4: Acid-Base Abnormalities

His very low HCO₃⁻ suggests a significant acid-base abnormality. In addition to evaluating his abdominal pain, exploring his acid-base disorder is critical.

The differential diagnosis of acid-base disorders is extensive (Table 4-1) but can be easily organized into 4 distinct subsets by first determining whether the primary disorder is a (1) metabolic acidosis, (2) metabolic alkalosis, (3) respiratory acidosis, or (4) respiratory alkalosis. The key pivotal feature that allows the clinician to narrow the differential to 1 of these subsets is to first evaluate the pH and then the HCO₃⁻ and PaCO_2.

Step 1: Determine Whether the Primary Disorder is an Acidosis or Alkalosis by Reviewing the pH.

1. pH < 7.4 indicates the primary disorder is an acidosis.

2. pH > 7.4 indicates the primary disorder is an alkalosis.

Step 2: Determine Whether the Primary Acidosis or Alkalosis is Metabolic or Respiratory by Reviewing the HCO₃⁻ and PaCO₂

1. Recall that CO₂ + H₂O ⟺ H₂CO₃ ⟺ HCO₃⁻ + H⁺; therefore

2. PaCO₂ changes drive pH as follows:

   1. Increased PaCO₂ drives reaction to right: This increases H⁺ which lowers pH, resulting in a respiratory acidosis.

   2. Decreased PaCO₂ drives reaction to left: This decreases H⁺ which raises pH, resulting in a respiratory alkalosis.

3. HCO₃⁻ changes drive pH as follows:

   1. Increase HCO₃⁻ drives the reaction to left: This consumes H⁺ which raises the pH, resulting in a metabolic alkalosis.

   2. Decreased HCO₃⁻ drives the reaction to the right: This increases H⁺ which lowers the pH, resulting in a metabolic acidosis. This occurs in 2 situations:

      1. Processes that produce H⁺ ion (and consume HCO₃⁻) (ie, ketoacidosis, lactic acidosis)

      2. Processes that lose HCO₃⁻ (ie, diarrhea)

4. For acidosis (pH < 7.4)

   1. HCO₃⁻ < 24 mEq/L: The primary disorder is a metabolic acidosis

   2. PaCO₂ > 40 mm Hg: The primary disorder is a respiratory acidosis

5. For alkalosis (pH > 7.4)

   1. HCO₃⁻ > 24 mEq/L: The primary disorder is a metabolic alkalosis

   2. PaCO₂ < 40 mm Hg: The primary disorder is a respiratory alkalosis

The differential diagnosis for metabolic acidosis is extensive but can be narrowed based on whether the anion gap is normal or elevated. The anion gap is an estimate of the unmeasured anions. Metabolic acidoses may be caused by processes that either produce acid (ie, ketoacids, lactic acid, sulfates, phosphates, or other organic acids), or by processes that lose HCO₃⁻ in the urine or stool (ie, diarrhea). Processes that produce acid also produce their associated unmeasured anions, resulting in an increased anion gap. On the other hand, processes that lose HCO₃⁻ do not generate unmeasured anions and the anion gap remains normal.

Step 3: Limit the Differential Diagnoses of Metabolic Acidosis by Calculating the Anion Gap

1. Anion gap = Na⁺ – (HCO₃⁻ + Cl⁻)

2. 12 ± 4 is often cited as an ideal cutoff, although in some institutions, a normal anion gap is only 7–9 mEq/L.

3. The normal anion gap is affected by the serum albumin level.

   1. Albumin is negatively charged so that lower serum albumin levels are associated with a lower anion gap.

   2. The normal anion gap is 2.5 mEq/L lower, for every 1 g/dL drop in the serum albumin (below 4.4 g/dL).

   3. The reference range at the institution performing the tests should be used.

4. An increased anion gap suggests that an anion gap metabolic acidosis is present.

Step 4: Explore the Differential Diagnoses of the Primary Disorder

After selecting the appropriate subset of hypotheses for the primary disorder, review the limited differential diagnoses (Table 4-1) and explore the demographics, risk factors, associated symptoms and signs of those diseases. This information allows the clinician rank the differential diagnosis for the primary acid-base disorder and then determine the appropriate testing strategy.

Step 5: Diagnose Primary Disorder

Synthesize the clinical and laboratory information to arrive at a diagnosis of the primary acid-base disorder.

Step 6: Check for Additional Disorders

Step 6A: Calculate Anion Gap (Even in Patients Without Acidosis) to Uncover Unexpected Anion Gap Metabolic Acidosis

Always check the anion gap. An elevated gap suggests an anion gap metabolic acidosis even when the HCO₃⁻ is above normal.

Step 6B: Calculate Whether Compensation is Appropriate

1. The acid-base system attempts to maintain homeostasis. Alterations in 1 system (respiratory or metabolic) trigger compensatory changes in the other system to minimize the impact on pH.

2. Formulas predict the expected change in PaCO₂ to compensate for metabolic processes and the expected change in HCO₃⁻ to compensate for respiratory processes (Table 4-2).

3. Compensation that is greater or less than expected suggests that an additional acid-base abnormality is present, not just compensation.

4. If an additional process is implicated, the differential diagnosis for that additional disorder should be explored.

Step 7: Reach Final Diagnosis

Figure 4-1 outlines the stepwise approach to acid-base disorders.

Step 1: Determine Whether the Primary Disorder is an Acidosis or Alkalosis by Reviewing the pH

Although an arterial pH has not yet been obtained, the patient's very low HCO₃⁻ strongly suggests a metabolic acidosis. Commonly, sick patients are discovered to have a metabolic acidosis when a basic metabolic panel reveals a very low serum HCO₃⁻. Although compensation for a respiratory alkalosis may result in a slightly low HCO₃⁻, a HCO₃⁻ in this range is almost never seen unless there is in fact a primary metabolic acidosis. Nonetheless, an arterial blood gas (ABG) measurement can document the acidosis and evaluate respiratory compensation.

Step 2: Determine Whether the Primary Acidosis or Alkalosis is Metabolic or Respiratory by Reviewing the HCO₃⁻ and PaCO₂

Step 3: For Patients With Metabolic Acidoses, Limit the Differential Diagnoses by Calculating the Anion Gap

Step 4: Explore the Differential Diagnoses of the Primary Disorder

The history of childhood-onset DM strongly suggests insulin-dependent DM. This form of DM is associated with total or near total insulin deficiency increasing the risk of DKA. This is the leading hypothesis. Active alternative hypotheses include other ketoacidoses (starvation, alcohol) and uremia from renal failure (potentially secondary to long-standing diabetes). Finally, lactic acidosis (from hypoxemia or shock) is a "must not miss diagnosis" that should always be considered in sick patients with metabolic acidosis. Table 4-3 ranks the differential diagnoses considering the available demographic information, risk factors, and symptoms and signs.

Leading Hypothesis: DKA

Textbook Presentation

DKA often begins with an acute illness (ie, pneumonia, urinary tract infection, myocardial infarction [MI]) in a patients with type 1 DM. Patients often complain of symptoms related to hyperglycemia (polyuria, polydipsia, and polyphagia) and to the precipitating illness (eg, fever, cough, dysuria, chest pain). Nonspecific complaints are common (nausea, vomiting, abdominal pain, and weakness). Patients are profoundly dehydrated and exhibit orthostatic changes or frank hypotension. Confusion, lethargy, and coma may occur secondary to dehydration, hyperglycemia, acidosis, or the underlying precipitating event.

Disease Highlights

1. Occurs primarily in patients with complete or near complete insulin deficiency

   1. Type 1 autoimmune insulin-dependent DM

   2. Type 2 DM can cause DKA

      1. Studies report type 2 DM in 12–47% of diabetic patients with DKA

      2. Type 2 DM is more frequently found in African Americans and Hispanics presenting with DKA than non-Hispanic whites. (Up to 47% of Hispanic diabetics had type 2 DM.)

      3. Many such patients can eventually be treated with oral hypoglycemics without insulin after a short period of insulin therapy.

   3. Diabetes secondary to severe chronic pancreatitis and near complete islet cell obliteration

2. Incidence is 4.6–8.0 cases/1000 person years in patients with DM

3. Precipitated by low insulin levels or illnesses that increase hormones counterregulatory to insulin (cortisol, epinephrine, glucagon, and growth hormone), or both.

   1. The precipitant is the most frequent cause of mortality in DKA.

   2. Most common precipitants

      1. Infection (urinary tract infections and pneumonia are most common). Patients may be afebrile.

      2. Discontinuation of insulin or oral hypoglycemics

      3. New-onset type 1 DM

   3. Other precipitants

      1. Other infections

      2. MI

      3. Cerebrovascular accident

      4. Acute pancreatitis

      5. Pulmonary embolism

      6. Gastrointestinal hemorrhage

      7. Severe emotional stress

      8. Drugs (eg, corticosteroids, thiazides, cocaine, antipsychotics)

4. Pathogenesis: The marked decrease in insulin levels together with an increase in counterregulatory hormones lead to the following events:

   1. Hyperglycemia: Caused by

      1. Reduced cellular uptake of glucose

      2. Increased hepatic glycogenolysis and gluconeogenesis

      3. Glucosuria helps prevent extreme hyperglycemia (> 500–600 mg/dL) but more extreme hyperglycemia occurs if urinary output falls.

   2. Ketoacidosis

      1. Marked insulin deficiency increases glucagon which in turn increases acetyl CoA production within liver.

      2. Massive production of acetyl CoA overwhelms Krebs cycle resulting in ketone production and ketonemia (primarily beta hydroxybutyric acid and to a lesser extent acetoacetic acid).

      3. Ketonemia leads to anion gap metabolic acidosis.

   3. Volume depletion: Ketonemia and hyperglycemia cause an osmotic diuresis, which results in profound dehydration and typical fluid losses of 3–6 L.

   4. Potassium loss

      1. The osmotic diuresis also causes significant potassium losses.

      2. Dehydration-induced hyperaldosteronism aggravates potassium loss.

      3. Typical potassium deficit is 3–5 mEq/kg body weight.

   5. Hyperkalemia

      1. Despite the total body potassium deficit, hyperkalemia is frequent.

      2. The etiology is multifactorial.

         • (1) Insulin normally drives glucose and potassium into the cells. Insulin deficiency decreases cellular uptake and causes hyperkalemia.

         • (2) Plasma hypertonicity drives water and potassium out of the cells and into the intravascular compartment accentuating the hyperkalemia.

   6. Hyponatremia

      1. Despite a free water deficit due to osmotic diuresis, many patients with DKA have hyponatremia.

      2. Hyperglycemia leads to an osmotic shift of water from the intracellular space to the extracellular space, diluting sodium frequently causing hyponatremia.

      3. The elevated serum osmolality stimulates antidiuretic hormone (ADH) release further accentuating the hyponatremia.

      4. However, the patient's sodium concentration may be low, normal, or even high depending on the balance of the above factors (which act to lower serum sodium) with the free water loss from osmotic diuresis (which acts to raise serum sodium).

      5. Correction factors help predict the serum sodium concentration after the hyperglycemia is treated which shifts the intravascular water back to the intracellular space.

      6. Experiments suggest that the sodium concentration will increase by 2.4 mEq/L for every 100 mg/dL that the glucose falls with treatment. (See Pseudohyponatremia in Chapter 24.)

5. Mortality rate of DKA is 5–15%. Risk factors for death include:

   1. Severe coexistent disease (adjusted OR 16.3)

   2. pH < 7.0 at presentation (adjusted OR 8.7)

   3. > 50 units of insulin required in first 12 hours (adjusted OR 7.9)

   4. Glucose > 300 mg/dL after 12 hours (adjusted OR 8.3)

   5. Depressed mental status after 24 hours (adjusted OR 8.6)

   6. Fever (axillary temperature ≥ 38.0°C) after 24 hours (adjusted OR 5.8)

   7. Increasing age

      1. Mortality rate < 1.25% in persons younger than 55 years

      2. Mortality rate 11.8% in persons older than 55 years

Evidence-Based Diagnosis

1. Diagnostic criteria established by the American Diabetes Association (ADA)

   1. Glucose > 250 mg/dL

   2. pH ≤ 7.3

   3. HCO₃⁻ ≤ 18 mEq/L

   4. Positive serum ketones

   5. Anion gap > 10 mEq/L

2. Signs and symptoms

   1. Polyuria and increased thirst are common.

   2. Lethargy and obtundation may be seen in patients with markedly increased effective osmolality (> 320 mOsm/L), especially in patients with significant acidemia.

      1. Effective osmolality can be calculated:

         • (1) (2 × Na⁺) + Glucose/18

         • (2) eg, Na⁺ of 140 mEq/L and glucose of 720 mg/dL = osmolality of 320 mOsm/L

      2. Consider neurologic insult (eg, cerebrovascular accident, drug intoxication) if neurologic changes are present in patients with a serum osmolality < 320 mOsm/L or if the neurologic abnormalities fail to resolve with therapy.

   3. Abdominal pain

      1. Present in 50–75% of DKA cases

      2. May be secondary to the DKA or another process precipitating DKA (ie, appendicitis, pancreatitis, cholecystitis, abscess)

      3. Abdominal pain is increasingly common with increasing severity of DKA (Table 4-4).

      Always search for the etiology of abdominal pain in patients with DKA, especially if it occurs in patients with mild acidosis (HCO₃⁻ > 10 mEq/L), persists after resolution of the acidosis, or patients are older than 40 years.

   4. Nausea and vomiting are common and nonspecific.

3. Hyperglycemia

   1. Glucose level is variable.

   2. 15% of patients with DKA have glucose levels < 350 mg/dL (particularly in pregnancy, in patients with poor oral intake, or those given insulin in route to the hospital).

   3. Glucose > 250 mg/dL has poor specificity for DKA (11%).

4. Ketones

   1. 3 ketones: beta hydroxybutyrate, acetoacetate, acetone

   2. Standard ketone test uses the nitroprusside reaction, which detects acetoacetate but is insensitive for beta hydroxybutyrate. In severe DKA, beta hydroxybutyrate is the prominent ketone, and the nitroprusside test may be falsely negative. In addition, captopril causes a false-positive nitroprusside reaction.

   3. Beta hydroxybutyrate can be measured directly and rapidly. It is highly accurate for diagnosis of DKA: 98% sensitive, 79–85% specific, LR+ 6.5, LR– 0.02 (cutoff > 1.5 mmol/L).

   4. Urine ketones are sensitive for DKA (98%) but not specific (35–69%). Blood measurements are preferred.

5. Anion gap

   1. Anion gap is elevated in most patients with DKA (even when nitroprusside reaction is negative).

   2. In patients evaluated in the emergency department with glucose > 250 mg/dL, the anion gap is 84–90% sensitive and 85–99% specific; LR+, 6–84; LR–, 0.11–0.16.

   3. If anion gap is elevated and ketones are negative, beta hydroxybutyrate measurements should be measured. If beta hydroxybutyrate measurements are not available (or negative), lactic acid should be measured to rule out lactic acidosis.

6. Nonspecific findings

   1. Amylase: Nonspecific elevations in amylase are common.

   2. Leukocytosis

      1. Mild leukocytosis (10,000–15,000 cells/mcL) is common and may occur secondary to stress or infection.

      2. One study documented higher WBCs in DKA patients with major infection than in patients without infection (17,900/mcL vs 13,700/mcL).

      3. Band counts were also higher in patients with infection (23% vs 6%).

Treatment

1. Treatment of DKA must include the following:

   1. Initial evaluation and frequent monitoring

   2. Detection and therapy of the underlying precipitant

      The most common cause of death in patients with DKA is the underlying precipitant. It must be discovered and treated.

   3. Fluid resuscitation

   4. Insulin

   5. Potassium replacement

2. Initial evaluation and monitoring

   1. Check electrolytes, glucose, serum ketones, serum lactate, ABG, anion gap, plasma osmolality, blood urea nitrogen (BUN), and creatinine.

   2. Serum creatinine may be artificially elevated due to interference of assay by ketones.

   3. The serum glucose should be checked hourly and the electrolytes should be measured frequently (every 2–4 hours) and the anion gap calculated.

3. Detection and therapy of the underlying precipitant

   1. Urinalysis and urine culture, chest radiograph, CBC with differential, ECG and troponin levels are appropriate.

   2. Beta-HCG should be measured in women of childbearing age.

   3. Other tests as clinically indicated (blood cultures, lipase, etc.)

4. Fluid resuscitation

   1. Evaluate dehydration: Check BP, orthostatic BP and pulse, monitor hourly urinary output

   2. IV normal saline 0.5–1.5 L bolus initially.

      1. Larger volumes (1–1.5 L) are useful for patients with significant hypotension.

      2. Smaller volumes (500 mL) may allow for more rapid correction of acidosis in patients without marked volume depletion.

   3. Reevaluate after each liter by rechecking BP, orthostatic BP and pulse, urinary output, cardiac and pulmonary exams. Repeat boluses until hypotension and oliguria resolve.

   4. Normal saline should be switched to 0.45% normal saline when intravascular volume improves in patients with normal or elevated corrected serum sodium to restore the free water deficit. (Continue 0.9% saline if the corrected serum sodium concentration is low.)

5. Insulin

   1. The ADA recommends an IV bolus of regular insulin (0.1 units/kg) followed by IV regular insulin at 0.1 units/kg/h. Alternatively, the bolus may be omitted and the insulin initiated at 0.14 units/kg/h. If glucose fails to fall by ≥ 10% in first hour, adjust insulin therapy.

   2. Marked hypokalemia (< 3.3 mEq/L) should be excluded before insulin therapy is administered (see below).

   3. Administer in monitored setting.

   4. Monitor glucose levels hourly: Target reduction 75–90 mg/dL/h and adjust insulin dose accordingly.

   5. The ADA recommends continued IV insulin until glucose < 200 mg/dL and 2 of the following criteria are met: anion gap ≤ 12, serum HCO₃⁻ is ≥ 15 mEq/L, and the venous pH > 7.3.

      1. Premature discontinuation of IV insulin may result in rebound ketoacidosis.

      2. If patient's glucose normalizes (< 200 mmol/d) before the anion gap normalizes and before the HCO₃⁻ is ≥ 18 mEq/L, reduce the insulin infusion and add glucose (D5W) to the IV to prevent hypoglycemia.

      3. Patients should receive their first dose of SQ insulin 1–2 hours before IV insulin is discontinued in order to prevent an insulin free window and recurrent ketoacidosis.

         In DKA, it is important to continue IV insulin until the anion gap returns to normal. Administer glucose as necessary to prevent hypoglycemia.

6. Potassium replacement

   1. Insulin shifts potassium back into the intracellular compartment. Fluid resuscitation and correction of the acidosis further lower the serum potassium concentration.

   2. Despite hyperkalemia on presentation, profound and potentially life-threatening hypokalemia is a common complication of therapy and often develops within the first few hours.

   3. Patients with normal or near normal serum potassium concentrations on admission should have cardiac monitoring due to the risk of arrhythmias.

   4. Potassium levels should be monitored hourly, and replacement should be initiated when urinary output resumes and potassium is < 5.0–5.2 mEq/L.

   5. Potassium therapy should be initiated immediately in patients with hypokalemia. In addition, insulin therapy should be delayed until the serum potassium > 3.3 mEq/L.

7. HCO₃⁻ therapy

   1. Use is controversial; if used, monitor patient for hypokalemia.

   2. HCO₃⁻ has not been shown to improve outcomes in patients with a serum pH > 6.9. It may also paradoxically lower CNS pH.

   3. The ADA recommends HCO₃⁻ therapy in patients with a pH < 6.9.

8. Phosphate therapy

   1. Dramatic falls in serum phosphate are common during treatment.

   2. Replacement should be considered in patients with marked hypophosphatemia (< 1.0 mg/dL) or with respiratory depression, cardiac dysfunction, or anemia.

Careful, frequent observation and evaluation of patients with DKA is critical.

Alternative Diagnosis: Uremic Acidosis

Textbook Presentation

Typically, patients with chronic kidney disease have low HCO₃⁻ levels, high creatinine levels (often > 4–5 mg/dL), and elevated BUN and phosphate levels. Patients often complain of a variety of constitutional symptoms secondary to their kidney disease, including fatigue, nausea, vomiting, anorexia, and pruritus.

Disease Highlights

1. Pathophysiology

   1. Each day, ingested nonvolatile acids neutralize HCO₃⁻.

   2. In health, the kidneys regenerate the HCO₃⁻ and maintain the acid-base equilibrium

   3. Renal impairment results in failed HCO₃⁻ regeneration and a metabolic acidosis.

2. Acidosis in patients with kidney disease may be of the anion gap type or non–anion gap type.

   1. In early kidney disease, ammonia-genesis is impaired, resulting in reduced acid secretion and a non–anion gap metabolic acidosis.

   2. In more advanced chronic kidney disease, the kidney remains unable to excrete the daily acid load and also becomes unable to excrete anions such as sulfates, phosphates, and urate. Therefore, an anion gap acidosis develops. HCO₃⁻ levels stabilize between 12 mEq/L and 20 mEq/L.

3. The acidosis has several adverse effects.

   1. Increased calcium loss from bone

   2. Increased skeletal muscle breakdown

Treatment

1. NaHCO₃⁻ replacement

2. Hemodialysis

Alternative Diagnosis: Starvation Ketosis

Typically, starvation ketosis occurs in patients with diminished carbohydrate intake. Ketosis is usually mild (HCO₃⁻ ≥ 14 mEq/L) and serum glucose is usually normal. Serum pH is usually normal.

Alternative Diagnosis: Alcoholic Ketoacidosis

Alcoholic ketoacidosis usually occurs in advanced alcoholism when the majority of calories come from alcohol. Ketoacidosis develops due to the combined effects of inadequate carbohydrate intake, ethanol conversion to acetic acid and stimulated lipolysis. Ketoacidosis may be precipitated by decreased intake, pancreatitis, gastrointestinal bleeding, or infection and may be profound. The plasma glucose level is typically normal to low. (Significant elevations suggest concomitant DKA.) It is important to consider other causes of metabolic acidosis in alcoholics with acidosis. First, patients with alcoholic ketoacidosis often have concomitant lactic acidosis. Shock and hypoxia should be carefully considered. Lactic acidosis may also occur due to an increase in NADH levels and can be particularly severe in patients with thiamine deficiency. Second, toxic ingestions (methanol, ethylene glycol, or salicylate) should also be considered, especially in patients with a large osmolar gap. (The osmolar gap = measured serum osmolality – calculated serum osmolality. The calculated osmolality = (2 x Na⁺) + Glucose (mg/dL)/18 + BUN (mg/dL)/2.8) + ETOH (mg/dL)/3.7. A normal osmolar gap < 10 mosm/kg.) The treatment for alcoholic ketoacidosis should include IV thiamine prior to IV glucose to avoid precipitating Wernicke encephalopathy or Korsakoff syndrome.

Step 5: Diagnose Primary Disorder

The high serum ketones confirm ketoacidosis as the primary metabolic disturbance and the high glucose and diabetic history clearly suggest DKA as the cause of the primary acid base abnormality. The high glucose and profound acidosis are not consistent with starvation ketoacidosis and the absence of a significant alcohol history argues against alcoholic ketoacidosis. The normal lactate effectively rules out lactic acidosis, and uremic acidosis is very unlikely with mild renal insufficiency (Creatinine = 1.8).

Step 6: Check for Additional Disorders

Step 6A: Check Anion Gap

Already completed (see above)

Step 6B: Calculate Whether Compensation is Appropriate

As shown in Table 4-2 the expected drop in PaCO₂ to compensate for a metabolic acidosis is 1.2 mm Hg per 1 mEq/L fall in HCO₃⁻. The patient's HCO₃⁻ is 6 mEq/L (normal is 24 mEq/L), which is an 18 mEq/L decrement. The PaCO₂ should fall by 1.2 × 18 = 21.6 mm Hg. Since the normal PaCO₂ is approximately 40 mm Hg, the PaCO₂ would be expected to be approximately 40 − 21.6 ≈ 18. The actual PaCO₂ (20 mm Hg) is close to this predicted value suggesting that respiratory compensation is indeed appropriate.

Step 7: Reach Final Diagnosis

Therefore, Mr. L is suffering from an anion gap metabolic acidosis secondary to DKA with appropriate respiratory compensation.

Evaluation and treatment identifies the precipitant of DKA and treats the acidosis, hyperglycemia, and profound dehydration.

The list of symptoms and signs can grouped together to make evaluation more organized: (1) dysuria, urinary frequency, flank pain, fever, and chills, (2) nausea and vomiting, (3) hypotension and tachycardia, and (4) low serum HCO₃⁻. In addition to investigating the probable urinary tract infection, it is critical to determine the nature of the acid-base abnormality.

Step 1: Determine Whether the Primary Disorder is an Acidosis or Alkalosis by Reviewing the pH

Similar to the first case, Ms. S has a low serum HCO₃⁻ suggesting a metabolic acidosis. On the other hand, it is conceivable (but unlikely), that the low serum HCO₃⁻ could occur in compensation for a profound respiratory alkalosis. An ABG can determine the primary disorder, limit the differential diagnosis of the primary disorder, and access compensation.

The low pH on the ABG confirms the primary process is an acidosis.

Step 2: Determine Whether the Primary Acidosis or Alkalosis is Metabolic or Respiratory by Reviewing the HCO₃⁻ and PaCO₂

Ms. S's serum HCO₃⁻ is 14 mEq/L, her PaCO₂ is 30 mm Hg. Both are quite low but only the low HCO₃⁻ would create an acidosis. (A low PaCO₂ would drive the pH up and cause an alkalosis.) Since her pH is low and the HCO₃⁻ is low the primary process is a metabolic acidosis.

Step 3: Limit the Differential Diagnoses of Metabolic Acidosis by Calculating the Anion Gap

The next step in the differential diagnosis is to calculate the anion gap. Her anion gap = 138 − (102 + 14) = 22.

Clearly, Ms. S is suffering from an anion gap metabolic acidosis. This is alarming because metabolic acidosis in the face of infection suggests lactic acidosis due to severe sepsis.

Step 4: Explore the Differential Diagnoses of the Primary Disorder

The leading and must not miss hypothesis would clearly be lactic acidosis, especially given the patients hypotension. If confirmed, the cause of the lactic acidosis must be determined (which would most likely be sepsis for Ms. S) and then treated. Although unlikely, alternative causes of an anion gap metabolic acidosis (Table 4-1) that would be reasonable to consider include alcoholic ketoacidosis and toxin-related acidosis (including salicylates). The normal glucose and lack of history of diabetes rules out DKA, and the severity of acidosis is not consistent with starvation ketoacidosis. The normal creatinine rules out uremic acidosis. The differential diagnosis for Ms. S is listed in Table 4-5.

Leading Hypothesis: Lactic Acidosis

Textbook Presentation

The presentation of lactic acidosis depends on the underlying etiology. The most common causes are hypoxemia, septic shock, cardiogenic shock, or hypovolemic shock. Patients with shock usually have hypotension and tachycardia and often have impaired mentation and decreased urinary output. Patients with septic shock typically have fever and tachypnea. While patients with cardiogenic or hemorrhagic shock often have cold extremities, patients with septic shock often have warm extremities and bounding pulses after fluid resuscitation. (Pulses are bounding due to a widened pulse pressure.) See Chapter 25 for a review of sepsis.

Disease Highlights

1. Lactic acidosis develops when oxygen delivery to the cells is inadequate. This results in anaerobic metabolism and the production of lactic acid. Therefore, the differential diagnosis can be remembered by tracing the pathway of oxygen from the environment through the blood to the cells and mitochondria. Any disease that interferes with oxygen delivery can cause lactic acidosis (Table 4-6).

   1. Low oxygen carrying capacity

      1. Hypoxemia (from pulmonary or cardiac disease)

      2. Severe anemia

      3. Carbon monoxide poisoning (interferes with oxygen binding)

      4. Methemoglobinemia

   2. Inadequate tissue perfusion; causes include

      1. Hypovolemic shock

      2. Cardiogenic shock

      3. Septic shock

      4. Regional obstruction to blood flow (eg, ischemic bowel or gangrene)

   3. Inadequate cellular utilization of oxygen (cyanide poisoning)

   4. Occasionally, lactic acidosis develops secondary to unusually high demand exceeding oxygen supply (eg, intense exercise, seizures).

2. Lactate elevation is associated with a substantially increased mortality. The mortality rate of patients with shock and lactic acidosis is 70% compared with 25–35% in patients with shock without lactic acidosis.

Evidence-Based Diagnosis

1. Serum lactate levels are more sensitive and specific than an increase in the anion gap.

2. An elevated anion gap is 44–67% sensitive.

3. An elevated anion gap may suggest lactic acidosis, but a normal anion gap does not exclude lactic acidosis.

The serum lactate level should be measured in critically ill patients in whom shock is suspected regardless of the anion gap.

Treatment

Treatment of lactic acidosis should target the underlying condition. A variety of buffering agents (ie, NaHCO₃⁻) have been tried and failed to demonstrate improved hemodynamics or survival.

Step 5: Diagnose Primary Disorder

The serum lactate confirms an anion gap metabolic acidosis due to lactic acidosis as the primary acid-base disorder. The clinical scenario and positive cultures strongly suggest that the diagnosis is lactic acidosis secondary to sepsis. Other tests are not necessary to confirm the diagnosis.

Step 6: Check for Additional Disorders

Step 6A: Check Anion Gap

Already completed (see above).

Step 6B: Calculate Whether Compensation is Appropriate

In a metabolic acidosis, the PaCO₂ is expected to fall by 1.2 mm Hg per 1 mEq/L fall in HCO₃⁻ (see Table 4-1). The patient's HCO₃⁻ is 14 mEq/L (10 mEq/L below normal). The PaCO₂ should fall by 1.2 × 10 = 12. Since normal PaCO₂ is approximately 40 mm Hg, we would expect the PaCO₂ to be approximately 28 mm Hg (40 − 12 = 28 mm Hg). The actual PaCO₂ is 30 mm Hg, quite close to the prediction. This suggests that respiratory compensation is appropriate.

Step 7: Reach Final Diagnosis

In summary, Ms. S is suffering from a lactic acidosis with appropriate respiratory compensation.

Your resident is concerned about the adequacy of Mr. R's ventilation and suggests checking his pulse oxymetry. You remind him that a pulse oximeter will not address the adequacy of the patient's ventilation nor will it determine whether respiratory failure is present.

Always check an ABG when the adequacy of a patient's ventilation is a concern. Patients with adequate oxygenation may still be in respiratory failure.

Clearly Mr. R has several problems that are easily identified, including (1) fever, cough, and history of COPD, (2) respiratory distress, and (3) acidosis. All of these problems are obviously potentially life threatening. Furthermore, a thorough evaluation of the acidosis may shed light on the status of the other problems.

Step 1: Determine Whether the Primary Disorder is an Acidosis or Alkalosis by Reviewing the pH

The low pH confirms the primary disorder is an acidosis.

Step 2: Determine Whether the Primary Acidosis or Alkalosis is Metabolic or Respiratory by Reviewing the HCO₃⁻ and PaCO₂

Step 3: Explore the Differential Diagnoses of the Primary Disorder

Respiratory acidosis may be caused by lung diseases, pleural diseases, or a variety of neuromuscular diseases (see Table 4-1). His prior history of COPD and acute pulmonary complaints of cough and fever clearly suggest that his respiratory acidosis is due to a pulmonary process. Specifically, Mr. R's history of very poor exercise tolerance at baseline suggests severe COPD. Such severe COPD could result in chronic carbon dioxide retention and chronic respiratory acidosis. A "must not miss" possibility is that his acute respiratory infection has precipitated acute respiratory failure (and acute respiratory acidosis). This is suggested by his worsening symptoms, respiratory distress, upright posture, pursed lip breathing, pulsus paradox, and decreased breath sounds. It is critical to distinguish acute respiratory acidosis from chronic respiratory acidosis because the former is more likely to progress rapidly to complete respiratory failure and respiratory arrest. Therefore, acute respiratory acidosis is both the leading hypothesis and the "must not miss" diagnosis. Table 4-7 ranks the differential diagnosis according to the available demographic information, risk factors, and symptoms and signs.

Patients with a history of asthma or COPD should be asked about a prior history of intubation or ICU admission. Such patients are at greater risk for respiratory failure.

Leading Hypothesis: Respiratory Acidosis

Textbook Presentation

The presentation of respiratory acidosis depends primarily on the underlying cause. The most common causes are severe underlying lung disease (eg, COPD, pneumonia, or pulmonary edema). Such patients are typically in extreme respiratory distress.

Disease Highlights

1. Insufficient ventilation results in increasing levels of PaCO₂. This in turn lowers arterial pH. Compensation occurs over several days, with increased renal HCO₃⁻ regeneration.

2. Ventilation is assessed by measuring the arterial PaCO₂ and pH. Significant hypoventilation and acidosis may occur without significant hypoxia.

3. Etiology: Although most commonly due to lung disease, respiratory acidosis may result from any disease affecting ventilation—from the brain to the alveoli. (See differential diagnosis of acid-base disorders in Table 4-1.)

4. Manifestations are primarily CNS.

   1. Severity depends on acuity. Patients with chronic hypercapnia have markedly fewer CNS effects than patients with acute hypercapnia.

   2. Anxiety, irritability, confusion, and lethargy

   3. Headache may be prominent in the morning due to the worsening hypoventilation that occurs with sleep.

   4. Stupor and coma may occur when the PaCO₂ > 70–100 mm Hg.

   5. Tremor, asterixis, slurred speech, and papilledema may be seen.

Evidence-Based Diagnosis

1. Typically characterized by PaCO₂ > 43 mm Hg.

   1. Occasionally, a normal PaCO₂ suggests respiratory failure.

      1. For example, during asthma attacks, patients typically hyperventilate and present with a PaCO₂ below normal. A normal PaCO₂ in such a patient may reflect respiratory fatigue and herald the development of frank respiratory failure.

      2. Patients with primary metabolic acidoses typically hyperventilate to compensate, lowering the PaCO₂ below normal.

         • (1) A PaCO₂ of ≥ 40 mm Hg is inappropriate in such cases and represents a respiratory acidosis.

         • (2) Inability to compensate for a metabolic acidosis (hyperventilate) is associated with an increased risk of respiratory failure and the subsequent need for mechanical ventilation.

   2. The alveolar-arterial oxygen gradient (PaO₂-PaO₂) can help distinguish hypercapnia due to pulmonary disease from hypercapnia due to CNS disease (central hypoventilation).

      1. This gradient compares the calculated alveolar partial pressure of oxygen (PaO₂) with the measured arterial partial pressure of oxygen (PaO₂).

         • (1) In the absence of lung disease, there is little difference between the alveolar and arterial O₂.

         • (2) A normal A-a gradient is around 10 mm Hg.

      2. Therefore, the A-a gradient is usually normal in hypoventilation due to CNS disease but increased in pulmonary disease.

      3. The PaO₂ is measured in an ABG whereas the PaO₂ is calculated from the following formula:

         PaO₂ = FIO₂ (pAtm – pH₂0) – PaCO₂/R.

         (FIO₂ is the fraction of inspired oxygen: 0.21 for patients not on supplemental oxygen. pAtm = 760 at sea level, the partial pressure of H₂O = 47 and PaCO₂ is the arterial PCO₂ measured in the blood gas. R refers to the respiratory quotient and is often estimated at 0.8.)

2. Pulsus paradox

   1. Defined as > 10 mm Hg drop in systolic BP during inspiration

   2. May be seen in patients using unusually strong inspiratory effort due to asthma, COPD, or other respiratory diseases

   3. When elevated in patients with asthma, it is highly specific for a severe attack but has poor sensitivity (Table 4-8).

   4. When pulsus paradox is marked, there is a high LR of severe disease.

Treatment

1. Treat underlying disease process (ie, bronchodilators for asthma, naloxone for opioid overdose).

2. Supplemental oxygen should be given as necessary to prevent hypoxemia.

   Supplemental oxygen occasionally worsens hypercapnia in some patients with severe COPD, asthma, and sleep apnea but should never be withheld from hypoxic patients.

3. Avoid hypokalemia and dehydration that may worsen metabolic alkalosis, raise the serum pH, and inadvertently further suppress ventilation.

4. Mechanical ventilation with either intubation or biphasic positive airway pressure (BiPAP) is lifesaving in some patients.

   1. Institution of mechanical ventilation is considered when pH < 7.1–7.25 or PaCO₂ > 80–90 mm Hg.

   2. In general, patients with acute hypoventilation require mechanical ventilation with milder hypercapnia than patients with chronic hypoventilation.

Step 4: Diagnose Primary Disorder

The patient's clinical picture and ABG clearly suggest the primary disorder is a respiratory acidosis.

Step 5: Check for Additional Disorders

Step 5A: Calculate Anion Gap (Even in Patients Without Acidosis) to Uncover Unexpected Anion Gap Metabolic Acidosis

Another "must not miss" diagnosis for Mr. R would be sepsis. His symptoms of fever and cough suggest the possibility of pneumonia, which can be complicated by sepsis resulting in an anion gap metabolic lactic acidosis. Although his elevated HCO₃⁻ does not immediately suggest a metabolic acidosis from sepsis, the HCO₃⁻ may not be low if there is also a superimposed metabolic alkalosis generating HCO₃⁻. These hidden acidoses can be discovered by evaluating the anion gap (which is usually elevated due the accumulation of lactate) or by measuring the serum lactate level.

Step 5B: Calculate Whether Compensation is Appropriate

In this case, it is critical to determine whether the PaCO₂ is chronically elevated or whether this represents an acute decompensation. Acute respiratory acidosis can be distinguished from chronic respiratory acidosis by evaluating the degree of metabolic compensation (provided there are no other acidoses also effecting HCO₃⁻). Because metabolic compensation takes time, chronic respiratory acidoses are associated with more complete compensation than acute respiratory acidoses. Table 4-2 shows the formulas that can be used to calculate the HCO₃⁻ levels. In acute respiratory acidosis, the HCO₃⁻ increases by only 1 mEq/L for every 10 mm Hg increase in PaCO₂ whereas in chronic respiratory acidosis, the HCO₃⁻ increases by 4 mEq/L for every 10 mm Hg increase in PaCO₂. In Mr. R's case, the PaCO₂ is 70 mm Hg, up by 30 mm Hg (from a normal of 40 mm Hg), so if this were an acute respiratory acidosis, the HCO₃⁻ level would be expected to increase by only 3 mEq/L (from a normal of 24 mEq/L to 27 mEq/L). If, on the other hand, this is a chronic respiratory acidosis, an increase of 4 mEq/L of HCO₃⁻ per 10 mm Hg increase in PaCO₂ would be expected. For a 30 mm Hg increase in PaCO₂, the predicted increase in HCO₃⁻ would be 3 × 4 = 12 mEq.

Step 6: Reach Final Diagnosis

The tiny metabolic compensation suggests that Mr. R is suffering from an acute respiratory acidosis with metabolic compensation. There is no evidence of a hidden anion gap acidosis. Therefore, Mr. R has an acute respiratory acidosis caused by pneumonia and COPD. He is at significant risk for complete respiratory failure and he is transferred him to the ICU.

It is vital to distinguish acute from chronic respiratory acidoses.

Renal Tubular Acidosis (RTA)

Textbook Presentation

Although there are a variety of RTAs, the most common type in adults is type IV RTA, caused most commonly by long-standing diabetes. Laboratory abnormalities include mild renal insufficiency, a mild non-anion gap acidosis (HCO₃⁻ ≈ 17 mEq/L) and hyperkalemia. Only the highlights of type IV RTA will be reviewed here.

Disease Highlights

1. Patients with type IV RTA have hypoaldosteronism.

2. Hypoaldosteronism decreases potassium and H⁺ excretion resulting in hyperkalemia and acidosis.

3. The hyperkalemia also interferes with ammonia production (the major renal buffer) and further impairs acid secretion. The inability to excrete the daily acid load causes a non–anion gap acidosis.

4. n patients with diabetes mellitus, type IV RTA is also associated with low renin levels.

5. Etiologies of type IV RTA are numerous.

   1. Diabetes with mild renal impairment is the most common.

   2. Other causes include

      1. Drugs (NSAIDs, ACE inhibitors, potassium sparing diuretics, trimethoprim, heparin, and cyclosporine)

      2. Addison disease

      3. Systemic lupus erythematosus

      4. AIDS nephropathy

      5. Chronic interstitial renal disease

Treatment

Dietary potassium restriction, loop diuretics, and fludrocortisone are useful.

D-Lactic Acidosis

D-lactic acidosis is a rare disorder seen in some patients with jejunoileal bypass or short bowel. The bypass or short bowel results in carbohydrate malabsorption and delivery of this carbohydrate to the colon where colonic bacteria metabolize it into D-lactic acid, which is absorbed. (Endogenous lactate is L-lactic acid.) Presenting manifestations include encephalopathy and metabolic acidosis after carbohydrate ingestion. Patients may appear intoxicated and show the following symptoms and signs: altered mental status ranging from drowsiness to coma (100%), slurred speech (65%), ataxia (45%), and disorientation (21%) that may follow large carbohydrate meals. Attacks last from hours to days. It is unclear if the neurologic symptoms are secondary to the D-lactic acid or other absorbed toxins. Laboratory tests may reveal an anion gap acidosis. However, the anion gap may be smaller than expected because D-lactate is not reabsorbed by the kidney (unlike L-lactate) and is excreted. Lactate measurements may be falsely negative since standard lactate tests measure L-lactate rather than D-lactate. Special assays must be requested to measure D-lactate.

Metabolic Alkalosis

Textbook Presentation

The most common clinical situations that give rise to metabolic alkalosis are recurrent vomiting or diuretic treatment. The metabolic alkalosis per se is usually asymptomatic. Muscle cramping due to coexistent hypokalemia may be seen.

Disease Highlights

1. Metabolic alkalosis develops only when there is both a source of additional HCO₃⁻ and a renal stimulus that limits its excretion.

   1. Increased HCO₃⁻ production develops when H+ is (1) lost from the gastrointestinal tract (ie, due to vomiting) or (2) lost from the genitourinary tract (ie, due to hyperaldosteronism) or (3) during administration of HCO₃⁻. Volume contraction around a constant amount of HCO₃⁻ also serves to increase the HCO₃⁻.

   2. Decreased HCO₃⁻ excretion is most commonly caused by decreased renal perfusion. This occurs when the effective circulating volume is reduced.

      1. Examples include dehydration or other pathologic states associated with decreased renal perfusion (ie, heart failure [HF], nephrotic syndrome).

      2. The mechanisms that interfere with HCO₃⁻ excretion are complex but include enhanced renal HCO₃⁻ reabsorption and decreased renal HCO₃⁻ secretion.

         • (1) Decreased effective circulating volume promotes avid Na⁺ absorption in the proximal tubule, which in turn facilitates HCO₃⁻ reclamation (Figure 4-2).

         • (2) Decreased effective circulating volume and Cl⁻ depletion also decrease HCO₃⁻ secretion by the collecting cells, which compounds the metabolic alkalosis. This develops because HCO₃⁻ secretion occurs in exchange with Cl⁻ reabsorption in the distal tubules (Figure 4-3). This requires Cl⁻ delivery to the collecting tubules, which decreases both due to enhanced proximal Cl⁻ reabsorption and gastrointestinal or diuretic Cl⁻ losses.

         • (3) Decreased effective circulating volume results in secondary hyperaldosteronism which activates H⁺ secretion by the collecting tubule cells and production of HCO₃⁻ which is reabsorbed into the blood.

         • (4) Low tubular Cl⁻ also draws chloride into the tubular cells (from the plasma) and promotes HCO₃⁻ reabsorption.

         • (5) Hypokalemia is an important mechanism that promotes HCO₃⁻ reabsorption. In the collecting tubule, it stimulates potassium reabsorption in exchange for H⁺ secretion. HCO₃⁻ is produced and reabsorbed into the blood.

2. Pathologic states associated with metabolic alkalosis (Table 4-1)

   1. Vomiting or nasogastric drainage. Pathophysiology:

      1. Gastric acid production (and secretion) is matched by HCO₃⁻ production. The H⁺ ion enters the gastric lumen, whereas the HCO₃⁻ enters the bloodstream.

      2. Dehydration decreases renal HCO₃⁻ excretion (see above).

   2. Dehydration or other causes of reduced glomerular filtration rate (GFR) (ie, HF, nephrotic syndrome)

   3. Diuretics

   4. Hypokalemia

   5. Hyperaldosteronism

      1. Adrenal adenoma

      2. Licorice ingestion or chewing tobacco (Normally, a renal enzyme converts cortisol to cortisone in order to prevent cortisol from exerting a significant mineralocorticoid effect. Licorice contains the steroid glycyrrhetinic acid which blocks this enzyme resulting in a heightened mineralocorticoid effect from endogenous cortisol.)

   6. Bartter or Gitelman syndromes

   7. Respiratory acidosis also promotes a compensatory metabolic alkalosis. Occasionally, rapid resolution of the respiratory failure will correct the hypercapnia, resulting in a transient inappropriate metabolic alkalosis (posthypercapnic metabolic alkalosis).

   8. Milk-alkali syndrome

Treatment

1. Volume resuscitation with NaCl in patients with true volume depletion usually results in resolution.

2. Replete potassium deficiency.

3. Carbonic anhydrase inhibitors and low bicarbonate dialysis can be used in severe cases, particularly in patients with HF (and ineffective circulating volume) who cannot tolerate NaCl.

Respiratory Alkalosis

Textbook Presentation

The presentation of respiratory alkalosis depends on the underlying disorder. Most causes are associated with tachypnea, which can be dramatic or subtle.

Disease Highlights

1. Hyperventilation induces hypocapnia causing respiratory alkalosis.

2. The most common causes are pulmonary diseases, cirrhosis, fever, pain, or anxiety (Table 4-1).

3. Hypocapnia acutely reduces CNS blood flow.

4. Symptoms include paresthesias (particularly perioral), vertigo, dizziness, anxiety, hallucinations, myalgias, and symptoms reflective of the underlying disorder.

5. Adverse effects include hypokalemia, hypocalcemia, lung injury, seizures, angina, and arrhythmias.

Treatment

Therapy is directed at the underlying disorder.

Mixed Disorders and the "Delta-Delta Gap"

1. Occasionally, 2 distinct metabolic processes will be present in the same patient (eg, 2 distinct acidoses, 1 anion gap and 1 non-anion gap). Alternatively, a patient may have both a metabolic alkalosis and metabolic acidosis (eg, metabolic alkalosis develops in a patient with vomiting and dehydration; if these symptoms are prolonged sufficiently, severe dehydration, hypovolemic shock, and lactic acidosis also develop).

2. These multiple metabolic processes can be difficult to tease out.

3. One approach to this problem is to evaluate the delta-delta gap. Here the absolute rise in the anion gap (ΔAG, the first delta) is compared with the absolute fall in HCO₃⁻ (ΔHCO₃⁻, the second delta¹).

   1. In simple anion gap acidoses, the deltas are similar.

   2. On the other hand, in a patient with both an anion gap and non-anion gap acidoses, the fall in HCO₃⁻ will be greater than the rise in the anion gap.

   3. In patients with an anion gap acidosis and a metabolic alkalosis, the fall in HCO₃⁻ will be antagonized by the concomitant metabolic alkalosis whereas the anions will still accumulate. Therefore, the fall in HCO₃⁻ is less than the increase in the anion gap.

4. While occasionally useful, there are several limitations to applying the delta-delta gap.

   1. The normal anion gap varies from institution to institution and with the patient's serum albumin.

   2. Even in simple anion gap acidosis, bone buffering of acid and renal excretion of anions complicate the delta-delta gap and make it difficult to interpret.

5. In simple anion gap acidosis (without concomitant metabolic alkalosis or non-anion gap acidosis) the typical ΔAG/ΔHCO₃⁻ is 1.6:1 in lactic acidosis and 1:1 in ketoacidosis.