In order to interpret acid–base disorders, a basic understanding of the general concepts is necessary. Many hospital laboratories report ranges in normal laboratory values, such as pH 7.35 to 7.45 and Paco2 35 to 45 mm Hg. What is important to understand is that under normal physiologic conditions, the human body attempts to maintain homeostasis by keeping the pH and Paco2 as close as possible to 7.40 and 40 mm Hg, respectively. Therefore, any variation from those values should be considered abnormal for the purposes of blood gas evaluation. Serum bicarbonate levels, on the other hand, may vary from 22 to 28 mEq/L on a daily basis, based upon a number of metabolic variables. In general terms, it is best to always keep in mind that acidosis is defined as the existence of a pH <7.40, whereas an alkalosis is defined as having a pH >7.40.
When presented with an ABG, your task is to determine the primary acid–base disturbance and whether compensation has occurred. Compensation is a process that the body undergoes in an effort to maintain homeostasis (pH = 7.40). For any respiratory abnormality, the body will compensate metabolically with changes in serum HCO3− through renal regulation. This compensation may take 3 to 5 days to completely occur. On the other hand, for any metabolic disorder, the body compensates through pulmonary regulation of Paco2. This compensation occurs much more rapidly than metabolic compensation, taking minutes to begin, with full compensation seen in hours. An example will help to enhance understanding of this concept.
When undergoing strenuous exercise, a number of changes occur within the body. First, as muscles become deprived of oxygen they begin to undergo anaerobic metabolism, producing lactic acid as a byproduct, thereby creating a metabolic acidosis. In an effort to compensate and maintain a normal pH, the respiratory rate increases, thereby causing CO2 to be ventilated out of the body, resulting in respiratory alkalosis. Therefore, if an ABG were drawn during the exercise activity, low HCO3− with an increased anion gap, as well as a low PaCO2 should be seen. Although, the pH may be slightly acidic depending on the level of exercise, the respiratory center will continue to compensate in order to prevent severe metabolic acidosis.
Determining the primary acid–base disturbance and whether or not compensation has occurred is not an easy task; however, if a stepwise approach is utilized, outlined in Figure 31-1, both simple and complex acid–base disorders can be determined. First, and most important, is the assessment of the patient in order to determine what may be physiologically occurring at that moment in time. At the same time, assessment of the pH points one in the direction of a primary acidosis (pH <7.40) or alkalosis (pH >7.40). Second, assessment of Paco2 and HCO3− will allow you to determine the primary disturbance and whether compensation has occurred. Third, if a metabolic acidosis is present, you must calculate an anion gap in an effort to further differentiate the cause of the disturbance and better determine treatment options. Finally, check to see if the patient is compensating for the primary disorder.
Example: A patient with community-acquired pneumonia presents with a pH of 7.46, Paco2 of 32 mm Hg, and serum HCO3− of 26 mEq/L. Using the first step, assessment of the patient, it is determined that the patient has a pulmonary process occurring (pneumonia). In addition, through assessment of the pH, it is evident that this patient has an alkalosis, as the pH is >7.40. Next, assessment of both the PaCO2 and the HCO3−, in the second step, must be done in order to determine which is causing the acid–base abnormality. In this case, the PaCO2 is lower than normal and the HCO3− is normal, indicating the major driving force for the pH to increase is respiratory alkalosis. It does not appear that the patient is compensating for the primary respiratory problem, as the bicarbonate is normal; although, the patient would not have had time to compensate for the acute respiratory alkalosis. Treatment of the patient's underlying pneumonia with antimicrobials (if bacterial in origin) should resolve this acid–base disturbance.
There are five acid–base disturbances that can occur in the human body, Table 31-1: metabolic acidosis, metabolic alkalosis, respiratory acidosis and respiratory alkalosis, and mixed acid–base disturbances. If the stepwise approach to assessing ABGs is used, all of these disturbances can be discovered.
A 58-year-old woman presented with a 4-day history of lethargy, anorexia, abdominal pain, and nausea. Her medical history was positive for type 2 diabetes, for which she was taking metformin 500 mg twice daily, and osteoarthritis of the knees, for which she had recently been started on rofecoxib (unknown dose). Her laboratory values on admission were the following:
Electrolytes: sodium 140 mEq/L (136-145 mEq/L); potassium 4.4 mEq/L (3.5-5 mEq/L); chloride 100 mEq/L (98-106 mEq/L); bicarbonate 5 mEq/L (22-28 mEq/L); blood urea nitrogen 77 mg/dL (10-20 mg/dL); creatinine 9 mg/dL (0.5-1.2 mg/dL); glucose 112 mg/dL (70-110 mg/dL); lactic acid 178 mg/dL (5-20 mg/dL). Arterial blood gas: pH 6.8; Paco2 20 mm Hg; Pao2 77 mm Hg.
Metabolic acidosis can be divided into that which is caused by an increased amount of unmeasured anions (increased anion gap metabolic acidosis) and that which is caused by a normal anion gap. In the case of an increased anion gap, several variables can lead to an increase in unmeasured anions. A useful way to remember the potential causes is through the use of the mnemonic "KILU", where "K" signifies ketoacidosis (caused by diabetes, starvation, and chronic alcoholism), "I" signifies ingestions (typically from salicylates, ethylene glycol, and methanol), "L" signifies lactic acidosis, and "U" signifies uremia.1 Some refer to the mnemonic "MUDPILES" (methanol, uremia, DKA, paraldehyde, INH/Iron, lactic acid, ethylene glycol/ethanol, salicylates) for elevated anion gap metabolic acidosis, though we developed the mnemonic KILU because it is more physiologic and refers to items which are pertinent to today's practice of medicine. When faced with a serum electrolyte panel that reveals a lower than normal serum HCO3−, indicating a metabolic acidosis, an anion gap must be calculated by subtracting the difference in serum concentrations of the major cation, sodium (Na+) and anions chloride (Cl−) and bicarbonate (HCO3−), see Equation 31-2.2,4
Under normal circumstances, the anion gap should be 8 to 16 mEq/L; however, negatively charged proteins, specifically albumin, can have a significant impact on the anion gap, such that a 1 g/dL drop in albumin will lower the anion gap by 2.5 mEq/L.2,4 If the albumin of a patient is known, the normal anion gap can be calculated by multiplying the serum albumin by 3. This proves to be crucial when calculating the delta gap, which is the difference between the observed and the expected anion gap, Equation 31-3.5 The delta gap is used, whenever an increased anion gap is observed, in order to determine what the bicarbonate level would be, in the absence of unmeasured anions. That is, the result of the delta gap is added back to the measured bicarbonate, resulting in the serum bicarbonate without an anion gap, Equation 31-3. This is especially useful in determining if treatment with sodium bicarbonate should be given to correct the acidosis.
From the Equation 31-2, the following can be calculated:
Expected anion gap = 12 mEq/L (no albumin is provided)
Based upon this case example, the increased anion gap is secondary to unmeasured anions, in this case lactic acid, secondary to metformin therapy in the setting of acute kidney injury. Therefore, if the pH were >6.9, it may be inappropriate to administer sodium bicarbonate; however, due to the severity of the acidosis, the administration would be justified. To complete this case example, it is necessary to assess the Paco2 in order to determine respiratory compensation. In this case it is lower than 40 mm Hg, therefore the patient has been appropriately compensated for the metabolic acidosis with a respiratory alkalosis.
Metformin is an extremely rare cause of lactic acidosis, particular care should be taken when using it in patients where renal blood flow has been altered, such as in acute kidney injury, sepsis, contrasted studies, and acutely decompensated heart failure. More commonly, isoniazid and nucleoside reverse transcriptase inhibitors, such as didanosine and stavudine, cause lactic acidosis. Another type of lactic acidosis, D-lactic acidosis (the "D" isomer of lactic acid), can rarely be encountered in practice as well. This type of lactic acidosis is caused by intravenous (IV) infusions of products containing the excipient propylene glycol, such as IV lorazepam and IV diazepam, and typically occurs after high doses of continuous infusions.6 Typical presentation is an increased osmolar gap, increased anion gap, and renal failure.7 Although propylene glycol can cause either a lactic acidosis or D-lactic acidosis, the D-isomer is not detected in the routine assay, and thus lactic acidosis may or may not be identified.7 In these patients, it is still recommended to check a lactic acid level or determine the osmolar gap, which if elevated, would indicate the presence of D-lactic acid.
A 42-year-old man with HIV is admitted to the hospital with headache and fever. He is diagnosed with cryptococcal meningitis and initiated on amphotericin B and flucytosine. One week later, the patient is found to be confused and the following laboratory values were drawn:
Electrolytes: sodium 152 mEq/L; potassium 3.4 mEq/L; chloride 120 mEq/L; bicarbonate 20 mEq/L; blood urea nitrogen 32 mg/dL; creatinine 1.4 mg/dL; glucose 112 mg/dL. Arterial blood gas: pH 7.30; Paco2 36; Pao2 85
Normal anion gap metabolic acidosis is a result of either bicarbonate loss or inadequate buffering.2 The most common cause of bicarbonate loss is excessive diarrhea, but can also be seen in proximal (type 2) renal tubular acidosis (RTA). Because stool has a basic pH, large volume diarrhea can result in a loss of HCO3−, resulting in a normal anion gap acidosis. In type 2 RTA, there is a disruption in the proximal tubular reabsorption of HCO3−, resulting in lower serum HCO3− levels. Medications such as carbonic anhydrase inhibitors and ifosfamide are common iatrogenic causes of type 2 RTA. One common mnemonic used to recall causes for normal gap metabolic acidosis is USED CAR: ureteral diversion, saline infusion, exogenous acid, diarrhea, carbonic anhydrase inhibitors, adrenal insufficiency, renal tubular acidosis.
Inadequate buffering in a normal anion gap acidosis, is a result of decreased distal H+ secretion by luminal H+-ATPase pumps in the collecting duct of the kidneys, defined as distal RTA (type 1).2 This decreased secretion of H+ results in the inability to establish normally acidic urine and therefore a urine pH that is typically above 5.3. Another mechanism of type 1 RTA is secondary to increased permeability of the luminal membrane, resulting in back diffusion of secreted H+ and distal secretion of K+. Amphotericin B is an agent which inserts into the cell membranes and creates pores which decrease the membrane permeability. The net result is H+ retention and K+ excretion resulting in normal anion gap acidosis and hypokalemia.9
In Case 2, the first step in the approach to evaluating ABGs leads the reader to determine the patient has a metabolic process occurring with the cryptococcal meningitis, and no reason to suspect a respiratory problem. In addition to evaluating the patient, evaluation of the pH reveals an acidosis is present. When assessing the metabolic component of the ABG, it is discovered the patient has a lower than normal HCO3−, indicating a metabolic acidosis is present. Evaluation of the respiratory component of the ABG shows that the Paco2 is lower than normal, indicating a respiratory alkalosis may be present due to compensation. Therefore, we determine that the patient has a metabolic acidosis with respiratory compensation. The next step, according to our approach, is to calculate an anion gap because of the presence of a metabolic acidosis. When this is calculated, it is determined that a normal anion gap is present (12 mEq/L). Therefore, it is evident that the acid–base disturbance present is a normal gap metabolic acidosis with appropriate respiratory compensation.
A 65-year-old man is admitted to the hospital for abdominal pain and diarrhea. He has a history of chronic constipation for which he takes lactulose. Three weeks prior to admission, an exploratory laparotomy revealed no obstruction. He then developed pneumonia and received 5 days of gatifloxacin. Five days prior to admission he developed large-volume, watery diarrhea, without nausea or vomiting. He had the following laboratory values upon admission: Electrolytes: sodium 143 mEq/L; potassium 3.3 mEq/L; chloride 102 mEq/L; bicarbonate 33 mEq/L; urea nitrogen 19 mg/dL; creatinine 1 mg/dL; glucose 109 mg/dL. Arterial blood gas: pH 7.44; Paco2 42 mm Hg; Pao2 53 mm Hg. Clostridium difficile toxin: negative × 3.
Metabolic alkalosis is characterized by a pH >7.40 and HCO3− >28 mEq/L. Causes of metabolic alkalosis can be divided into gastrointestinal loss of H+, renal loss of H+, intracellular shift of H+, or retention of HCO3−.2 Gastrointestinal loss of H+ usually is a result of vomiting and nasogastric (NG) suctioning, or through antacid use. Renal H+ loss is associated with a number of conditions including diseases of mineralocorticoid excess, such as primary hyperaldosteronism or Cushing disease. In these conditions, the presence of hypokalemia exists, which acts as a stimulus for H+ secretion and HCO3− reabsorption. Diuretics also promote renal H+ loss through distal secretion. This condition, referred to as "contraction alkalosis," occurs secondary to increased production of aldosterone and reabsorption of Na+ and HCO3− in the proximal tubule, in response to hypovolemia. Additionally, diuretics can cause hypokalemia that may result in the previously mentioned H+ secretion and HCO3− reabsorption. In addition to diuretic use, vomiting can also lead to a condition of contraction alkalosis where Na+, Cl−, and H2O are lost without HCO3−. Finally, retention of bicarbonate, due to excessive administration of sodium bicarbonate, can also result in metabolic alkalosis.
Because the most common causes of metabolic alkalosis include vomiting, NG suction, and diuretics, the usual treatment involves administration of IV fluids containing NaCl.2 However, in some cases, patients may be resistant to administration of IV NaCl, usually due to edematous states or hypokalemia. In those patients, withholding conventional diuretics and possibly administering a carbonic anhydrase inhibitor, acetazolamide, is recommended.
In the case above, the stepwise approach indicates the patient currently has a metabolic process occurring (large volume diarrhea), as well as a pH that shows alkalosis. The second step of the approach demonstrates that the Paco2 is slightly higher than normal, representing a potential respiratory acidosis, with an HCO3− that is higher than normal, demonstrating a metabolic alkalosis. Because the pH is elevated, this leads us to the conclusion that the patient has metabolic alkalosis with and respiratory compensation. It is puzzling, however, that this patient has had large amounts of diarrhea and has an alkalosis, a state in which one would normally expect to see metabolic acidosis (through loss of bicarbonate in the stool). Nevertheless, upon closer examination, the etiology becomes clear. The metabolic alkalosis that was present in this patient was most likely a result of hypokalemia combined with lactulose therapy. Lactulose creates an acidic stool, thereby converting ammonia (NH3) into ammonium (NH4+) for excretion. Therefore, the patient was losing H+ through diarrhea, in a way that was analogous to vomiting or NG suctioning. The patient was given IV fluids, lactulose therapy was discontinued, and the metabolic alkalosis resolved.
An 89-year-old man with a history of heart failure and chronic kidney disease (baseline creatinine 1.6 mg/dL) was being treated in the hospital for a left femoral neck fracture. While in the hospital, he developed a urinary tract infection with Pseudomonas aeruginosa, and began to experience decreased mental status, a temperature of 103°F (39°C), and a white blood cell count (WBC) of 41,000 cells/mm3. At that time he was on room air and his ABG showed pH 7.43, Paco2 19 mm Hg, Pao2 57 mm Hg. Therapy with gentamicin was begun and the patient's WBC began to drop and his mental status began to improve. Days later he began to experience acute kidney injury secondary to gentamicin as evidenced by a serum creatinine of 4.5 mg/dL and a gentamicin trough of 6 mg/dL, therefore gentamicin was discontinued. His mental status began to deteriorate and he began to go into respiratory failure. The ABG revealed pH 7.19, Paco2 57 mm Hg, and Pao2 59 mm Hg. After 3 days of mechanical ventilation, the patient improved and was extubated.
Respiratory acidosis is characterized by a pH <7.40, and results from retention of Paco2; therefore an elevated Paco2 should be evident. Acutely, respiratory acidosis is most commonly associated with severe asthma exacerbations, pneumonia, pulmonary edema, and suppression of the respiratory center secondary to medications such as opioids, benzodiazepines, paralytics, and neuromuscular blockers.2 Chronic respiratory acidosis is most commonly associated with chronic obstructive pulmonary disease (COPD) and extreme obesity. Because the renal compensation may take days, through secretion of H+, acute respiratory acidosis must be treated by removal of the offending agent, or treating the underlying cause. Supplemental oxygenation may be required in severe cases.
In the case presented, the stepwise approach demonstrates the patient has a pulmonary process occurring (respiratory failure), as well as a pH that is acidotic.11 Evaluation of the Paco2 from the time of respiratory failure indicates a respiratory acidosis. Although the HCO3− is not available for assessment, one would not expect to see much of a change from normal, as metabolic compensation would take several days to occur. Through assessment of the patient we know a pulmonary process is occurring at this moment in time; therefore, it is clear the patient has a primary respiratory acidosis, with no evidence of metabolic compensation. The authors believed the acute respiratory failure was secondary to a rare adverse effect of gentamicin therapy, neuromuscular blockade. After gentamicin was discontinued and mechanical ventilation was employed, the patient improved. While it is rare, aminoglycosides have been associated with neuromuscular blockade, an adverse effect of which all clinicians should be cognizant, although more commonly seen with gentamicin and neomycin than with tobramycin and amikacin.
Respiratory Alkalosis / Mixed Acid–Base Disorders
A 58-year-old schizophrenic man was brought to the hospital because of strange behavior. He was completely disoriented and provided no history. The following laboratory values were collected: Electrolytes: sodium 139 mEq/L; potassium 4.7 mEq/L; chloride 90 mEq/L; bicarbonate 14 mEq/L; urea nitrogen 18 mg/dL; creatinine 1 mg/dL; glucose 100 mg/dL. Arterial blood gas: pH 7.49; Paco2 15 mm Hg; Pao2 169 (2 L nasal O2).
Respiratory alkalosis is characterized by a pH >7.40 and hyperventilation resulting in a lower than normal Paco2. This is commonly seen during states of hypoxia, such as in pneumonia, pulmonary thromboembolism, heart failure, and severe anemia.2 Other causes include psychogenic hyperventilation, pregnancy, hepatic failure, salicylate overdose, fever, infections, cerebrovascular events, and drugs such as catecholamines, methylphenidate, nicotine, and progesterone. Treatment of respiratory alkalosis should be solely aimed at correcting the underlying cause.
The case provided above is complicated, in the sense that it is a mixed acid–base disorder. If the stepwise approach is used, we see the patient's pH is elevated, indicating alkalosis. Unfortunately, it is difficult to assess the patient due to his current mental status; therefore we must rely exclusively upon laboratory values. The Paco2 is markedly decreased, indicating a respiratory alkalosis. Furthermore, the Hco3− is also markedly decreased indicating metabolic acidosis. After recognizing a metabolic acidosis, the next step is calculation of the anion gap, which in this case is 35 mEq/L, strikingly elevated. At first glance it is difficult to ascertain which came first, though one might simply state the patient has a metabolic acidosis with respiratory compensation. However, upon further laboratory analysis, it was noted that his salicylate level was extremely elevated. The classic presentation of salicylate overdose involves respiratory alkalosis followed by an increased anion gap metabolic acidosis. A family member then brought in an empty bottle of Alka-Seltzer that was found near the patient's bedside, which contains aspirin. Thus, the patient experienced respiratory alkalosis and an increased anion gap acidosis secondary to aspirin overdose.