Acid-Base Disorders 2013 Stephen D. Sisson MD

Objectives At the completion of this module, learners will rate their knowledge as "good" or better on the following topics in acid-base disorders: 1. The general approach to the patient with an acid-base disorder 2. Arterial versus venous blood gas interpretation 3. The differential diagnosis of a. The role of the in evaluating the patient with a metabolic acidosis b. The role of the anion gap in the patient with a normal anion gap metabolic acidosis 4. The role of the osmolar gap in a patient with delirium 5. The differential diagnosis of metabolic alkalosis a. The role of urine chloride in evaluating the patient with a metabolic alkalosis 6. The differential diagnosis of respiratory acidosis 7. The differential diagnosis of respiratory alkalosis

Case 1: Approach to the patient with a potential acid/base disorder John Chase is a 47-year-old man with a history of diabetes and gastroparesis. He presents to the Emergency Department with an 8-hour history of nausea and vomiting typical for a flare of his gastroparesis. Past medical history is otherwise unremarkable. On physical exam, Mr. Chase looks quite uncomfortable, and vomits several times during the examination. He is afebrile, and vital signs are notable for mild orthostasis. Despite his discomfort, physical exam is only notable for the complete absence of bowel sounds. Laboratory evaluation was begun in triage, and results are now available to you:

ABG: pH 7.40/pCO2 40/pO2 96 BMP: Na 128/K 3.1/Cl 83/HCO3 22/BUN 24/Cr 1.9/Glucose 556

Which ONE of the following statements is correct?

A. Mr. Chase has a single acid/base disorder: metabolic acidosis. B. Mr. Chase has a single acid/base disorder: metabolic alkalosis. C. Mr. Chase has a combined metabolic acidosis and metabolic alkalosis. D. Mr. Chase has a combined metabolic and respiratory disorder. E. Serum pH, pCO2 and HCO3 are normal, thus no acid/base disorder is present.

Pop Up answers A. Incorrect. While Mr. Chase has a metabolic acidosis, he has another acid/base disorder as well. B. Incorrect. While Mr. Chase has a metabolic alkalosis, he has another acid/base disorder as well. C. Correct! As we shall learn later, Mr. Chase has a metabolic acidosis and metabolic alkalosis, which counterbalance each other to the extent that pH, pCO2 and serum are normalized. A tip off is the presence of an elevated anion gap, which is calculated at 23. D. Incorrect. There is no evidence of a respiratory disorder. E. Incorrect. Normal pH, pCO2 and HCO3 do not exclude acid/base disorders.

Summary answer The correct answer is C: Mr. Chase has a combined metabolic acidosis and metabolic alkalosis.

Introduction This module presents a step-wise approach to the patient with a potential acid/base disorder. Following these steps will help to generate a differential diagnosis on a patient with a suspected acid/base disorder, setting the stage for the next steps in evaluation and management of the patient. Certain diagnoses (e.g., lactic acidosis) are potentially disastrous if missed, thus making comprehension of acid/base disorders among the essential skills of a physician.

An important aspect of evaluating a patient with an acid-base disorder is to evaluate the entire clinical picture, and balance the clinical presentation with the laboratory results. In other words, the differential diagnosis generated should be interpreted in light of the clinical presentation. While this module reviews the majority of causes of acid/base disorders, rare and unusual clinical disorders should not be excluded if the presentation does not match the differential.

When interpreting acid/base disorders, it is useful to try to explain the disorder in the simplest terms possible. Single acid/base disorders are more common than double acid/base disorders, which in turn are more common than triple acid/base disorders (which are rare). Also be aware that an acidemic disorder may counterbalance an alkalemic disorder, so that serum pH may be normal. A normal pH does not exclude an acid base disorder. Among the most common clinical examples in which two acid/base disorders are present yet the pH remains normal is in the presence of a coexistent metabolic acidosis and metabolic alkalosis. A tip off to this situation is an elevated serum anion gap (discussed below). Mr. Chase, the patient discussed above, likely has a metabolic alkalosis from vomiting and dehydration, and also has a metabolic acidosis, probably from diabetic ketoacidosis.

Compensatory mechanisms The body will attempt to normalize acid/base equilibrium in response to an acid/base disorder. If a primary disorder results in acidosis, the body will compensate by creating an alkalosis (and vice-verse if the primary disorder is an alkalosis). If the primary disorder is respiratory, the body will compensate with a metabolic process (and vice-verse if the primary disorder is metabolic). For example, if the primary process is a respiratory acidosis, the body will attempt to compensate by creating a metabolic alkalosis.

Step 1 in evaluating acid/base disorders The first step in determining whether or not an acid/base disorder is present is to look at the serum pH. Normal serum pH is 7.40 (7.35-7.45). Values lower than normal represent an acidosis; values higher than normal represent an alkalosis. This first step is very important, because the body does not overcorrect for a primary disorder, unless a second disorder is present. For example, if the primary disorder is an acidosis (respiratory or metabolic), the serum pH will be low. At this point it is useful to note that when the primary disorder is a respiratory alkalosis, the body can occasionally correct the pH to normal.

Once you have determined whether the patient has an acidosis or an alkalosis, look at the pCO2 and the

HCO3 to see which process (i.e. respiratory vs. metabolic) will explain the primary disorder. Normal serum bicarbonate is 24mEq/dl (plus or minus 2); normal serum pCO2 is 40 (plus or minus 5). Here is a sample case:

A 41-year-old man presents with the following blood tests; define his acid/base disorder.

ABG: pH 7.26/pCO2 34/pO2 96 BMP: Na 130/K 3.5/Cl 100/HCO3 18/BUN 18/ 1.9/Glucose 88

Starting with the serum pH, we see that it is lower than normal. Therefore, he has an acidosis. The next step is to determine if the acidosis is metabolic or respiratory. If the acidosis were metabolic, serum bicarbonate would be low. If the acidosis were respiratory, pCO2 would be elevated. In this patient, we see that serum bicarbonate is low, suggesting the presence of a metabolic acidosis as the explanation of the low serum pH.

Venous blood gas monitoring Because arterial blood gas monitoring is painful to the patient and often difficult to obtain, some will use the venous blood gas to trend results after an initial arterial blood gas has been obtained. When initially evaluating a patient for an acid/base disorder, arterial blood gas results should be used, and should the patient change clinically, repeat arterial blood gas determinations should be obtained. Central venous blood gas samples have stronger correlations to arterial blood gas results than do peripheral blood gas samples, and therefore are preferred. 1

Venous blood has already had oxygen extracted for use by tissues, and is returning carbon dioxide in peripheral tissues to the lungs. As a result, venous blood pH is lower than arterial blood, and venous pCO2 is higher than arterial blood. Therefore, when estimating the arterial pH from a central venous blood gas, we add 0.05 to estimate the arterial pH (with peripheral venous blood samples, we add 0.03). Since venous pCO2 is higher than arterial pCO2, we subtract 5 from the venous pCO2 to estimate arterial pCO2. With peripheral venous blood samples, results are much more variable, and we subtract 3-8 from venous pCO2 to estimate arterial pCO2.1, 2 These results are summarized in Table 1.

Table 1: Venous blood gas results conversion to estimate arterial blood gas results

*Less reliable than central venous blood sampling

Case 2: Metabolic acidosis Your next patient is Eric Murphy, a 67-year-old male brought in by ambulance after a witnessed loss of consciousness. He is accompanied by his girlfriend, who provides most of the history. Mr. Murphy has a history of an enlarged prostate, and has been complaining of worsening dysuria for the past 10 days, with fevers and malaise. Urine has been foul-smelling and cloudy during this time period. Yesterday, Mr. Murphy seemed confused and disoriented, and this morning he collapsed after standing up to get out of bed. A preliminary exam finds Mr. Murphy febrile and hypotensive, but no localizing signs are noted on exam. Laboratory examination is as follows:

ABG: pH 7.20/pCO2 20/pO2 88 BMP: Na 136/K 5.0/Cl 108/HCO3 8/BUN 47/Creatinine 2.2/Glucose 70

Which ONE of the following statements is correct?

A. Mr. Murphy's most significant acid/base disorder is a respiratory alkalosis. B. The differential diagnosis in this patient includes pulmonary embolus, cirrhosis, and restrictive lung disease. C. This patient has a double acid/base disorder: respiratory acidosis and metabolic acidosis. D. Mr. Murphy has a metabolic acidosis with respiratory compensation; serum lactate is likely to be elevated. E. Mr. Murphy has a metabolic alkalosis; the differential includes over-diuresis, vomiting, and renal artery stenosis

Pop Up Answers A. Incorrect. Serum pH is low, demonstrating an acidosis. Serum bicarbonate is low, consistent with metabolic acidosis. B. Incorrect. These disorders would result in a respiratory alkalosis, not a metabolic acidosis (which is Mr. Murphy's major acid/base disorder). Although his pCO2 is decreased, this is in response to the metabolic acidosis. C. Incorrect. While he does have a metabolic acidosis, there is no evidence of respiratory acidosis. We will learn that his pCO2 is appropriately compensating for his metabolic acidosis. D. Correct! This patient has a metabolic acidosis with an elevated anion gap. A serious diagnosis that must be considered in any patient with a metabolic acidosis with elevated anion gap is lactic acidosis. It is strongly recommended to check the serum lactate in all patients with an unexplained metabolic acidosis with an elevated anion gap. E. Incorrect. Serum pH is low, serum bicarbonate is low, both consistent with metabolic acidosis.

Summary answer The correct answer is D: Mr. Murphy has a metabolic acidosis with respiratory compensation; serum lactate is likely to be elevated.

Having reviewed the general approach to the patient with a possible acid/base disorder, we next review the diagnosis and initial management of patients presenting with a metabolic acidosis. The unifying defect in patients with metabolic acidosis is decreased serum bicarbonate. Patients with a metabolic acidosis will present with a low serum pH and low serum bicarbonate. Compensation, discussed below, is by respiratory alkalosis, thus serum pCO2 is typically reduced as well.

The differential diagnosis of a patient with a metabolic acidosis is broad and can be narrowed and further evaluated by calculating the anion gap. The anion gap is made of negatively charged phosphates, sulfates, organic acids and plasma (including albumin). Rather than measure these on every patient, we calculate the difference between the dominant positive charge (i.e. ) and the dominant negative charges (i.e. chloride and bicarbonate), knowing that the difference is made up of these negative charges, and call them the anion gap. In other words, the anion gap is merely shorthand for the sum of those negative charges that we choose not to measure. The normal anion gap is 12, plus or minus 2.

Anion gap = Sodium – (Chloride + Bicarbonate)

Some include the serum , adding it to the serum sodium, when calculating the anion gap. In this instance, the normal anion gap is 16. Since the serum potassium often fluctuates from other causes that do not pertain to acid/base disorders, we will not use the serum potassium when calculating the anion gap in this module.

The anion gap should be calculated on all patients who present with a metabolic acidosis (in fact, the anion gap should be calculated on all patients, including those with normal serum bicarbonate). The steps in evaluation would be as follows: 1. Evaluate the serum pH. a. In metabolic acidosis the pH is typically low. 2. Evaluate the pCO2 and serum bicarbonate a. In metabolic acidosis, the serum bicarbonate is typically low. b. In metabolic acidosis, the pCO2 is typically low as the body compensates with a respiratory alkalosis. 3. Calculate the anion gap.

Reviewing Mr. Murphy's presentation:

ABG: pH 7.20/pCO2 20/pO2 88 BMP: Na 136/K 5.0/Cl 108/HCO3 8/BUN 47/Creatinine 2.2/Glucose 70

Step 1: Evaluate the serum pH. Normal pH is 7.40; Mr. Murphy's pH is low, demonstrating an acidosis. Step 2: Evaluate the pCO2 and serum bicarbonate. Mr. Murphy's numbers are consistent with a metabolic acidosis. In metabolic acidosis, the pCO2 is typically low, as the body compensates by creating a respiratory alkalosis, as seen in this case. Step 3: Calculate the anion gap. Mr. Murphy's anion gap is 136 – (108 + 8), or 136 – 116 = 20, which is elevated. We then consider the differential diagnosis to be that of a patient with an elevated anion gap metabolic acidosis.

Metabolic acidosis with an elevated anion gap When the above steps are followed and the anion gap is elevated (i.e. greater than 12), the differential of the most common causes is remembered by the mnemonic "MUDPILES."

M: methanol U: uremia D: DKA*/Drugs (e.g., metformin, stavudine, topiramate) P: phosphate/paraldehyde I: ischemia/isoniazid (rare)/iron (rare) L: lactate E: ethylene glycol S: starvation/salicylates

*Alcoholic ketoacidosis will present similarly. Others remember this by including "EtOH" after "ethylene glycol" on the list above.

Note that low serum albumin will decrease the apparent anion gap. To correct the anion gap for low serum albumin, add 2.5 to the anion gap for every 1g/dl that serum albumin is decreased from the normal value of 4g/dl.

The differential diagnosis of anion gap metabolic acidosis contains several urgent conditions, with lactic acidosis among the most concerning. Serum lactate should be checked on every patient with an unexplained anion gap metabolic acidosis. Other tests to consider in a patient with an anion gap metabolic acidosis would be serum ketones (for diabetic ketoacidosis, alcoholic ketoacidosis, and starvation ketosis), salicylate level, and serum toxicology screen (for the presence of methanol or ethylene glycol; note not all hospitals measure for these in a serum toxicology screen, so additional testing may be required). Uremia may be obvious from results of the and physical exam, but most consider this a diagnosis of exclusion, and other causes of an anion gap metabolic acidosis should be considered in the patient with renal insufficiency. Mr. Murphy's anion gap metabolic acidosis was a lactic acidosis from urosepsis; his serum lactate was checked and was elevated.

Normal ("non") anion gap metabolic acidosis In normal anion gap acidosis, the increased anion is chloride, which is measured, so the anion gap does not increase (normal anion gap acidosis is also known as hyperchloremic acidosis). Many call normal anion gap metabolic acidosis "non-anion gap metabolic acidosis". This can be misleading, as it suggests the anion gap is zero. Normal anion gap metabolic acidosis is a more accurate term, signifying that the anion gap in these disorders is typically 12 (plus or minus 2).

The mnemonic for the most common causes of a normal-anion gap metabolic acidosis is "DURHAM."

D: diarrhea U: ureteral diversion R: H: hyperalimentation A: Addison's disease/acetazolamide/ammonium chloride M: miscellaneous (chloridorrhea, amphotericin B, toluene*, others)

*Toluene will initially result in an anion gap metabolic acidosis, but toluene causes a renal tubular acidosis, and a normal anion gap metabolic acidosis results.

Low anion gap metabolic acidosis Low anion gap acidosis is less frequently seen, and if present may be due to hypoalbuminemia, multiple myeloma, and ingestion of bromide. The acid-base disorders in these diseases are of little clinical consequence. It's useful to recall that albumin is one of those negatively charged proteins that is included in the anion gap, thus low serum albumin will decrease the anion gap. Some remember this by the mnemonic "BAM":

B: Bromism (ingestion of bromo seltzer) A: Albumin (low albumin) M: Multiple myeloma

As stated previously, for every 1g/dl that serum albumin is below normal (i.e. below 4g/dl), correct the anion gap by adding 2.5.

Table 2: Review of differential diagnoses in metabolic acidosis

Case 3: Corrected bicarbonate John Chase returns after his hospitalization for gastroparesis, to follow up on his diabetes. Unfortunately, he ran out of insulin two days ago, and presents with the following laboratory results:

ABG: pH 7.20/pCO2 18/pO2 88 BMP: Na 125/K 6.8/Cl 97/HCO3 6/BUN 30/Cr 1.9/ glucose 788

Which statement is correct?

A. This patient has a single acid/base disorder, which is an elevated anion gap metabolic acidosis. B. This patient has a double acid/base disorder, which is an anion gap metabolic acidosis and a respiratory alkalosis. C. This patient has two different metabolic acidosis disorders.

D. Mr. Chase likely has an elevated anion gap from uremia. E. We need to correct the serum sodium for the elevated glucose before calculating the anion gap.

Pop Up answers A. Incorrect. This patient has more than one acid/base disorder. He does have an elevated anion gap metabolic acidosis, but he has a second acid/base disorder as well. B. Incorrect. While Mr. Chase does have two acid/base disorders, his low pCO2 is appropriate compensation for his metabolic acidosis. C. Correct! Mr. Chase has an elevated anion gap metabolic acidosis and a normal anion gap metabolic acidosis. D. Incorrect. While uremia can cause an elevated anion gap metabolic acidosis, there are more likely causes here, such as diabetic ketoacidosis. Uremia as a cause of an elevated anion gap metabolic acidosis should be considered after other causes are excluded. E. Incorrect. While the serum sodium is artifactually lowered by hyperglycemia (i.e. pseudohyponatremia), the is typically equally affected, and the anion gap should be calculated without correcting for pseudohyponatremia.

Summary answer The correct answer is C: This patient has two different metabolic acidosis disorders.

Having reviewed the steps in evaluating a patient with metabolic acidosis, we now review how to determine the presence of a coexistent elevated anion gap and normal anion gap metabolic acidosis.

Determination of a coexistent elevated anion gap and normal anion gap metabolic acidosis Both an elevated anion gap metabolic acidosis and normal anion gap metabolic acidosis may coexist. These coexistent disorders may be missed if additional consideration is not given to the anion gap. For a pure elevated anion gap metabolic acidosis, the serum bicarbonate will decrease by the same amount that the anion gap increases. For example, if the anion gap increases by 6, the serum bicarbonate will decrease by 6. Consider, however, a situation in which the anion gap increases by 6, yet the serum bicarbonate is decreased significantly more, say by 14. This means that there is another metabolic acidosis present, driving down the serum bicarbonate, but not affecting the anion gap. In other words, a

normal anion gap metabolic acidosis is also present. It is therefore recommended that when calculating the anion gap, compare the change in the anion gap with the change in the serum bicarbonate (often called the delta-delta equation, or the corrected bicarbonate).

Don't forget that it is the change in the anion gap and the change in the serum bicarbonate that we are comparing, not the actual values. Also note that lactate will often drive the serum bicarbonate down significantly more than it increases the anion gap, making the corrected bicarbonate less useful in the presence of lactic acidosis.

As a sample case, reviewing Mr. Chase's presentation:

ABG: pH 7.20/pCO2 18/pO2 88

BMP: Na 125/K 6.8/Cl 97/HCO3 6/BUN 30/Cr 1.9/ glucose 788

He has an acidosis, as his pH is low. This is explained by his low serum bicarbonate, suggesting a metabolic acidosis. His anion gap is calculated as 125 – (97 + 6), or 22. He therefore has an elevated anion gap metabolic acidosis (probably from DKA; it would be useful to check serum lactate and serum ketones). The next step is to calculate the corrected bicarbonate on his values. His anion gap has increased by 10 (from a normal of 12 to 22), and his serum bicarbonate has decreased by 18 (from a normal of 24 to 6). These numbers are not close, suggesting the presence of a normal anion gap metabolic acidosis in addition to his elevated anion gap metabolic acidosis. We would then consider the mnemonic "DURHAM" to generate a second differential diagnosis to explain why Mr. Chase has a normal anion gap metabolic acidosis on top of his elevated anion gap metabolic acidosis.

Case 4: Urine anion gap The senior physician involved in Mr. Chase's care tells you to order urine and calculate the urine anion gap. Which one of the following statements is correct?

A. Order urine sodium, potassium, chloride and bicarbonate to calculate the urine anion gap the same way we calculate the serum anion gap. B. The urine anion gap will be greater than zero in patients with a Type 1 or Type 4 renal tubular acidosis. C. The urine anion gap is greater than zero when the patient has ingested methanol, ethanol, or polyethylene glycol. D. The urine anion gap is used to determine the presence of a Type 2 RTA, and should be greater than zero if present.

Pop Up Answers A. Incorrect. The urine anion gap is calculated as (Urine sodium + urine potassium) – urine chloride. Urine bicarbonate is not included when calculating the urine anion gap. B. Correct. The urine anion gap is > 0 when a Type 1 or Type 4 RTA is present. C. Incorrect. These substances cause an osmolar gap but not a urine anion gap. D. Incorrect. Type 1 and Type 4 RTAs are acid excretion defects of the kidney, and result in a urine anion gap greater than zero. Type 2 RTAs are bicarbonate resorption defects, and do not affect the urine anion gap.

Summary answer The correct answer is B: The urine anion gap will be greater than zero in patients with a Type 1 or type 4 renal tubular acidosis.

Role of the urine anion gap in the patient with a normal anion gap metabolic acidosis One of the main diagnostic dilemmas in a patient with a normal anion gap acidosis is whether or not the underlying process is due to a renal tubular acidosis (RTA) or due to other causes. The presence of a renal tubular acidosis (specifically a Type 1 or Type 4 RTA) may be uncovered by determining the urine anion gap. The urine anion gap is calculated as the urine sodium plus urine potassium, minus the urine

chloride:

To explain this, we review some . When the kidney is presented with an acidosis, its

+ - normal response is to excrete acid (in the form of ammonium, NH4 ). To maintain neutrality, Cl is excreted along with this. Therefore, urine chloride serves as a surrogate marker for urine ammonium, which is a marker for urine acid excretion. Urine chloride is high when the kidney excretes a lot of acid, and low when the kidney is not excreting acid. In Types 1 and 4 renal tubular acidosis, the kidney is not appropriately excreting acid, and therefore only small amounts of urine ammonium (and therefore urine chloride) will be excreted, and urine Na + K - Cl will be greater than zero. A urine anion gap greater than zero in the presence of a normal anion gap metabolic acidosis suggests the kidney is not excreting acid, and therefore a Type 1 or Type 4 RTA must be present. A urine anion gap less than zero in the presence of metabolic acidosis suggests the kidney is excreting acid, making a Type 1 or Type 4 RTA unlikely. (Type 2 RTA is a defect in bicarbonate absorption, and this equation does not apply). So when a patient has a normal anion gap metabolic acidosis, consider checking urine electrolytes, and calculating the urine anion gap, to explore whether a renal tubular acidosis may explain the acid/base disorder.

Reviewing Mr. Chase's presentation:

ABG: pH 7.20/pCO2 18/pO2 88 BMP: Na 125/K 6.8/Cl 97/HCO3 6/BUN 30/Cr 1.9/ glucose 788

We've already determined that he has an elevated anion gap metabolic acidosis (probably DKA, but further testing is required) and a normal anion gap metabolic acidosis. We would then order urine electrolytes (sodium, potassium and chloride) and calculate the urine anion gap. Let's say we do this, and his urine anion gap is greater than zero. This suggests his kidneys are not excreting acid, making an RTA likely. Patients with diabetes often have a Type 4 RTA, especially if renal insufficiency is present (as seen in Mr. Chase, who has a creatinine of 1.9). Mr. Chase probably has a Type 4 RTA from his diabetes (his elevated potassium may be additional evidence of this, although in the presence of DKA there are

other explanations for his elevated potassium).

Case 5: Respiratory compensation A beginning medical student on-services today and is assigned to follow Mr. Chase. After reviewing the chart, she notes that Mr. Chase's pCO2 is 18, and asks you to explain why he has a respiratory alkalosis. Reviewing his numbers:

ABG: pH 7.20/pCO2 18/pO2 88 BMP: Na 125/K 6.8/Cl 97/HCO3 6/BUN 30/Cr 1.9/ glucose 788

Which response is correct?

A. Mr. Chase probably has some asthma, causing a respiratory alkalosis. B. The student is correct, normal pCO2 is 40, so an additional acid/base disorder is present. C. Renal insufficiency is a cause of respiratory alkalosis, explaining the low pCO2 D. Mr. Chase does not have an additional acid/base disorder, but is merely compensating for his metabolic acidoses.

Pop Up Answers A. Incorrect. There is no clinical evidence of asthma mentioned, and his pCO2 represents appropriate respiratory compensation. B. Incorrect. Mr. Chase has an appropriate respiratory compensation for his metabolic acidoses. We can predict this using Winter's formula (described below). C. Incorrect. Renal insufficiency does not cause respiratory alkalosis. D. Correct! We can predict that his pCO2 should be 17 +/- 2, as is seen on his ABG.

Summary answer The correct answer is D: Mr. Chase does not have an additional acid/base disorder, but is merely compensating for his metabolic acidoses.

Respiratory compensation in metabolic acidosis Once you have defined the metabolic acidosis, the body's attempt to compensate must be assessed. As

we know, a normal pCO2 is 40. When presented with a primary metabolic acidosis, the body will attempt

to compensate by hyperventilating, which will lower the pCO2 and combat the fall in serum pH. However, some patients will have coexisting respiratory disorders, and may present with an inappropriate compensatory response. We must determine if appropriate respiratory compensation is present, or if a second acid/base disorder coexists.

In a patient who presents with a primary metabolic acidosis, we can use the serum HCO3 to predict what the pCO2 should be in the normal host with the following equation (a.k.a. Winter's formula):

If the measured pCO2 is not close to what we predict, a second disorder coexists (if the pCO2 is less than predicted, respiratory alkalosis is present; if the pCO2 is higher than predicted, respiratory acidosis is

present). The limit of respiratory compensation for a metabolic acidosis is pCO2 of approx. 20. Do not use this equation when the primary disorder is not a metabolic acidosis.

Reviewing one final time Mr. Chase's presentation:

ABG: pH 7.20/pCO2 18/pO2 88 BMP: Na 125/K 6.8/Cl 97/HCO3 6/BUN 30/Cr 1.9/ glucose 788

His serum bicarbonate is 6, so using Winter's formula his pCO2 should be predicted by (1.5 x 6) + 8 +/-2, or 17 +/-2. His pCO2 of 18 represents appropriate respiratory compensation, and no respiratory disorder is present. If his pCO2 was 40, he would have a second disorder (i.e. respiratory acidosis). If his pCO2 were 12, he would have a second disorder (this time respiratory alkalosis). In each case, we would generate an additional differential diagnosis based on the respiratory disorder.

As a note on terminology, when compensation is present and appropriate, although we say the patient

does have a respiratory alkalosis, it is a compensatory respiratory alkalosis, and does not represent an additional acid/base disorder.

Case 6: Osmolar gap A 34-year-old male with a history of schizophrenia comes in complaining of blurred vision and nausea. Family members stated that he had been drinking a strong-smelling liquid from a container found in the garage, but no other history is available. On exam, he is delirious, but afebrile and with otherwise normal vital signs. Papilledema and retinal hemorrhages are noted on funduscopic examination. The remainder of the physical exam is unremarkable. Data are as follows:

ABG: pH 7.23/pCO2 23/pO2 97 BMP: Na 142/K 4.4/Cl 108/HCO3 10/BUN 14/Cr 1.1/Glucose 99 Serum osmolality: 367

Which statement is correct?

A. If the strong-smelling liquid from the garage were methanol, measured serum osmolality is likely to be greater than calculated serum osmolality. B. The patient has a respiratory alkalosis, probably from one of his medications. C. Possible causes of this clinical presentation include ingestion of alkali, ethylene glycol, or methanol. D. Both an elevated anion gap and a normal anion gap metabolic acidosis are present in this patient.

Pop Up answers A. Correct! Methanol ingestion causes delirium, elevated anion gap metabolic acidosis, and papilledema/retinal hemorrhage on physical exam. B. Incorrect. Serum pH is low, so he has an acidosis. Serum bicarbonate is low, so he has a metabolic acidosis. C. Incorrect. While ethylene glycol and methanol cause an elevated anion gap metabolic acidosis,

alkali ingestion does not. D. Incorrect. His anion gap is 24, representing an increase of 12 (from the normal anion gap of 12). His serum bicarbonate is 10, representing a decrease of 14 (from normal serum bicarbonate of 24). Realizing a margin of error of +/- 2, there is no evidence of a double acid/base disorder.

Summary answer The correct answer is A: If the strong-smelling liquid from the garage were methanol, measured serum osmolality is likely to be greater than calculated serum osmolality.

In this section, we discuss the osmolar gap.

Ingestion of osmotically active substances may lead to metabolic disturbances that have significant overlap with acid/base disorders discussed in this module. In addition to ethanol (discussed below) four clinically important substances that are occasionally (either by accident or intent) ingested by individuals include the following:

Methanol: also known as wood alcohol, used in antifreeze and solvents. Results in an elevated anion gap metabolic acidosis. Causes delirium, and is distinguished by causing papilledema and retinal hemorrhages on physical exam.

Ethylene glycol: also used in antifreeze. Results in an elevated anion gap metabolic acidosis. Causes delirium, and is distinguished by resultant oxalate crystals in the urine during metabolism and excretion.

Isopropyl alcohol: also known as rubbing alcohol. Does not cause an acid/base disorder, but when metabolized will show up as acetone in the bloodstream (only resolving ketoacidosis from diabetes /starvation, or isopropyl alcohol ingestion cause acetone in the bloodstream).

Toluene: an organic solvent that is distinguished by causing an elevated anion gap metabolic acidosis, but later results in a normal anion gap metabolic as it results in renal tubular acidosis.

Note that three of the above result in metabolic acidosis, and that isopropyl alcohol cause acetone in the blood (detected when serum ketones are measured). All substances can cause delirium, and a high index of suspicion must be maintained for considering ingestion of the above toxins when evaluating a delirious patient. A clue to the presence of any of these substances is the presence of an osmolar gap.

The osmolar gap We can estimate serum osmolality using the following equation:

In the normal host, the estimated serum osmolality should be close to the actual, measured serum osmolality (within 10 points). But consider the situation in which the measured serum osmolality is much higher (i.e. >10 points) than the estimated serum osmolality. In this situation, an osmolar gap is said to be present, and serves as a clue to the presence of osmotically active compounds in the bloodstream. If ethanol is present, serum osmolality is estimated by adding [ethanol/4.6] to the equation above.

Reviewing the data from our patient:

ABG: pH 7.23/pCO2 23/pO2 97 BMP: Na 142/K 4.4/Cl 108/HCO3 10/BUN 14/Cr 1.1/Glucose 99 Serum osmolality: 367

The estimated serum osmolality = (2x142) + 14/2.8 + 99/18, or 294, which is significantly lower than the measured serum osmolality of 367, suggesting the presence of an osmotically active substance. The presence of papilledema and retinal hemorrhages in this patient with delirium and an elevated anion gap metabolic acidosis suggest methanol ingestion.

Case 7: Metabolic alkalosis Vincent Chase (John's brother) is a 56-year-old man who presents for routine follow up. He has no medical complaints. You have been evaluating him for elevated blood pressure, which had been normal until six months ago, when it was first noted to be elevated. Physical examination today is normal, except for a blood pressure of 166/98. You review blood work from last visit:

ABG: pH 7.48/pCO2 46/pO2 92 BMP: Na 129/K 3.1/Cl 93/HCO3 32/BUN 12/Creatinine 1.0

Which of the following statements is correct?

A. His primary disorder is a metabolic acidosis. B. His primary disorder is a respiratory acidosis. C. Dehydration is the likely cause of Mr. Chase's acid/base disorder D. Urine chloride is likely to be low in Mr. Chase E. A secondary cause of hypertension should be suspected in Mr. Chase.

Pop Up Answers A. Incorrect. Serum pH is elevated, making the primary disorder an alkalosis. B. Incorrect. Serum pH is elevated, making the primary disorder an alkalosis. C. Incorrect. There is no history that would suggest dehydration, and physical examination was normal. D. Incorrect. While the urine chloride is useful in narrowing the differential diagnosis in a patient with metabolic alkalosis, which Mr. Chase has, it is likely to be normal in this case. E. Correct! Patients with Cushing's disease, Conn's disease, and renal artery stenosis may present with a metabolic alkalosis, and should be suspected in Mr. Chase.

Summary answer The correct answer is E: A secondary cause of hypertension should be suspected in Mr. Chase.

Having reviewed metabolic acidosis, we now turn to metabolic alkalosis. The primary defect in a

metabolic alkalosis is an increase in the serum bicarbonate. Metabolic alkalosis implies a gain of bicarbonate or a loss of acid. Clinical examples of how bicarbonate is gained include administration of sodium bicarbonate, baking soda, citrate, lactate, or acetate (the normal liver converts these all to bicarbonate). Acid may be lost through vomiting or NG suction, or through the kidneys, such as with over-diuresis, hypermineralocorticoid states, and the administration of non-resorbable anions (e.g., penicillin, carbenicillin), which complex with positively-charged hydrogen in the renal tubules.

The presence of a metabolic alkalosis always implies that two events have occurred: initiation of the alkalosis and maintenance of the alkalosis. The initiating factors may include the events outlined above, or other pathologic states (discussed in the differential diagnosis below). The kidney is always

+ responsible for maintaining a metabolic alkalosis (by resorbing HCO3 or excreting H ). Two states favor maintenance of alkalosis by the kidney:

1. Volume depletion: In volume depletion, the kidney becomes Na+ avid (which will result in water resorption). As Na+ is resorbed, it will need a negatively charged to resorb along with it, maintaining electrical neutrality. Normally, chloride serves as the negative charge, but in volume

- depletion, chloride is typically very low. In this situation, HCO3 , another negative charge, is resorbed at the expense of acid/base status, and alkalosis persists. 2. Hypermineralocorticoid states: Mineralocorticoids stimulate renal hydrogen ion excretion.

Role of the urine chloride in evaluating metabolic alkalosis In metabolic acidosis, we used the anion gap to narrow the differential diagnosis. In metabolic alkalosis, we use the urine chloride to narrow the differential diagnosis. Low urine chloride (<10mEq/dl) is associated with volume depletion, and may result from NG suction, vomiting, and over-diuresis (Figure 1). For unclear reasons, a patient with hypercapnia, once corrected, will have a similar clinical picture, with metabolic alkalosis and low urine chloride. In a patient who has a metabolic alkalosis and a normal urine chloride, we can further narrow our differential by determining whether or not the patient is hypertensive. Patients with a metabolic alkalosis, normal urine chloride, and hypertension should be suspected to have a secondary cause of hypertension, as Cushing's syndrome, primary aldosteronism (Conn's syndrome), and renal artery stenosis may all present this way. (It is for this reason that the basic metabolic panel is part of the evaluation of the patient with newly diagnosed hypertension). Patients

with renal failure who are given too much alkali will present similarly. Finally, patients with metabolic alkalosis who have normal urine chloride and are not hypertensive may have hypomagnesemia, hypokalemia, Bartter's syndrome (loop of Henle defect of sodium chloride resorption), or licorice ingestion (which enzymatically inhibits degradation of cortisol).

Figure 1: Differential diagnosis of metabolic alkalosis

Patients with metabolic alkalosis and low urine chloride (i.e. <10) respond well to treatment with volume repletion with saline, hence these disorders are often called "saline-responsive metabolic alkaloses".

Respiratory compensation in metabolic alkalosis

We do not have a simple equation (such as Winter's formula) to predict the pCO2 implied by the serum

HCO3. This is due to the wide variation in pCO2 seen in different individuals with a pure metabolic alkalosis with appropriate respiratory compensation (this may be due in part to different individuals'

responsiveness toCO2 as a respiratory stimulant). In general, the pCO2 rises 0.5 - 1 for every 1 unit increase in serum HCO3 from a baseline of 24. The maximum pCO2 in compensation is 55-60.

Reviewing Vincent Chase's numbers:

ABG: pH 7.48/pCO2 46/pO2 92 BMP: Na 129/K 3.1/Cl 93/Bicarb 32/BUN 12/Creatinine 1.0

Mr. Chase has an alkalosis, as serum pH is elevated. This would not be explained by the elevated pCO2, but is explained by the elevated serum bicarbonate, which tells us that Mr. Chase has a metabolic alkalosis. The next step would be to check urine chloride, to help narrow the differential diagnosis. In Mr. Chase's case, urine chloride was normal (i.e. >10), which fits with the clinical picture, as there is no history of vomiting, NG suction, etc. His recently diagnosed hypertension at the age of 56, along with a metabolic alkalosis, suggests a secondary cause of hypertension. One possible explanation would be Conn's syndrome, which would also explain the hypokalemia also noted in Mr. Chase. Respiratory compensation is calculated by recalling that for every 1 that serum bicarbonate increases (from baseline of 24), the pCO2 will increase (from a baseline of 40) by a range of 0.5 to 1. Mr. Chase's bicarbonate of 32 is increased by 8, consistent with an increase in his pCO2 by 4-8, as seen with his pCO2 of 46. He therefore has a single acid/base disorder, that being metabolic alkalosis with a compensatory respiratory acidosis.

Case 8: RESPIRATORY ACIDOSIS Ari Gold is your next patient. He is a 39-year-old talent agent, and he presents with complaints of chest pain and dyspnea for the past two days. He traces his symptoms back to a neighborhood baseball game, during which he was struck in the right chest with a baseball bat. Chest pain began at that time, and dyspnea worsened this morning. On physical examination, he is afebrile, with normal blood pressure. Pulse is 100, and respirations are 24. There is tenderness and ecchymosis over the right 7th and 8th ribs. EKG, done in triage, is normal. Blood work shows the following:

ABG: pH 7.32/pCO2 50/pO2 77 BMP: Na 140/K 4.4/Cl 105/HCO3 25/BUN 11/Cr 0.7/Glucose 88

Which of the following statements is correct?

A. Mr. Gold has a respiratory alkalosis, and he should be evaluated for a pulmonary embolus. B. The chest pain Mr. Gold is experiencing is suppressing his respiratory drive, resulting in respiratory acidosis. C. Mr. Gold has a metabolic alkalosis and a urine chloride should be sent. D. Mr. Gold has a respiratory acidosis, and should be evaluated for a pneumothorax. E. Mr. Gold has a metabolic acidosis; serum lactate should be sent.

Pop Up answers A. Incorrect. Serum pH is low, so he does not have a respiratory alkalosis. B. Incorrect. Pain does not suppress respiratory drive (although narcotics, used to treat pain, do suppress respiratory drive). C. Incorrect. Although his serum bicarbonate is minimally elevated, it is likely compensatory to his primary disorder. D. Correct! Mr. Gold has a respiratory acidosis. With his chest trauma, consideration should be given to pneumothorax or flail chest as an explanation of his clinical presentation. E. Incorrect. Although he has an acidosis, it is respiratory, not metabolic.

Summary answer The correct answer is D: Mr. Gold has a respiratory acidosis, and should be evaluated for a pneumothorax.

Having completed discussion of metabolic acid/base disorders, we now turn to respiratory acid/base disorders, beginning with respiratory acidosis.

The primary defect in respiratory acidosis is an increase in pCO2. Normal pCO2 is 40 (35-45).

Respiratory acidosis develops when hypoventilation results in decreased clearance of CO2 generated by tissue metabolism. Hypoventilation may involve either a segment of a lung, a single lung, or both lungs. An example of a single segment of a lung being hypoventilated would be the presence of a foreign body or tumor obstructing a segmental airway. Alternatively, this foreign body could obstruct an entire lung. Obstructive sleep apnea is a good example of hypoventilation affecting both lungs.

Differential diagnosis of respiratory acidosis Whereas in metabolic acidosis we use the anion gap to narrow the differential diagnosis, and in metabolic alkalosis we use the urine chloride to narrow the differential diagnosis, no such laboratory result exists for narrowing the differential in respiratory acidosis. The differential diagnosis of respiratory acidosis is generated by considering three structures involved in ventilation: the chest cavity (which expands and contracts the lungs), central processes (i.e. those that affect the central respiratory drive center), and the lungs and airways themselves. The differential can then be generated into three sections, as shown in Figure 2.

Figure 2: Differential diagnosis of respiratory acidosis

There is significant overlap in disorders that cause a respiratory acidosis or a respiratory alkalosis. For instance, patients with asthma typically present early in an asthma flare with respiratory alkalosis, as they take short, shallow breaths and "blow off" pCO2. As they tire, however, ventilation deteriorates, and pCO2 normalizes. If untreated, pCO2 will increase such that a respiratory acidosis is seen. Pneumonia is another disorder that may result in a respiratory acidosis or respiratory alkalosis, depending on how much lung is involved and whether or not pleurisy develops (which causes the patient to take short, shallow breaths and blow off pCO2). A final example is respiratory center ischemia, infection or infarction. At times, respiratory center ischemia, infection or infarction will result in respiratory center hypofunction (causing respiratory acidosis), and at times respiratory center hyperfunction will result (causing respiratory alkalosis).

Here is a sample patient:

Lloyd is a 36-year-old administrative assistant who come in to follow up on a sleep study. Lloyd has Class 2 obesity, complains of daytime somnolence, has hypertension, and his partner states that Lloyd snores so loudly it wakes the neighbors. While at the sleep study lab, an arterial blood gas and basic metabolic panel were drawn:

ABG: pH 7.34/pCO2 60/pO2 80 BMP: Na 140/K 4.0/Cl 105/HCO3 32/BUN 12/Cr 0.8/Glu 76

We see that Lloyd has an acidosis, and pCO2 is elevated, consistent with respiratory acidosis. His serum bicarbonate is also elevated, suggesting a compensatory response by creating a metabolic alkalosis. These results, along with other components of the clinical presentation, suggest obstructive sleep apnea, which is a common cause of chronic respiratory acidosis.

Compensation in respiratory acidosis Whereas the lungs can respond rapidly to a metabolic challenge, the kidneys cannot respond immediately to a challenge from the lungs. Therefore, respiratory processes (both acidosis and alkalosis) have an acute compensatory phase, in which plasma buffers help maintain pH, and a chronic phase, in which the kidney participates. The acute response takes minutes to hours, while the chronic response takes 3-5 days. Acute compensation for respiratory acidosis is not as profound as that of chronic compensation, so the change in serum bicarbonate will be less (acutely), and the drop in pH will be more. With chronic compensation, there will be a more profound increase in the serum bicarbonate, and a less profound impact on the serum pH.

For acute respiratory acidosis, compensation is as follows:

• For every pCO2 increase of 10:

o Serum bicarbonate increases by 1 o Serum pH decreases by 0.08

For chronic respiratory acidosis:

• For every pCO2 increase of 10

o Serum bicarbonate increases by 3-4 o Serum pH decreases by 0.03

We can see from the above the better, more profound response with chronic respiratory disorders, lessening the impact on serum pH.

Looking at Lloyd's numbers:

ABG: pH 7.34/pCO2 60/pO2 80 BMP: Na 140/K 4.0/Cl 105/HCO3 32/BUN 12/Cr 0.8/Glu 76

We see his pCO2 is up by 20 (or two "units of 10"). If his respiratory acidosis were acute, we would expect pH to decrease by (2 x 0.08), or 0.16, resulting in pH of (7.40-0.16 = 7.24). His pH change is less severe. In addition, if this were an acute process, we would expect his serum bicarbonate to increase by 2 (increase of 1 for every 10 increase in pCO2). His serum bicarbonate is significantly higher, suggesting a better response from a chronic respiratory acidosis. Plugging in the numbers for chronic respiratory acidosis, we would expect his pH to drop by 0.03 for every 10 increase in pCO2, resulting in pH of 7.34 (as we see here). Looking at his serum bicarbonate, chronic respiratory acidosis increases serum bicarbonate by 3-4 for every 10 increase in pCO2. Lloyd's serum bicarbonate of 32, increased by 8, suggests chronic compensation. As a quick rule of thumb, serum bicarbonate greater than 30 in the presence of respiratory acidosis suggests a chronic disorder

Because of the compensatory response of the kidneys, chronic respiratory acidosis is not particularly dangerous. However, with acute respiratory acidosis, the acidemia can be severe and life threatening. In addition, as pCO2 increases, the partial pressure of O2 in the alveolus will decrease, and inadequate

oxygenation becomes one of the most threatening aspects of a patient with an acute respiratory

acidosis. When the pCO2 reaches 80-90, hypoxemia will be severe. Patients with chronic respiratory acidosis get into trouble when they develop an acute respiratory acidosis on top of their chronic respiratory acidosis.

Case 9: Respiratory alkalosis You are working the night shift in the Emergency Department when a patient, Mrs. Ari, is wheeled back to you. She is a young woman, who appears anxious. She is also obviously tachypneic. Her husband is not far behind, carrying their newborn baby, demanding that you figure out what is going on with his wife. Before you get any more history, the nurse rushes in with the following blood tests:

ABG: 7.51/pCO2 25/pO2 57 BMP: Na 135/K 3.3/Cl 105/HCO3 20/BUN 12/Cr 0.9/Glu 88

Which statement is correct?

A. This patient has a metabolic acidosis with appropriate respiratory compensation. B. This patient has a metabolic alkalosis and a respiratory alkalosis. C. This patient has a respiratory alkalosis and should be evaluated for pulmonary embolus. D. This patient has a respiratory acidosis and should be treated for an asthma exacerbation.

Pop Up Answers A. Incorrect. Serum pH is elevated, consistent with an alkalosis. B. Incorrect. While she does have a respiratory alkalosis, serum bicarbonate is low, and in this case represents a compensatory metabolic acidosis. C. Correct! Note her history of recent pregnancy/childbirth. Also note her pO2 is only 57. Pulmonary embolus, which is in the differential diagnosis of respiratory alkalosis, should be considered with this clinical presentation. D. Incorrect. Serum pH is elevated, and pCO2 is decreased, consistent with respiratory alkalosis.

Summary answer The correct answer is C: This patient has a respiratory alkalosis and should be evaluated for pulmonary embolus.

Our final section of this module is on evaluation of a patient with a respiratory alkalosis.

The primary defect in respiratory alkalosis is a decrease in pCO2.

With respiratory alkalosis, there is increased clearance of CO2, most commonly due to conditions associated with increased ventilation. The differential diagnosis of respiratory alkalosis is broad, and can be narrowed by considering systemic disorders, central respiratory drive causes, and pulmonary causes, as shown in Figure 3. Figure 3: Differential diagnosis of respiratory alkalosis

There are several components of this differential diagnosis worth commenting on:

• Sepsis and salicylates each cause both an elevated anion gap metabolic acidosis and a respiratory alkalosis. If you are evaluating a patient who has both an elevated

anion gap metabolic acidosis and a respiratory alkalosis (not compensatory, but a second disorder), sepsis or salicylate toxicity are the only single disorders that cause both. (Of course, a patient may have two coexistent disorders causing a similar picture, such as a patient with DKA who presents with a pulmonary embolus.)

• Ischemia, infection or infarction of the respiratory drive center may result in decreased respiratory drive (and respiratory acidosis) or increased respiratory drive (and respiratory alkalosis).

• Progesterone is occasionally used as a respiratory stimulant in patients with obstructive sleep apnea and hypoventilation.

• Pulmonary embolus may be catastrophic if missed, and should be considered in patients who present with respiratory alkalosis.

• Bronchospasm (i.e. asthma) typically presents with a respiratory alkalosis (as explained in the last section), but as the patient tires, respiratory acidosis may result.

• Pneumonia may also result in respiratory acidosis or alkalosis, depending on how much lung tissue is involved, how much splinting occurs due to pleuritic chest pain and other factors.

Compensation in respiratory alkalosis As with respiratory acidosis, there is an acute and chronic phase to respiratory alkalosis. The acute compensatory mechanism involves mainly plasma buffers, (15 minutes to 1 hour), and chronic compensation is due to the work of the kidney, and takes 1-3 days to exert an effect.

To assess the compensatory effects for respiratory alkalosis, use the following guidelines:

For acute respiratory alkalosis:

• For every pCO2 decrease of 10

o Serum bicarbonate decreases by 2 For chronic respiratory alkalosis:

• For every pCO2 decrease of 10

o Serum bicarbonate decreases by 5

Note that in contrast to respiratory acidosis, we did not include changes in pH for respiratory alkalosis. This is because the pH changes in respiratory alkalosis are less predictable than with respiratory acidosis. The pH changes are typically less in respiratory alkalosis than in respiratory acidosis, and in some cases, compensation can return the serum pH to normal. Respiratory alkalosis is the only single acid/base disorder in which compensation can return the pH to normal.

Table 3 reviews compensation in respiratory acidosis and respiratory alkalosis.

Table 3: Compensation in respiratory acidosis and alkalosis

Here is one final case before proceeding to the post test.

One of your favorite patients comes to see you in clinic. He had been complaining of generalized aches and pains after lifting a couch, and took "some pills" given to him by a friend. He continues to complain of some low back pain, but as you examine him, you note he is tachypneic. You order some labs:

ABG: pH 7.40/pCO2 26/pO2 98 BMP: Na 138/K 4.0/Cl 97/HCO3 18/BUN 22/Cr 1.1/Glu 84

What is the acid/base disorder? (Scroll down for the answer)

As always, we start by looking at the serum pH. In this case, it is normal. Recall that a normal pH does not exclude an acid/base disorder. Clues that an acid base disorder exists are the low pCO2 and the low serum bicarbonate. Further evaluation shows the anion gap to be elevated (it's 23). Taking the approach that this patient has an elevated anion gap metabolic acidosis, we can then evaluate his respiratory compensation. Using Winter's formula, we predict his pCO2 should be 35 (i.e. 1.5 x HCO3 + 8 +/-2). His pCO2 is significantly lower, suggesting a second disorder (i.e. respiratory alkalosis) is present. This patient therefore has two disorders, an elevated anion gap metabolic acidosis and a respiratory alkalosis, classic for salicylate toxicity (the only other disorder that causes both elevated anion gap metabolic acidosis and respiratory alkalosis is sepsis).

References

1. Walkey AJ, Farber HW, O’Donnell C, et al. The accuracy of the central venous blood gas for acid-base monitoring. Jour Intensive Care Med. 2010; 25(2): 104-110. [link] 2. Malatesha G, Singh NK, Bharija A, Rehani B, Goel A. Comparison of arterial and venous pH, bicarbonate, pCO2 and pO2 in initial emergency department assessment. Emerg Med J. 2007; 24: 569-71. [link] 3. Androgue HJ, Madias NE. Management of life-threatening acid-base disorders (Part 1). New Engl J Med 1998; 338:26-34. [link] 4. Androgue HJ, Madias NE. Management of life-threatening acid-base disorders (Part 2). New Engl J Med 1998; 338:107-111. [link] 5. Battle DC et al. The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis. New Engl J Med 1988; 318:594-9 [link] 6. Coe FL, Kathpalia S. Hereditary Tubular Disorders. In: Harrison's Principles of Internal Medicine (13th ed.) New York: McGraw Hill 1994; 1323-29. 7. Feldman M, Soni N, Dickson B. Influence of Hypoalbuminemia or hyperalbuminemia on the serum anion gap. J Lab Clin Med. 2005; 146: 317-20. [link] 8. Fencl V, Rossing TH. Acid-base disorders in critical care medicine. Ann Rev Med 1989; 40:17-29. 9. Narins RG, Emmett M. Simple and mixed acid-base disorders: a practical approach. Medicine 1980; 59(3):161-187 10. Rose BD. Renal Tubular Acidosis. In: Clinical Physiology of Acid-Base and Disorders (3rd ed.) McGraw Hill 1989; 527-38. 11. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983; 61:1444-1461. [link] 12. Laffey JG, Kavanaugh BP. Hypocapnia. New Engl J Med. 2002; 347:43-53. [link]