omitted from the calculation.10
It is important to realize that the serum concentration may be affected by the presence of unmeasured endogenous acids (lactic acid or ketoacids). Bicarbonate will attempt to buffer these acids, resulting in a 1 mEq loss of serum HCO-for each 1 mEq of acid titrated. Because the cation side of the equation is not affected by this transaction, the loss of serum results in an increase in the calculated anion gap. Identification of an increased anion gap is very important as a limited number of clinical scenarios lead to this unique acid-base disorder. A mnemonic to recall the differential diagnosis for an anion gap acidosis is shown in Table 28–3. The concept of the increased anion gap will be applied later in Patient Encounters 6 through 10.
Step 3 in Figure 28–1 suggests that any time an ABG is analyzed it is wise to concurrently inspect the serum chemistry values and to calculate the anion gap. The body does not generate an anion gap to compensate for a primary disorder. As such, if the calculated anion gap exceeds 12 mEq/L (mmol/L) there is a primary metabolic acidosis regardless of the pH or the serum concentration. The anion gap may be artificially lowered by decreased serum albumin, multiple myeloma, lithium intoxication, or a profound increase in the serum potassium, calcium, or magnesium.11
Step 4 in Figure 28–1 shows how calculation of the anion gap also facilitates determination of the excess gap or the degree to which the calculated anion gap exceeds the normal anion gap. The excess gap is calculated as follows:
Excess gap = anion gap − 12 = [Na+ − (Cl– + )] − 12.
The excess gap represents the amount of that has been lost due to buffering unmeasured cations. The excess gap can be added back to the measured to determine what the patient’s bicarbonate would be if these endogenous acids were not present. This is a very valuable tool that can be used in narrowing the differential diagnosis of certain acid–base disorders as well as in uncovering occult or mixed acidbase disorders.
Patient Encounters 6 Through 10: Application of Advanced Pathophysiology
Case Study 6
A 31-year-old psychiatric facility resident is admitted to the ICU after ingesting an unknown quantity of aspirin tablets. The presenting labs show a pH of 7.50, PaCO2 of 20 mm Hg (2.7 kPa), of 16 mEq/L (mmol/L), a sodium concentration of 140 mEq/L (mmol/L), and a chloride concentration of 103 mEq/L (mmol/L).
What is the primary acid-base disorder?
Is there a mixed disorder?
Given the clinical history, what is the most likely explanation for the ABG findings?
Case Study 7
A 56-year-old man is brought to the emergency department by his family. He has felt unwell for the past week and did not attend his regular hemodialysis sessions. He began vomiting 36 hours ago but refused medical evaluation. When family members found him unresponsive this morning they sought medical attention. Lab analyses show: pH of 7.40, PaCO2 of 40 mm Hg (5.3 kPa), of 24 mEq/L (mmol/L), sodium concentration of 145 mEq/L (mmol/L), and chloride concentration of 100 mEq/L (mmol/L).
What is the primary acid-base disorder?
Is there a mixed disorder?
Given the clinical history, what is the most likely explanation for the ABG findings?
Case Study 8
A 39-year-old woman is brought to the emergency department by rescue squad after being found “profoundly intoxicated” in a city park. Shortly after arrival, she has several episodes of emesis with witnessed aspiration. She is transferred to the ICU where she develops progressive hypoxia during the ensuing hours. Following elective intubation her blood work shows a pH of 7.50, PaCO2 of 20 mm Hg (2.7 kPa), of 15 mEq/L (mmol/L), sodium concentration of 145 mEq/L (mmol/L), and chloride concentration of 100 mEq/L (mmol/L).
What is the primary acid-base disorder?
Is there a mixed disorder?
Given the clinical history, what is the most likely explanation for the ABG findings?
Case Study 9
A 69-year-old insulin-dependent diabetic man is being evaluated for unresponsiveness. His wife says he had “stomach flu” for several days with frequent bouts of emesis. She thinks he has stopped taking his insulin because he has not been eating. He became somnolent yesterday and she called an ambulance when she noticed his breathing was very slow and shallow. The blood work drawn prior to urgent intubation shows a pH of 7.10, PaCO of 50 mm Hg (6.7 kPa), of 15 mEq/L (mmol/L), sodium concentration of 145 mEq/L (mmol/L), and chloride concentration of 100 mEq/L (mmol/L).
What is the primary acid-base disorder?
Is there a mixed disorder?
Given the clinical history, what is the most likely explanation for the ABG findings?
Case Study 10
The final patient is a 23-year-old woman who was admitted 6 hours ago for diabetic ketoacidosis. With appropriate therapy, her hyperglycemia has improved and her serum ketones are improving. Because she continues to feel poorly, repeat blood work is obtained. Studies show a pH of 7.15, PaCO2 of 15 mm Hg (2 kPa), of 5 mEq/L (mmol/L), sodium concentration of 140 mEq/L (mmol/L), and chloride concentration of 110 mEq/L (mmol/L).
What is the primary acid-base disorder?
Is there a mixed disorder?
Given the clinical history, what is the most likely explanation for the ABG findings?
Table 28–3 Mnemonics for the Differential Diagnoses of Metabolic Acidosis
In summary, the approach to assessment of acid–base status involves four key steps as outlined in Figure 28–1: Step 1—initial inspection of the pH, PaCO2, and ; Step 2—assessment of the adequacy of compensation; Step 3—calculation of the anion gap; and Step 4—calculation of the excess gap.
ETIOLOGY AND TREATMENT
Arterial blood gases, serum electrolytes, physical examination findings, the clinical history, and the patient’s recent medications must be reviewed in order to establish the etiology of a given acid–base disturbance. Tables 28–3through 28–7 outline the most commonly encountered causes for each of the primary acid–base disorders. The therapeutic approach to each of these acid–base derangements should emphasize a search for the cause, as opposed to immediate attempts to normalize the pH.
It is critical to treat the underlying causative process to effectively resolve most observed acid–base disorders. However, supportive treatment of the pH and electrolytes is often needed until the underlying disease state is improved.12,13
All patients with significant disturbances in their acid–base status require continuous cardiovascular and hemodynamic monitoring. Because frequent assessment of the patient’s response to treatment is critical, an arterial line is often placed to minimize patient discomfort with serial ABG collections. If the anion gap was initially abnormal, serial chemistries should be followed to ensure that the anion gap resolves with treatment. Specific treatment decisions depend on the underlying pathophysiologic state (e.g., dialysis for renal failure, insulin for diabetic ketoacidosis, or improving tissue perfusion and oxygenation for lactic acidosis).
Metabolic Acidosis
Metabolic acidosis is characterized by a reduced arterial pH, a primary decrease in the concentration, and a compensatory reduction in the PaCO2. The etiologies of metabolic acidosis are divided into those that lead to an increase in the anion gap and those associated with a normal anion gap and are listed in Table 28–4. Although there are numerous mnemonics to recall the differential diagnosis of the metabolic acidosis, two simple ones are shown in Table 28–3. High anion gap metabolic acidosis is most frequently caused by lactic acidosis, ketoacidosis, and/or renal failure. Although there is considerable variation, the largest anion gaps are caused by ketoacidosis, lactic acidosis, and methanol or ethylene glycol ingestion.14
Table 28–4 Common Causes of Metabolic Acidosis
Symptoms of metabolic acidosis are attributable to changes in cardiovascular, musculoskeletal, neurologic, or pulmonary functioning. Respiratory compensation requires marked increases in minute ventilation and may lead to dyspnea, respiratory fatigue, and respiratory failure. Acidemia predisposes to ventricular arrhythmias and reduces cardiac contractility, each of which can result in pulmonary edema and/or systemic hypotension.15 Neurologic symptoms range from lethargy to coma and are usually proportional to the severity of the pH derangement. Chronic metabolic acidosis leads to a variety of musculoskeletal problems including impaired growth, rickets, osteomalacia, or osteopenia. These changes are believed to be caused by the release of calcium and phosphate during bone buffering of excess H+ions.
As previously discussed, in anion gap metabolic acidosis, the isoelectric state is maintained because unmeasured anions are present. With a normal anion gap metabolic acidosis, the isoelectric state is maintained by an increase in the measured chloride. Because of this, normal anion gap metabolic acidosis is often referred to as hyperchloremic acidosis.
In patients with a normal anion gap metabolic acidosis, it is often helpful to calculate the urine anion gap (UAG).16 The UAG is calculated as follows:
UAG = (Urine Na+ + Urine K+) − Urine Cl−.
The normal UAG ranges from 0 to 5 mEq/L (mmol/L) and represents the presence of unmeasured urinary anions. In metabolic acidosis, the excretion of NH4+ and concurrent Cl− should increase markedly if renal acidification is intact. This results in UAG values from −20 to −50 mEq/L (mmol/L). This occurs because the urinary Cl− concentration now markedly exceeds the urinary Na+ and K+ concentrations. Diagnoses consistent with an excessively negative UAG include proximal (type 2) renal tubular acidosis, diarrhea, or administration of acetazolamide or hydrochloric acid (HCl). Excessively positive values of the UAG suggest a distal (type 1) renal tubular acidosis.
In order to effectively treat metabolic acidosis, the causative process must be identified and treated.17 The precise role of adjunctive therapy with sodium bicarbonate (NaHCO3) is not universally agreed upon. However, most practitioners accept that NaHCO3 is indicated when renal dysfunction precludes adequate regeneration of or when severe acidemia (pH less than 7.10) is present. The metabolic acidosis seen with lactic acidosis and ketoacidosis generally resolves with therapy targeted at the underlying cause and NaHCO3 may be unnecessary regardless of the pH. The metabolic acidosis of renal failure, renal tubular acidosis, or intoxication with ethylene glycol, methanol, or salicylates is much more likely to require NaHCO3 therapy.
If NaHCO3 is used, the plasma should not be corrected entirely. Instead, aim at increasing above an absolute value of 10 mEq/L (10 mmol/L). The total deficit can be calculated from the current bicarbonate concentration (curr), the desired bicarbonate concentration (post), and the body weight (in kilograms) as follows:
deficit = [(2.4/curr) + 0.4] × weight × (curr–post
No more than half of the calculated deficit should be given initially to avoid volume overload, hypernatremia, hyperosmolarity, overshoot alkalemia, and/or hypokalemia. The calculated deficit reflects only the present situation and does not account for ongoing H+ production and loss. When giving therapy, serial blood gases are needed to monitor therapy.
Another option for patients with severe acidemia is tromethamine (THAM).18 This inert amino alcohol buffers acids and CO2 through its amine (-NH2) moiety:
THAM-NH2 + H+ = THAM-NH3+
THAM-NH2 + H2O + CO2 = THAM-NH3+ + .
Protonated THAM (with Cl− or ) is excreted in the urine at a rate that is slightly higher than creatinine clearance. As such, THAM augments the buffering capacity of the blood without generating excess CO2. THAM is less effective in patients with renal failure and toxicities may include hyperkalemia, hypoglycemia, and possible respiratory depression.
Chronic metabolic acidosis can successfully be managed using potassium citrate/citric acid (Polycitra-K) or sodium citrate/citric acid (Bicitra).
Metabolic Alkalosis
Metabolic alkalosis is characterized by an increased arterial pH, a primary increase in the HCO3− concentration, and a compensatory increase in the PaCO2. Patients will always hypoventilate to compensate for metabolic alkalosis—even if it results in profound hypoxemia. For a metabolic alkalosis to persist, there must concurrently be a process that elevates serum concentration (gastric or renal loss of acids) and another that impairs renal excretion (hypovolemia, hypokalemia, or mineralocorticoid excess). The etiologies of metabolic alkalosis are listed in Table 28–5.
Patients with metabolic alkalosis rarely have symptoms attributable to alkalemia. Rather, complaints are usually related to volume depletion (muscle cramps, positional dizziness, weakness) or to hypokalemia (muscle weakness, polyuria, polydipsia).
In order to effectively treat metabolic alkalosis, the causative process must be identified and treated. The major causes of metabolic alkalosis are often readily apparent after carefully reviewing the patient’s history and medication list. In hospitalized patients always look for administration of compounds such as citrate in blood products and acetate in parenteral nutrition that can raise the HCO3− concentration. If the etiology of the metabolic alkalosis is still unclear, measurement of the urinary chloride may be useful. Some processes leading to metabolic alkalosis (vomiting, nasogastric suction losses, factitious diarrhea) will have low urinary Cl− concentrations (less than 25 mEq/L or mmol/L), while others (diuretics, hypokalemia, and mineralocorticoid excess) will have higher urinary Cl− concentrations (greater than 40 mEq/L or mmol/L).
Table 28–5 Common Causes of Metabolic Alkalosis
In general, contributing factors such as diuretics, nasogastric suction, and corticosteroids should be discontinued if possible. Any fluid deficits should be treated with IV normal saline. Recognize that patients with varieties of metabolic alkalosis with high urine Cl- (though rather uncommon) will be resistant to saline loading. Potassium supplementation should always be given if it is also deficient.
In patients with mild or moderate alkalosis who require ongoing diuresis but have rising concentrations, the carbonic anhydrase inhibitor acetazolamide can be used to reduce the concentration. Acetazolamide is typically dosed at 250 mg every 6 to 12 hours as needed to maintain the pH in a clinically acceptable range. This agent results in gradual changes in the serum and is not used to acutely correct a patient’s acid-base status. If alkalosis is profound and potentially life-threatening (due to seizures or ventricular tachyarrhythmias), consideration can be given to hemodialysis or transient HCl infusion. The hydrogen ion deficit (in milliequivalents or millimoles) can be estimated from the current bicarbonate concentration (curr), the desired bicarbonate concentration (post), and the body weight (in kilograms) as follows:
H+ deficit = 0.4 × weight × (curr - post).
After estimating the H+ deficit, 0.1 to 0.2 N HCl is infused at 20 to 50 mEq/h (mmol/h) into a central vein. Arterial pH must be monitored at least hourly and the infusion stopped as soon as clinically feasible. Ammonium chloride and arginine hydrochloride, agents that result in the formation of HCl, are not commonly prescribed, as they may lead to significant toxicity. Ammonium chloride may cause accumulation of ammonia leading to encephalopathy while arginine hydrochloride can induce life-threatening hyperkalemia through unclear mechanisms.
Respiratory Acidosis
Respiratory acidosis is characterized by a reduced arterial pH, a primary increase in the arterial PaCO2 and, when present for sufficient time, a compensatory rise in the concentration. Because increased CO2 is a potent respiratory stimulus, respiratory acidosis represents ventilatory failure or impaired central control of ventilation as opposed to an increase in CO2 production. As such, most patients will have hypoxemia in addition to hypercapnia. The most common etiologies of respiratory acidosis are listed in Table 28–6.
Severe, acute respiratory acidosis produces a variety of neurologic abnormalities. Initially these include headache, blurred vision, restlessness, and anxiety. These may progress to tremors, asterixis, somnolence, and/or delirium. If untreated, terminal manifestations include peripheral vasodilation leading to hypotension and cardiac arrhythmias. Chronic respiratory acidosis is typically associated with cor pulmonale and peripheral edema.
Table 28–6 Common Causes of Respiratory Acidosis
In order to effectively treat respiratory acidosis, the causative process must be identified and treated. If a cause is identified, specific therapy should be started. This may include naloxone for opiate-induced hypoventilation or bronchodilator therapy for acute bronchospasm. Because respiratory acidosis represents ventilatory failure, an increase in alveolar ventilation is required. This can often be achieved by controlling the underlying disease (e.g., bronchodilators and corticosteroids in asthma) and/or physically augmenting ventilation.
Although their precise role and mechanisms of action are unclear, agents such as medroxyprogesterone, theophylline, and doxapram stimulate respiration and have been used to treat mild to moderate respiratory acidosis. Moderate or severe respiratory acidosis requires assisted ventilation. This can be provided to spontaneously breathing patients via bilevel positive airway pressure (BiPAP) delivered via a tight-fitting mask, or by intubation followed by mechanical ventilation. In mechanically ventilated patients, respiratory acidosis is treated by increasing the minute ventilation. This is achieved by increasing the respiratory rate and/or tidal volume.
As with the treatment of metabolic acidosis, the role of NaHCO3 therapy is not well defined for respiratory acidosis. Realize that administration of NaHCO3 can paradoxically result in increased CO2generation ( + H+ → H2CO3 → H2O + CO2) and worsened acidemia. Careful monitoring of the pH is required if NaHCO3 therapy is started for this indication. The use of tromethamine in respiratory acidosis (see Metabolic Acidosis, above) has unproven safety and benefit.
The goals of therapy in patients with chronic respiratory acidosis are to maintain oxygenation and to improve alveolar ventilation if possible. Because of the presence of renal compensation it is usually not necessary to treat the pH, even in patients with severe hypercapnia. Although the specific treatment varies with the underlying disease, excessive oxygen and sedatives should be avoided as they can worsen CO2 retention.
Respiratory Alkalosis
Respiratory alkalosis is characterized by an increased arterial pH, a primary decrease in the arterial PaCO2 and, when present for sufficient time, a compensatory fall in the concentration. Respiratory alkalosis represents hyperventila-tion and is remarkably common. The most common etiologies of respiratory alkalosis are listed in Table 28–7 and range from benign (anxiety) to life-threatening (pulmonary embolism). Some causes of hyperventilation and respiratory acidosis are remarkably common (hypoxemia or anemia).
The symptoms produced by respiratory alkalosis result from increased irritability of the central and peripheral nervous systems. These include light-headedness, altered consciousness, distal extremity paresthesias, circumoral paresthesia, cramps, carpopedal spasms, and syncope. Various supraventricular and ventricular cardiac arrhythmias may occur in extreme cases, particularly in critically ill patients. An additional finding in many patients with severe respiratory alkalosis is hypophosphatemia, reflecting a shift of phosphate from the extracellular space into the cells. Chronic respiratory alkalosis is generally asymptomatic.
Table 28–7 Common Causes of Respiratory Alkalosis
It is imperative to identify serious causes of respiratory alkalosis and institute effective treatment. In spontaneously breathing patients, respiratory alkalosis is typically only mild or moderate in severity and no specific therapy is indicated. Severe alkalosis generally represents respiratory acidosis imposed on metabolic alkalosis and may improve with sedation. Patients receiving mechanical ventilation are treated with reduced minute ventilation achieved by decreasing the respiratory rate and/or tidal volume. If the alkalosis persists in the ventilated patient, high-level sedation or paralysis is effective.
SUMMARY
Acid–base disturbances are common clinical problems that are not difficult to analyze if approached in a consistent manner. The pH, PaCO2, and should be inspected to identify all abnormal values. This should lead to an assessment of which deviations represent the primary abnormality and which represent compensatory changes. The serum electrolytes should always be used to calculate the anion gap. In cases in which the anion gap is increased, the excess anion gap should be added back to the measured . The anion gap and the excess gap are useful tools that can identify hidden disorders. This rigorous assessment of the patient’s acid–base status, incorporated with the available clinical data, increases the likelihood that the clinician will successfully determine the cause of each identified disorder. Although supportive therapy is often required for profound acid–base disturbances, definitive therapy must target the underlying process that has led to the observed derangements.
Patient Care and Monitoring
1. Every patient with a suspected acid-base disturbance should have an arterial blood gas and a serum chemistry panel drawn concurrently. The results of these tests should be reviewed using a systematic approach to ensure proper interpretation.
2. What is the primary disorder? Has compensation occurred?
3. Is the anion gap excessively large? If so, does calculation of the excess gap identify another acid-base disorder?
4. Continuous cardiovascular and hemodynamic monitoring should be used for significant pH disturbances, as the most serious sequelae of acid-base disorders include electrolyte abnormalities, cardiac dysrhythmias, and systemic hypotension.
5. All acid-base abnormalities result from underlying disease processes. Definitive therapy for these disturbances requires treatment of the illness that has disrupted the pH equilibrium.
6. Review each patient’s history, physical exam, and current medication list for clues regarding potential causes of the observed acid-base disorder.
7. Serial arterial blood gases and serum chemistries should be compared, as every patient’s acid-base status is continuously changing based on the underlying disease state and any therapy initiated.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
REFERENCES
1. Rose BD, Post TW. Clinical Physiology of Acid–Base and Electrolyte Disorders. 5th ed. New York, NY: McGraw-Hill, 2001: 299.
2. Schlichtig R, Grogono A, Severinghaus J. Human PaCO2 and standard base excess for compensation of acid–base imbalances. Crit Care Med 1998;26:1173–1179.
3. Pierce NF, Fedson DS, Brigham KL, et al. The ventilatory response to acute base deficit in humans. Time course during development and correction of metabolic acidosis. Ann Intern Med 1970;72:633–640.
4. Javaheri S, Kazemi H. Metabolic alkalosis and hypoventilation in humans. Am Rev Respir Dis 1987;136:1011–1016.
5. Polak A, Haynie GD, Hays RM, Schwartz WB. Effects of chronic hypercapnia on electrolyte and acid–base equilibrium. J Clin Invest 1961;40:1223–1237.
6. Gennari FJ, Goldstein MB, Schwartz WB. The nature of the renal adaptation to chronic hypocapnia. J Clin Invest 1972;51:1722–1730.
7. van Yperselle de Striho C, Brasseur L, de Coninck JD. The “carbon dioxide response curve” for chronic hypercapnia in man. N Engl J Med 1966;275:117–122.
8. Haber RJ. A practical approach to acid–base disorders. West J Med 1991;155:146–151.
9. Arbus GS. An in-vivo acid–base nomogram for clinical use. Can Med Assoc J 1973;109:291–293.
10. Narins R. Clinical Disorders of Fluid and Electrolyte Metabolism. 5th ed. New York, NY: McGraw-Hill, 1994: 778.
11. Goodkin DA, Gollapudi GK, Narins RG. The role of the anion gap in detecting and managing mixed metabolic acid–base disorders. Clin Endocrinol Metab 1984;13:333–349.
12. Adrogué HJ, Madias NE. Management of life-threatening acid–base disorders. First of two parts. N Engl J Med 1998;338:26–34.
13. Adrogué HJ, Madias NE. Management of life-threatening acid–base disorders. Second of two parts. N Engl J Med 1998;338:107–111.
14. Abelow B. Understanding Acid–Base. Baltimore, MD: Williams & Wilkins, 1998: 229.
15. Kearns T, Wolfson A. Metabolic acidosis. Emerg Med Clin North Am 1989;7:823–835.
16. Batlle DC, Hizon M, Cohen E, Gutterman C, Gupta R. The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl J Med 1988;318:594–599.
17. Hood FL, Tannen RL. Protection of acid–base balance by pH regulation of acid production. N Engl J Med 1998;339:819–826.
18. Chernow B, ed. The Pharmacologic Approach to the Critically Ill Patient. 3rd ed. Baltimore, MD: Williams & Wilkins, 1994: 965.