Pathophysiology and Management of Respiratory and Mixed Acid-Base Disorders

Pathophysiology and Management of Respiratory and Mixed Acid-Base Disorders

Seth B. Furgeson

William D. Kaehny

Respiratory acid-base disorders are caused by primary changes from normal excretion of carbon dioxide (CO2) by the lungs. Primary means that the changes are not secondary to changes in pH caused by metabolic acid-base disorders. Under usual metabolic conditions, the body makes 13,000 to 15,000 mmol of CO2 per day from the catabolism of carbohydrate, protein, and fat. If the lungs excrete this amount, the quantity of CO2 in the body remains the same. This is reflected by the amount of CO2 dissolved in blood and the partial pressure of the CO2 gas in equilibrium with it (PCO2). A small amount of the dissolved CO2 reacts with water to form carbonic acid (H2CO3), the acid part of the Henderson-Hassel balch acid-base equation discussed in Chapter 3 and in detail elsewhere (1). This relationship between PCO2 and pH is shown below:

If the lungs’ excretion does not match the daily production of CO2, the quantity of CO2 in the body changes; therefore, the amount dissolved in the blood and the pressure it generates (PCO2) change in the same direction. This change generates either of the two simple (or primary) respiratory acid-base disorders: hypercapnia, or high CO2 level, generates respiratory acidosis; hypocapnia, or low CO2 level, generates respiratory alkalosis.

The whole body responds to changes in CO2 content in a programmed fashion. In step 1, the pH change causes rapid chemical buffering. Buffers within cells either take up hydrogen ions [H+], producing a bicarbonate [HCO3] in the blood, or give up H+ to titrate (consume) HCO3 in the blood. In step 2, the abnormal blood PCO2 alters the renal tubular cell PCO2, causing changes in H+ secretion that result in changes in renal net acid excretion (NAE) that, in turn, raise or lower blood [HCO3]. This process is called by its traditional name of compensation, but it is more of an adaptation to a new state of CO2 balance. This process takes days to reach a new steady state. Thus, it occurs only in chronic respiratory acid-base disorders. In step 3, the respiratory system corrects the problem and restores the whole-body CO2 content and the arterial PCO2 (PaCO2) to previously normal values. Obviously, this can occur only if the causative disorder is cured or corrected. Notably, changes in oxygen (O2) supply and demand and the PaO2 do not define respiratory acid-base disorders, but they can cause both respiratory acid-base disorders and metabolic acidosis through their effects on respiratory drive and lactic acid metabolism (2).

Carefully obtained arterial blood for analysis is the usual way of diagnosing respiratory acid-base disorders. There are a variety of approaches used to correctly classify acid-base disorders (3). A commonly used approach is a physiologic one based on the Henderson-Hasselbach equation. To accurately identify an acid-base disorder using this approach, one needs measurements of pH, PCO2, HCO3, and the anion
gap. This approach uses only the carbonic acid/bicarbonate buffer system to assess acid-base disorders and is the approach that will be used in this chapter. The two other approaches to acid-base disorders are the base excess approach and the physicochemical approach (Stewart approach). The former analysis takes into consideration all buffer systems in the body, whereas the latter approach measures the variables of strong ion difference and weak acid concentration. These two approaches have been reviewed extensively (3) and will not be discussed further in this chapter.

Respiratory Acidosis

Respiratory acidosis is a disorder caused by processes that increase PCO2, which thereby leads to a decrease in the pH. The PCO2 increases when the lungs fail to excrete metabolically produced CO2. A decrease in effective alveolar ventilation is the usual way that the PCO2 is increased. Effective alveolar ventilation can be diminished in two major ways, namely, decreased minute ventilation or ventilation-perfusion inequality (4). If effective ventilation is fixed by a ventilator or respiratory disease, the introduction of nutrition, parenteral or enteral, will increase the generation of CO2. Using glucose as the source of nonprotein calories increases CO2 production by 20% compared with glucose-lipid mixtures (5).

With decreased effective alveolar ventilation, CO2 excretion falls short of production, and the quantity of CO2 carried per milliliter of blood increases, as reflected in an increased PaCO2. When a steady state of hypercapnia is reached, the ventilatory excretion of CO2 again equals production. This new state occurs because a higher concentration of CO2 is carried to the pulmonary vascular bed, allowing more CO2 excretion.

When the PaCO2 rises, the amount of dissolved CO2 increases and shifts the equilibrium reaction to favor the production of H2CO3; thus, CO2 + H2O → H2CO3. This increased acid results in a fall in pH or respiratory acidosis. This process can be visualized more simply as a rise in PaCO2, which reduces the ratio of the HCO3 concentration to the PaCO2, thereby causing a fall in pH:

The chemistry of these reactions is discussed in Chapter 3.



The immediate response to the low pH generated by the increased PaCO2 and H2CO3 is to buffer (or bind) hydrogen ions with nonbicarbonate buffers. Bicarbonate does not work as an effective buffer in this situation because it reacts with hydrogen ions to form H2CO3, which is the original culprit. In the extracellular fluid (ECF) space, proteins constitute the only buffer, whereas within the cells, hemoglobin, phosphate, proteins, and lactate are the major nonbicarbonate buffers; 97% of the buffering of H2CO3 derives from intracellular rather than extracellular fluid buffers (6).

Renal Compensation

The definitive compensation for respiratory acidosis resides solely in the kidneys. The kidneys respond to the increased systemic PCO2 by increasing the production and excretion of ammonium (NH4+). The renal tubular cells metabolize glutamine to produce two NH3 molecules and α-ketoglutarate (AKG). The AKG goes to the liver, where metabolism produces two HCO3. The kidney excretes the NH3 as NH4+, which marks the addition of the new HCO3 to the body stores by the liver. If the kidneys fail to excrete the NH4+, it travels to the liver, and metabolism generates H+, which negates the addition of the HCO3 to the body. Thus, increased renal excretion of NH4+ is a crucial component of the generation of new HCO3. The increased urinary NH4+ excretion is balanced by increased Cl excretion, with a resultant fall in plasma (Cl). When a steady state of hypercapnia is reached, chloride excretion returns to normal and equals intake. NH4+ excretion also returns to normal, even though H+ secretion remains increased. The persistently increased H+ secretion is needed to reclaim the increased filtered HCO3 load that results from the increase in plasma concentration (7, 8). Experimental evidence has shown that both the proximal tubule and the distal tubule participate in adaptation to
respiratory acidosis. In the proximal tubule, increases in PaCO2 cause corresponding activation of the luminal Na/H exchanger and basolateral Na/HCO3 exchanger, leading to net reabsorbtion of bicarbonate (9). There also appears to be increased activity of H+/ATPase in the distal tubule (10). The chemical buffering and renal compensation that occur with chronic respiratory acidosis are diagramed in Figure 4-1.

Figure 4-1 Pathophysiology of chronic respiratory acidosis. Chemical buffering and renal compensation combine to elevate the plasma [HCO3]. The renal mechanisms involve an adaptive increase in ammonium and chloride excretion until the new steady state is reached.

Correction of Respiratory Acidosis

The third, or corrective, response to respiratory acidosis is the restoration of effective ventilation. Correction or amelioration of an acute neurologic process causing hypoventilation or a ventilatory or gas-exchange defect may be possible. Unfortunately, many processes that result in chronic hypercapnia are caused by irreversible parenchymal lung damage and thus can be corrected only partially at best.

In metabolic acidosis, the corrective agent, the kidney, is sometimes a cause of the disorder, as in uremic acidosis, but at other times is not, as in diabetic ketoacidosis. In respiratory acidosis, however, the respiratory system, which includes neural control—mechanical, circulatory, and membrane exchange components—always is involved as the cause of the disorder and is also the corrective agent.


Acute respiratory acidosis results from acute alveolar hypoventilation with a primary elevation of the PaCO2, when only the buffering defense has had time to come into play. Although buffering occurs almost immediately, the renal response does not exert a noticeable influence for 12 to 24 hours (11). This is the period of time in which pure acute respiratory acidosis is observed. An appropriate defense of pH in acute respiratory
acidosis is characterized by an elevation of the plasma [HCO3] by about 1 mmol/L (>24) for each 10 mm Hg acute increment in PaCO2 (>40) (12):

Clinical Features and Systemic Effects of Acute Respiratory Acidosis

The acute onset of hypercapnia is invariably accompanied by hypoxemia, which usually dominates the clinical picture. Depending on the underlying disorder and the state of consciousness, the patient may present with the signs and symptoms of acute respiratory distress, including marked restlessness, tachypnea, and marked dyspnea. As the process worsens, stupor and eventually coma develop. CO2 has vasodilating properties, and thus hypercapnia is associated with increased cerebral blood flow (13, 14). This increase in blood flow to the brain probably accounts for the headaches and occasional signs of increased intracranial pressure that can occur with both acute and chronic hypercapnia (15, 16). Severe acute respiratory acidosis can cause refractory hypotension through two mechanisms (17). First, cardiac contractility is reduced and cardiac output falls. Second, peripheral arterial smooth muscle relaxes, causing vasodilation and decreased systemic vascular resistance. Modest acute increases in PaCO2 (13-19 mm Hg) actually increase cardiac output as well as pulmonary artery pressure (18).

In intensive care units, hypoventilation is frequently induced in patients with severe lung injury and acute respiratory distress syndrome (ARDS). This strategy was shown to reduce mortality and ventilator time in the ARDSNet trial (19). Although the difference in PaCO2 was not large (5 mm Hg), this trial did suggest that the benefits of low tidal volume ventilation outweigh the risks of mild acute hypercapnia. It should be noted that many patients in the trial were treated with bicarbonate therapy to minimize the fall in blood pH.

Laboratory Findings in Acute Respiratory Acidosis

With acute respiratory acidosis, the arterial blood reflects the pathophysiologic state with an elevated PCO2, a moderately elevated plasma [HCO3] (<30 mmol/L), and a low pH. If the patient is breathing room air, then the PaO2 is decreased. The venous serum electrolytes reveal a modestly elevated total CO2 content, with usually normal plasma concentrations of sodium, potassium, and chloride.

Causes of Acute Respiratory Acidosis

Some of the causes of acute respiratory failure, which leads to acute CO2 retention, are listed in Table 4-1.

Treatment of Acute Respiratory Acidosis

The key to treatment of acute respiratory acidosis is the restoration of effective ventilation. Modest amounts of sodium bicarbonate (NaHCO3) may be given intravenously to mitigate severe acidosis; the latter is only
a holding measure to prevent the serious cardiovascular effects of marked acidemia until definitive therapy is established (20). Because equilibration of HCO3 across the blood-brain barrier is markedly slower than that of CO2 with bicarbonate administration, a delay in the correction of the cerebral pH may occur, and cerebrospinal fluid pH falls initially (21).

Table 4-1 Causes of Acute Respiratory Acidosis

Neuromuscular Abnormalities

Brainstem injury

High cord injury

Guillain-Barré syndrome

Myasthenia gravis


Narcotic, sedative, or tranquilizer overdose

Status epilepticus

Postoperative hyponatremia with herniation

Airway Obstruction

Foreign body

Aspiration of vomitus

Laryngeal edema

Severe bronchospasm

Thoracic-Pulmonary Disorders

Flail chest


Severe pneumonia

Smoke inhalation

Severe pulmonary edema

Vascular Disease

Massive pulmonary embolism

Respirator-Controlled Ventilation

Low rate and/or tidal volume

Large dead space

Total parenteral nutrition (increased CO2 production)


Chronic respiratory acidosis is caused by chronic decreased effective alveolar ventilation with a primary elevation of the PaCO2. The duration of the elevation of PaCO2 must be sufficient to permit adaptation of the renal mechanisms to be maximized. In dogs, a new steady state of blood acid-base values occurs 5 days after the onset of hypercapnia (11). The exact time interval needed to establish “chronic” hypercapnia in humans has not been established. A quantitative relationship has been described between the steady-state PaCO2 and the H+ concentration in patients with chronic hypercapnia. This relationship is linear and is described by a slope of about 0.25 nmol of H+ per 1 mm Hg increase in PaCO2 (22, 23). A clinical guide for bedside use expresses the relationship between PaCO2 and plasma [HCO3] in chronic hypercapnia as follows: For each increment of 10 mm Hg in PaCO2, the plasma [HCO3] rises by 4 mmol/L, with a range of 4 mmol/L in either direction. The following formula summarizes this rule of thumb:

Clinical Features and Systemic Effects of Chronic Respiratory Acidosis

Patients with chronic respiratory acidosis exhibit few, if any, signs or symptoms related directly to CO2 retention and acidosis. However, papilledema and other neurologic disturbances have been described in several patients (22, 23). These findings are not caused by the hypercapnia per se nor by the pH changes that mediate cerebral vascular reactivity through intracellular calcium. Rather, secondary changes in catecholamines are the likely causes (13). The signs and symptoms of the chronic pulmonary disease, with or without cor pulmonale, usually predominate. Chronic respiratory acidosis causes decreased bone mineralization, although to a lesser degree than does metabolic acidosis (24, 25, 26). This effect does not appear to be mediated by altered function of bone osteoclasts or osteoblasts and is not accompanied by hypercalciuria (27, 28).

Laboratory Findings in Chronic Respiratory Acidosis

Arterial blood examination reveals a low pH (not <7.25 even with severe chronic CO2 retention), an elevated PaCO2, and an elevated plasma [HCO3]. Thus, a blood pH <7.25 is a marker of imposed acute hypercapnia or metabolic acidosis. Plasma sodium and potassium concentrations are usually normal. Total plasma CO2 content is elevated, and plasma chloride concentration is reciprocally decreased. The anion gap is usually normal (22). In the absence of diuretic use or vomiting, these serum electrolyte findings should lead the clinician to check arterial blood gas values. The urine pH is usually acid.

Causes of Chronic Respiratory Acidosis

Chronic respiratory acidosis is seen most commonly in patients with chronic obstructive pulmonary disease (COPD). However, any condition that can lead to chronic retention of CO2 (27) will cause the same acid-base disturbance. Examples of such conditions are given in Table 4-2.

The epidemic of obesity has led to an increased prevalence of the obesity hypoventilation syndrome (OHS). Patients with OHS exhibit hypercapnia while awake (PaCO2 > 45 mm Hg), obesity (BMI > 30 kg/m2), and absence of alternative causes of hypoventilation. Most patients with OHS have sleep-disordered breathing and obstructive sleep apnea. The hypoventilation may be secondary to altered respiratory muscle mechanics and decreased ventilator drive (29, 30). Patients with OHS commonly develop hypoxemia, pulmonary hypertension, and signs of right-sided congestive heart failure. In patients with nocturnal hypercapnia due to sleep apnea but daytime normocapnia, metabolic alkalosis may actually develop. Nocturnal hypercapnia can lead to renal generation of bicarbonate. People on low-salt diets (low chloride) are unable to excrete this bicarbonate and thus develop posthypercapnic metabolic alkalosis.

Table 4-2 Causes of Chronic Respiratory Acidosis

Neuromuscular Abnormalities

Chronic narcotic or sedative ingestion

Primary hypoventilation

Pickwickian syndrome


Diaphragmatic paralysis


Sleep apnea syndrome

Thoracic-Pulmonary Disorders

Chronic obstructive pulmonary disease


End-stage interstitial pulmonary disease

Treatment of Chronic Respiratory Disease

Chronic respiratory acidosis can be corrected effectively only by restoring or improving the ability of the respiratory system to excrete CO2. Often, this is impossible because of an irreversible pathologic condition. However, adequate airway drainage, relief of bronchospasm, and treatment of pulmonary infections and congestive heart failure may lead to significant improvement. Because the arterial pH remains >7.25 even with chronic PaCO2 elevations to 110 mm Hg (31), the acidosis per se is not dangerous, although the patient is at more risk for serious acidemia if metabolic acidosis occurs. Attention to the maintenance of adequate O2 tension (PO2) is the critical need.

People with end-stage renal disease (ESRD) who also have COPD or another cause of chronic hypercapnia are unable to generate the usual amounts of bicarbonate for compensation in chronic respiratory acidosis. Thus, they may benefit from dialysis using a higher bicarbonate dialysate.


When a patient in a steady state of chronic hypercapnia suffers a new insult to his or her ability to excrete CO2, the PaCO2 rises acutely to a new level. Thus, the plasma [HCO3] and blood pH are lower than predicted for a given chronic level of PaCO2. However, the change in pH is not as great as would be expected for a similar acute increment in PaCO2 occurring in a previously normal person. That is, the pH is better protected against an acute rise in PaCO2 when there is a background of chronic respiratory acidosis than it is with acute respiratory acidosis alone (32, 33). The mechanism for this is not entirely clear but has been attributed partially to the physicochemical effect of the preexisting higher [HCO3], which would reduce the fall in pH compared with that seen for a similar increment in PaCO2 in a patient with a normal [HCO3]. In addition, the kidney rapidly increases H+ excretion when an acute rise in PCO2 is superimposed on chronic respiratory acidosis. This is in contrast to acute respiratory acidosis alone, in which renal acid excretion makes little quantitative contribution to H+ balance. Treatment is directed toward correcting the acute disorder and providing supplemental O2.

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Nov 17, 2018 | Posted by in NEPHROLOGY | Comments Off on Pathophysiology and Management of Respiratory and Mixed Acid-Base Disorders
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