Differential Diagnosis of Acid-Base Disturbances

…it should be emphasized that a given set of acid-base values is never diagnostic of a particular acid-base disorder, but rather consistent with a wide range of acid-base abnormalities.

J.A. Kraut and N.E. Madias⁵⁴⁰

For each class of disorders (i.e., metabolic acidosis, respiratory alkalosis, etc.), a wide range of possibilities exists… When the diagnosis is not immediately apparent from the history or clinical setting, however, laboratory data can be extremely helpful.

Jordan J. Cohen and Jerome P. Kassirer⁴⁸³

As with all acid-base disorders, analysis of arterial blood gas samples and serum electrolytes provide the quantitative basis for diagnosis and treatment.

Erik Swenson⁴⁸⁴

The value of establishing a diagnosis is to provide a logical basis for treatment and prognosis.

Clayton L. Thomas⁴⁸²

INTRODUCTION

A systematic method for classification of acid-base status, based on the arterial blood gas report, was described in Chapter 2, and limits, rules, and steps in classification were clearly delineated. Application of these principles leads to consistent results regardless of the background of the interpreter. In fact, these limits and steps can be programmed into a computer that will provide reproducible classifications.

There is no question that blood gas classification is useful in the clinical assessment of acid-base status. It is an excellent way to summarize the blood gas report and to focus attention on important problem areas. However, many acid-base disorders go unrecognized if only the blood gas report is considered. Furthermore, general acid-base diagnoses such as metabolic acidosis or respiratory alkalosis do not provide a great deal of information about the underlying disorder. Optimal patient treatment and follow-up requires a more specific, in-depth, understanding of the nature of the problem.

Definitive Acid-Base Diagnosis

General versus Definitive Diagnosis

An acid-base diagnosis based on blood gas classification alone lacks specificity. Even after complete acid-base assessment, a diagnosis of respiratory acidosis or metabolic acidosis is a general acid-base diagnosis. A general acid-base diagnosis does not reveal the patient’s underlying disease or problem.

Examples of more definitive acid-base diagnoses are lactic metabolic acidosis secondary to hypoxia or respiratory alkalosis secondary to hypoxemia. Compared with a general acid-base diagnosis, a definitive diagnosis provides the clinician with a much clearer understanding of the acid-base pathophysiology. Furthermore, depiction of the specific root problem in a given acid-base disturbance is a prerequisite to optimal treatment and therapy.

Thus, the clinician should not conclude acid-base assessment with only a blood gas classification or a general acid-base diagnosis (e.g., respiratory acidosis, metabolic alkalosis). A more descriptive etiology (i.e., definitive diagnosis) must be determined after careful analysis of physical findings, symptoms, history, and supplemental laboratory data. Furthermore, identification of the specific acid or base that has caused the disturbance (e.g., increased carbonic acid, increased lactic acid, loss of bicarbonate) also helps to clarify thinking and understanding.

Common Causes of General Disturbances

In this chapter, some of the more common causes of respiratory and metabolic acid-base disturbances are briefly discussed. The novice clinician is encouraged to review this information before he or she attempts to make a definitive acid-base diagnosis at the bedside. A diligent attempt has been made to include all the common causes of these general acid-base disorders and some causes that are less common. Obviously, it is impossible to list every possible cause.

In general, the boxes have been constructed as functional groupings of acid-base disorders. Problems with similar mechanisms (e.g., neuro- muscular problems) have been clustered together rather than trying to list every specific disease that could cause a particular type of acid-base disorder.

It is noteworthy that often more than one root problem is responsible for a general acid-base diagnosis. A patient may have metabolic alkalosis due to a combination of factors. For example, it is not uncommon for a patient to be receiving both diuretics and steroids and, in addition, to manifest hypokalemia. In this case, three different underlying factors could be contributing to a metabolic alkalosis. Therefore, it is advisable to review and consider all possibilities, even if one mechanism is already evident.

RESPIRATORY ACIDOSIS

Respiratory acidosis may result from a variety of acute and chronic causes. It threatens acid-base balance through the accumulation of carbonic acid. Furthermore, it compromises oxygenation via decreased alveolar delivery and hypoxemia.

Physiologic Response to Respiratory Acidosis (Hypercapnia)

The clinical manifestations of acute hypercapnia are predominantly neurologic.⁴⁸⁵ Symptoms may vary from anxiety and irritability to lethargy and somnolence. Pulmonary symptoms may include dyspnea and distress. Stupor and coma appear to be rare but may occur when PaCO₂ exceeds 70 mm Hg.⁴⁸⁵

It is also important to remember that hypercapnia causes increased cerebral perfusion and intracranial pressure. Indeed, during acute hypercapnia, cerebral blood flow may more than double while, conversely, it will decrease by more than 50% when PaCO₂falls by about 10 mm Hg.⁴⁹⁶ This may be especially important in the patient with CNS trauma or following CNS surgery where low intracranial pressure is a goal in patient treatment. In chronic hypercapnia, cerebral blood flow is normal and responsiveness to changes in PaCO₂ is reduced. It appears that interstitial acidosis is really the primary regulator of cerebral dilation and perfusion.⁴⁹⁷

Cardiovascular effects in mild to moderate hypercapnia typically include an increased cardiac output and tachycardia mediated through an adrenergic response. On clinical examination, the skin may be flushed and warm. The patient may also be diaphoretic and demonstrate a bounding pulse. In severe hypercapnia, hypotension and/or arrhythmia may occur as a direct effect of PaCO₂ on the myocardium and vasculature.⁴⁸⁵

Physiologic changes may be more related to concurrent acidemia and hypoxia than hypercapnia. Certainly there is a less dramatic response when hypercapnia develops slowly. The somewhat innocuous nature of hypercapnia has lead to the therapeutic approach of “permissive hypercapnia”⁴⁹⁸ where hypercapnia is tolerated in an effort to avoid excessive alveolar volume and pressure (see Chapter 10). Many believe that substantial hypercapnia is likely associated with very few adverse effects.⁴⁹⁸

Common Causes of Respiratory Acidosis

As discussed previously, it is important to identify the underlying cause of the acid-base disorder to optimize management. Some common causes of respiratory acidosis are shown in Box 13-1.

Box 13-1 Causes of Respiratory Acidosis

Chronic obstructive pulmonary disease (COPD)

Oxygen excess in COPD

Extreme ventilation-perfusion mismatch

Exhaustion

Neuromuscular disorders

Poliomyelitis

Amyotrophic lateral sclerosis

Guillain-Barré syndrome

Electrolyte deficiencies (K⁺, PO₄⁻

Myasthenia gravis

Iatrogenic respiratory acidosis

Neurologic disorders

Excessive CO₂ production

Total parenteral nutrition

Sepsis

Severe burns

NaHCO₃ administration

Some may find it easier to think of the potential origins of the various fundamental acid-base disturbances. For example, as shown in Figure 13-1, eight common sources of primary respiratory acidosis are: the lungs (e.g., chronic obstructive pulmonary disease [COPD]), drugs (e.g., anesthetics/narcotics), mechanical ven- tilation (e.g., iatrogenic hypoventilation), muscle fatigue (e.g., status asthmaticus), central nervous system (CNS; e.g., central alveo- lar hypoventilation), neuromuscular junction (e.g., Guillain-Barré syndrome), increased metabolism in cells/tissues (e.g., burn patients), and oxygen excess depressing ventilatory drive (e.g., in COPD).

Figure 13-1 Potential sources of respiratory acidosis.

Chronic Obstructive Pulmonary Disease

The most common cause of chronic respiratory acidosis is COPD. Emphysema, chronic bronchitis, and asthma are the major subgroups of COPD. COPD is characterized by progressive airway disease that leads to gas trapping, uneven distribution of ventilation, hypoxemia, and, ultimately, in severe disease, respiratory acidosis.

The patient with COPD is readily recognized on physical examination by the presence of a barrel chest, adventitious (abnormal) breath sounds, labored breathing, and forced expiration. Hyperaeration and flattened diaphragm are present on the chest radiograph. Pulmonary function studies show a diminished forced expiratory flow (FEF) in the mid-expiratory flow in moderate disease, progressing to a decreased forced expiratory volume in 1 second (FEV₁) in more severe disease.

Chronic respiratory acidosis is only seen in approximately 25% to 33% of patients with significant chronic airflow obstruction.⁴⁹⁹ Chronic hypercapnia appears to be a mechanism whereby some patients avoid excessive respiratory muscle fatigue. Indeed, because of the hypercapnia, these patients can eliminate CO₂ with far less ventilatory effort.⁴⁹⁹ ⁵⁰⁰ Therefore, hypercapnia appears to be a useful strategy for avoiding inspiratory muscle overloading and failure.⁴⁹⁹ Notwithstanding, due to their limited ventilatory reserve, acute pneumonia can and frequently does lead to a superimposed acute ventilatory failure in these individuals.⁵⁰¹

Oxygen Excess in Chronic Obstructive Pulmonary Disease

As described previously, chronic respiratory acidosis is common in end-stage COPD. In addition, when high concentrations of oxygen are administered to patients with end-stage COPD (especially those with hypercarbia), they may manifest an acute rise in PaCO₂ levels above their chronically elevated baseline PaCO₂. This acute respiratory acidosis is most apt to occur when PaCO₂ levels are very high and/or when PaO₂ levels are very low at the time when the oxygen is administered.⁴⁸⁶ ⁴⁸⁷ Actually, baseline hypoxia and acidosis are better predictors of those patients likely to have worsening respiratory acidosis than baseline PaCO₂.⁴⁸⁵

Even slight elevations in FIO₂ may cause this effect.⁴⁸⁸ ⁴⁸⁹ The acute hypercarbia may be progressive and may occasionally result in respiratory arrest. The rise in PaCO₂ may be caused by obliteration of the hypoxic drive of the peripheral chemoreceptors; however, some evidence suggests that it is due primarily to a worsening of ventilation-perfusion matching.⁴⁹⁰ In all likelihood, it is a multi-factorial response.

Regardless of the potential for acute respiratory acidosis, when hypoxia is suspected, oxygen must be administered in doses sufficient to relieve it. The target of oxygen therapy in COPD is typically a PaO₂ of approximately 60 mm Hg, although not higher.⁴⁸⁶ ⁴⁹¹ When acute respiratory acidosis is observed in a patient with COPD who has a PaO₂ level greater than 60 mm Hg, the FIO₂ may be excessive. The higher the PaO₂ and FIO₂level, the more likely that the respiratory acidosis is at least in part related to the oxygen therapy.

A trial of decreased FIO₂ followed by arterial blood gases should reveal whether excess oxygen was in fact the cause of the acute respiratory acidosis. If PaCO₂ improves at a lower FIO₂, it is logical to assume that oxygen therapy was excessive.

Interestingly, oxygen therapy may worsen hypercapnia in other chronic disorders as well. Although the mechanism is unclear, these include patients with neuromuscular disease, asthma, diaphragmatic dysfunction, or obesity hypoventilation syndrome.⁴⁸⁵

Drugs

Depressant drugs such as morphine may diminish respiratory drive,⁴⁹² with resultant hypercarbia and acidosis. The response of a given patient depends on the individual, the drug, and the dosage. Barbiturates, anesthetics, narcotics, and sedatives may cause this effect. Narcotic overdose characteristically manifests itself in a slow respiratory rate in the spontaneously breathing patient.

Individuals with COPD are particularly vulnerable to the respiratory effects of sedatives and narcotics and may exhibit further CO₂ retention even at normal dosages. Although the usual setting for drug-induced hypoventilation is the emergency room, respiratory acidosis secondary to drug effects may also be seen in the postoperative or critical care milieu.

Neuromuscular blocking agents may also be used to control ventilation in the ICU. This is particularly true with many of the new ventilatory techniques such as inverse I:E ratios and “permissive hypercapnia,” which may render the patient uncomfortable or anxious. Barring the obvious problem of potential ventilator disconnect, one must be careful to avoid paralysis without adequate sedation. The terror of conscious paralysis is unthinkable.

Extreme Ventilation-Perfusion Mismatch

As stated earlier, the mechanism that ultimately leads to respiratory acidosis in COPD is most likely deterioration in the ventilation-perfusion match. Regardless of the disease, whenever gas exchange capabilities of the lung become extremely compromised, the ability of the lungs to excrete CO₂ may become impaired. This may occur in severe lung cancer, pneumonia, or any other severe pulmonary parenchymal disease. In summary, any acute or chronic disease that results in severe lung damage may ultimately lead to respiratory acidosis.

Exhaustion

Acute respiratory acidosis may likewise occur as a result of simple exhaustion due to excessive work of breathing over an extended period. This mechanism may explain the sudden onset of respiratory acidosis that has been observed in patients with status asth- maticus after a sustained period of laborious breathing.

In progressive pulmonary disease of any origin, there appears to be some point at which the work of breathing is so great that adequate ventilation can no longer be maintained. The patient may respond to this scenario with progressive hypercapnia or even with respiratory arrest due to extreme fatigue. Mechanical ventilation is indicated at this point “to give the patient a rest.”

There is also some evidence to suggest that the onset of exhaustion is related to the degree of lactic acidosis that develops as a result of the extreme workload.⁴⁴⁷

Neuromuscular Disorders

Neuromuscular Disease

Diseases that affect the neuromuscular junction or the function of the respiratory muscles themselves may progress to hypoventilation and respiratory acidosis. Some of the more common disorders that may affect neuromuscular integrity include myasthenia gravis, poliomyelitis, amyotrophic lateral sclerosis, and the Guillain-Barré syndrome.

Guillain-Barré syndrome is characterized by loss of reflexes and symmetric paralysis, typically beginning in the legs, with eventual nearly complete or complete recovery.⁵⁰² Acute Guillain-Barré usually begins with fine paresthesias in the toes or fingertips, followed within days by leg weakness that makes walking and climbing stairs difficult. Weakness usually ascends and pain is common. Approximately two-thirds of cases follow an infection. Increased protein in the cerebrospinal fluid is a valuable diagnostic marker. Patients with very low (i.e., < 18 mL/kg) or rapidly declining vital capacities should be transferred and observed in ICU.

The trend of neuromuscular dysfunction on ventilation can be observed at the bedside through serial measurements of vital capacity. A falling vital capacity may indicate progressive hypoventilation and perhaps the onset of respiratory acidosis. Figure 13-2 designates suggested clinical management of the Guillain-Barré syndrome based on progressive deterioration of the vital capacity.

Figure 13-2 Vital capacity in management of Guillain-Barré syndrome.

Myasthenia gravis affects approximately 25,000 people each year in the United States. The basic abnormality in myasthenia gravis is a decrease in the number of acetylcholine receptors in the neuromuscular junction.⁵⁰³ Figure 13-3 illustrates the decreased number of acetylcholine receptors and the widened synaptic space in myasthenia gravis as compared to the normal neuromuscular junction. The clinical result of this disease is neuromuscular weakness and fatigue.

Figure 13-3 **Neuromuscular junction in myasthenia gravis.** (Note the decreased acetylcholine receptors and the widened synaptic space.)

Electrolyte Deficiencies

Hypokalemia, a common electrolyte disorder in the critical care setting, is also associated with muscle weakness and even paralysis. The clinician must be particularly alert to this problem when trying to wean patients from mechanical ventilation. The presence of hypokalemia may result in unsuccessful weaning attempts. Low phosphate levels, although less common, may similarly impede normal neuromuscular control.

Iatrogenic Respiratory Acidosis

During mechanical ventilation, some aspects of the ventilatory pattern (e.g., tidal volume, respiratory rate) may not be under the direct control of the patient; rather, they are a product of the machine settings. This is particularly true in the apneic or paralyzed patient in whom the rate and volume of ventilation is exclusively a result of the ventilator settings. Thus, especially in the patient on mechanical ventilation, there is always the possibility of therapy-induced (iatrogenic) respiratory acidosis.

Inappropriately low ventilator settings for tidal volume or respiratory rate results in an elevated PaCO₂ and a blood gas classification of respiratory acidosis. Thus, insufficient mechanical ventilation may induce respiratory acidosis, particularly when drugs have been administered to facilitate control of the patient’s ventilation.

Subsequent manipulation of ventilatory settings corrects only the iatrogenic respiratory acidosis. These ventilator changes cannot, of course, correct the underlying condition (e.g., respiratory acidosis secondary to CNS depression) that was responsible for the initiation of mechanical ventilation in the first place.

Permissive Hypercapnia

In most applications of mechanical ventilation, the goal is to normalize PaCO₂. Notwithstand- ing, in contrast to traditional mechanical ventilation, it is now common in acute lung injury and acute respiratory distress syndrome (and some other disorders) to allow respiratory acidosis to develop in an effort to avoid excessive alveolar pressure or volume. This so-called permissive hypercapnia is considered to be potentially less harmful than using higher lung inflation pressures to ensure a normal PaCO₂. Nevertheless, severe hypercapnia should still be avoided, even in this population, and even mild hypercapnia may be harmful if there is concern regarding excessive cerebral perfusion or when there is substantial acidemia.

Neurologic Disorders

Neurologic disease or trauma (including spinal cord injury) may also lead to hypoventilation and respiratory acidosis. The mechanism by which this effect occurs is via depression or malfunction of the respiratory centers or an increased intracranial pressure. Similarly, CNS dysfunction is probably responsible for the respiratory acidosis that commonly follows cerebral hypoxia and cardiac arrest.

The CNS is also responsible for the respiratory acidosis that occurs during sleep in patients with central sleep apnea. In addition, central mechanisms may play a role in the chronic respiratory acidosis associated with obesity that is known as the Pickwickian syndrome. Finally, Ondine’s curse, a condition characterized by unexplained hypoventilation, most likely has a neurologic origin.

Excessive CO₂ Production

As described in Chapter 8 in the section on CO₂ homeostasis, the PaCO₂ depends not only on the quantity of CO₂ leaving the blood (i.e., A), but also on metabolism and CO₂ production (CO₂). The significance and effects of CO₂ production on ventilation and acid-base status in critically ill patients have only recently been appreciated. Carbon dioxide production depends on both the type and the quantity of metabolism.

Type of Metabolism

The Respiratory Quotient and CO₂ Production.

As described in Chapter 7, the respiratory quotient (RQ) relates CO₂ production to oxygen consumption (CO₂/O₂). The numeric value of the RQ, in turn, depends on the type of body fuel being metabolized. Fat metabolism for example, results in less CO₂ production (RQ of 0.7) than carbohydrate metabolism (RQ of 1.0).

Total Parenteral Nutrition and the Respiratory Quotient.

Total parenteral nutrition (TPN) is a nutritional support formula administered intravenously to critically ill patients to avoid the adverse effects of malnutrition.⁴⁹³ TPN consists of a mixture of glucose and amino acids. As such, TPN is high in carbohydrates and increases the RQ and the production of CO₂ after administration. In the patient unable to meet the increased ventilatory requirement necessary to excrete this additional CO₂, respiratory acidosis may ensue.

Specifically, acute respiratory acidosis has been observed in patients with chronic lung disease in response to the administration of TPN.⁴⁹⁴ This effect may occur both in nonintubated patients and in patients on mechanical ventilation.⁴⁹⁴ ⁴⁹⁵ During mechanical ventilation, the risk of TPN-induced respiratory acidosis is reduced if the minute volume of the ventilator is increased just before TPN administration.⁴⁹⁵

In addition, the development of hypercapnia has been reported in two young patients without COPD during weaning from mechanical ventilation while receiving TPN.³³⁸ Furthermore, when the number of carbohydrate calories given to these patients was decreased, CO₂ production likewise dropped, and the respiratory acidosis was corrected.³³⁸ In summary, a high RQ may contribute to the onset or maintenance of respiratory acidosis.

Quantity of Metabolism: Thermic Effect

Just as a high RQ can increase CO₂ production, a general increase in the quantity of energy metabolism (thermic effect), such as may occur with fever, will also increase CO₂ production and may contribute to respiratory acidosis.

Malignant hyperthermia (MH) is an inherited condition in which some medications (especially anesthetics) trigger sustained skeletal muscle contraction and hypermetabolism.⁵⁰⁴ Symptoms include rapid, acute severe respi- ratory acidosis; hyperthermia; ventricular dysrhythmias; hyperkalemia; and muscular rigidity.⁵⁰⁵ The clinical course of the disorder is short, usually 1 to 3 days. Untreated, MH may have a 70% mortality.⁵⁰⁴ Treatment includes termination of the triggering agent, and control of pH, temperature, and potassium.⁵⁰⁵

Patients with severe burns also have an increase in total body metabolism secondary to tissue destruction and the reparative process. This response is greater than the hypermetabolism seen in sepsis or other forms of trauma. The magnitude and duration of the metabolic response parallel burn severity with metabolism doubling in a 60% total body burn.⁵⁰⁶

Other causes of hypermetabolism include sepsis, fever, thyrotoxicosis, and trauma.⁴⁸⁵ In fever, CO₂ production will increase approximately 13% for each degree centigrade elevation in body temperature. TPN is associated not only with a high RQ; it also has a thermic effect secondary to the protein component of the solution.⁵⁵⁰ Consequently, TPN tends to increase CO₂ production through changes in both the type and quantity of metabolism.⁵⁵⁰

Indeed the thermic effect appears to have an even stronger impact on CO₂ production than the type of substrate used for metabolism. The administration of excess calories will also lead to increased CO₂ production through lipogenesis, which has an RQ of nearly 8.0.⁵⁰⁷

Thus, the number of calories, the percentage of carbohydrate, and the nature of the patient’s illness must all be considered regarding the CO₂ production load. In contrast, CO₂ production may sometimes be reduced by decreased glucose intake, cooling, or paralyzing the patient.⁴⁹⁸

Sodium Bicarbonate Administration

Administration of sodium bicarbonate (NaHCO₃) intravenously also increases blood CO₂ levels via the hydrolysis reaction. In spontaneously breathing individuals who are capable of increasing alveolar ventilation, this excess CO₂ is immediately excreted. However, in the patient unable to excrete the additional blood CO₂ (e.g., because of neurologic disease or controlled mechanical ventilation), hypercarbia and acute respiratory acidosis develop.³⁶⁵

Severe hypercapnia and respiratory acidosis of mixed venous blood has been shown to accompany resuscitation during cardiac arrest.⁵⁶⁷ It is presumed that these mixed venous gases reflect tissue conditions. The administration of NaHCO₃ in this setting may further elevate the tissue PCO₂ and thus exacerbate the tissue acidosis. This issue is discussed in greater detail in Chapter 14 in the section on treatment of metabolic acidosis.

RESPIRATORY ALKALOSIS

Respiratory alkalosis, like respiratory acidosis, may result from a variety of acute and chronic causes. It disrupts acid-base balance by depleting the normal blood stores of carbonic acid. Respiratory alkalosis is a very common acid-base disorder.

Physiologic Response to Respiratory Alkalosis (Hypocapnia)

Patients with respiratory alkalosis often present with dyspnea and chest pain or tightness.⁵¹² In addition to renal compensation (i.e., decreased [HCO₃]) for respiratory alkalosis, hypocapnia will decrease cerebral blood flow, alter some electrolyte concentrations, and increase the production of lactic acid.

Regarding potassium, there is an initial abrupt onset of hyperkalemia. This is rapidly followed by the development of hypokalemia.⁵⁰⁸ Typically, serum potassium will decrease 0.3 mEq/L for each 0.1 unit increase in pH.⁵⁰⁸ Occasionally, electrolyte disturbances will be associated with muscle spasm. In addition, respiratory alkalosis increases production and decreases the clearance of lactic acid; however, the increase in lactic acid levels is only modest.⁵⁰⁸