Acid-base imbalance, Abnormal blood pH

Table I.

Disorder	Arterial pH	SBE (mEq/L)	pCO2 (mmHg)	HCO3 (mmol/L)
Metabolic acidosis	< 7.35	</= -5	40 + SBE	</= 20
Metabolic alkalossis	> 7.45	>/= 5	40 + (0.6 x SBE)	>/= 20
Respirtatory acidosisAcuteChronic	< 7.35	0 +/- 40.4 x pCO2 – 40	>45>45	= [(pCO2 -40)/10] +24= [(pCO2 -40)/3] +24
Respiratory akalosisAcute Chronic	> 7.45	0 +/- 40.4 x pCO2 – 40	<35<35	= 24 – [(40-pCO2)/5]= 24 – [(40-pCO2)/2]

Definitions:

Acidemia: Arterial blood pH < 7.35

Alkalemia: Arterial blood pH > 7.45

Acidosis: A physiologic process leading to acidemia

Alkalosis: A physiologic process leading to alkalemi.

Respiratory: The primary disorder results from an abnormal pCO₂ –increased = acidosis; decreased = alkalosis

Metabolic: The primary disorder does not result from abnormal pCO₂

Mixed (Complex): More than one disorder is present

Compensation: Changes in pCO₂ or strong ions (Na+,Cl- ) resulting from normal physiologic mechanisms to restore acid-base balance

Standard base excess (SBE): Quantity of metabolic acid-base disturbance where a positive value indicates alkalosis and a negative value (also referred to as a base deficit) indicates an acidosis

Strong ion difference: The difference in charge between “strong” (completely dissociated) cations (positive) and anions (negative). (See pathophysiology section.)

Anion gap: The difference in charge between commonly measured electrolytes (See laboratory findings section.)

Acid-base disorders result from:

Increased intake

Acidosis: chloride administration (e.g. saline), aspirin overdose

Alkalosis: NaHCO₃ administration, antacid abuse, buffered replacement fluid (hemofiltration)

Altered production

Increased acid production: lactic acidosis, diabetic ketoacidosis

Altered excretion

Hypercapnic respiratory failure, permissive hypercapnia

Alkalosis: vomiting, large gastric aspirates, diuretics, hyperaldosteronism, corticosteroids

Acidosis: diarrhea, small bowel fistula, urethroenterostomy, renal tubular acidosis, renal failure, distal renal tubular acidosis, acetazolamide

Approach to diagnosis

Alterations in acid-base balance produce characteristic patterns in arterial blood gases and plasma electrolytes. These changes can be used to make the diagnosis of respiratory, metabolic or “complex” disorders (Table I).

Acidosis is associated with a decreased arterial plasma pH (<7.35) whereas alkalosis is associated with an increased arterial plasma pH (>7.45).

Alterations not conforming to (within 2-3 units) the patterns described in Table I represent either laboratory error or complex (mixed) disorders.

Laboratory error is best assessed by repeating the measurements.

An acid-base disorder that fails to conform to the patterns shown in Table I is by definition a mixed (complex) disorder; see below.

Clinical features

The clinical features of acid-base disorders vary by the type of disorder and according to the underlying disease process.

They also can be due to efforts of the body to compensate for the primary acid-base disorder. For example, metabolic acidosis will induce hyperventilation to reduce the pCO₂ in order to compensate. Conversely, metabolic alkalosis will induce hypoventilation.

Laboratory findings suggestive of acid-base disorders include the following:

Serum bicarbonate concentration < 20 or > 28 mmol/L.

Standard base excess < -4 or > 4 mEq/L

Anion gap (Na + K – Cl – HCO₃) > 12 mEq/L

Corrected anion gap (cAG) = AG – (2 x Albumin) – (0.5 x Phosphate) [albumin in g/dl and phosphate in mg/dl]

Normal cAG = 0 +/- 5 mEq/L

Key management points

1. Life support. Critical illness may manifest as acid-base abnormalities. These underlying conditions must be treated promptly.

• respiratory failure: respiratory acidosis

• circulatory shock: lactic acidosis

2. Make a specific diagnosis. Acid-base orders are signs of underlying disease. Important patterns not to miss include:

• Respiratory acidosis without evidence of lung disease: opioid overdose

• Respiratory alkalosis with metabolic acidosis: sepsis, salycilate toxicity

• Unexplained increased anion gap: sepsis, ketosis, poisoning

3. Treat the underlying cause (see specific chapters: metabolic acidosis, metabolic alkalosis, respiratory acidosis, respiratory alkalosis).

4. Specific therapy for acid-base disorders (e.g., buffer therapy) should be reserved for severe and/or persistent disorders.

2. Emergency Management

General management principles

Correct (where possible) the underlying cause:

• NaCl solution infusion for vomiting-induced alkalosis

• Insulin, Na+ and K+ in diabetic ketoacidosis

Correct pH in specific circumstances only (e.g., NaHCO₃ in renal failure)

Facilitate normal physiology; for example, provide ventilatory support for patients who have respiratory acidosis or who are failing to compensate for metabolic acidosis.

A particularly dangerous situation is when a patient with metabolic acidosis is compensating by hyperventilation and then develops respiratory muscle fatigue leading to respiratory failure. Combined respiratory and metabolic acidosis can be rapidly fatal and should be treated promptly with mechanical ventilatory support.

Avoid large-volume saline-based fluids. Consider lacted Ringer’s solution or hetastarch in balanced electrolyte solution (Hextend) for fluid resuscitation.

Several underlying diseases can cause acid-base derangements, many of which can life-threatening –every effort should be made to make a specific diagnosis as quickly as possible.

Management with renal replacement therapy (RRT)

Acid-base abnormalities may be caused by improper use of RRT (e.g., during citrate anticoagulation) and are amenable to correction with RRT.

Correction of plasma pH occurs because of change in plasma strong ion difference and, to a small extent, change in weak acid concentration.

Avoid overcorrection of acid-base abnormalities, particularly in cases of metabolizable acid anions (e.g., lactate, ketones) (see “metabolic acidosis”).

3. Diagnosis

Establishing the diagnosis

First, characterize the disorder (see Table I).

Second, confirm that a mixed disorder does not exist (see below).

Third, make a specific diagnosis.

Metabolic acidosis

A reduced arterial blood pH with a reduced strong ion difference and a base deficit >2mEq/l.

Outcome in critically ill patients has been linked to the severity and duration of metabolic acidosis and hyperlactatemia.

Differential diagnosis

Step 1: Calculate the corrected anion gap

AG = (Na + K) – (Cl + HCO₃)

cAG = AG – (2 x Albumin) – (0.5 x Phosphate) [albumin in g/dl and phosphate in mg/dl]

Normal cAG = 0 +/- 5 mEq/L

Causes of metabolic acidosis with increased anion gap

Lactic acidosis. Can be due to tissue hypoperfusion (e.g., circulatory shock). The anion gap (or strong ion gap) is increased with lactic, and other organic acids, and poisons. Anaerobic metabolism contributes in part to this metabolic acidosis, but other cellular mechanisms are involved and may be more important. May be seen with increased muscle activity (e.g., post-seizure, respiratory distress). Lung lactate release seen in acute lung injury. High sustained levels suggest tissue necrosis (e.g., bowel, muscle).

Ketoacidosis: high levels of beta-hydroxybutyrate and acetoacetate related to uncontrolled diabetes mellitus, starvation and alcoholism.

Renal failure: accumulation of organic acids (e.g., sulfuric).

Drugs: in particular, aspirin (salicylic acid) overdose, acetazolamide (carbonic anhydrase inhibition), ammonium chloride. Vasopressor agents may be implicated, possibly by inducing regional ischemia or, in the case of epinephrine, accelerated glycolysis.

Ingestion of poisons (e.g., paraldehyde, ethylene glycol, methanol).

Causes of metabolic acidosis without increased anion gap

• Hyperchloremia (e.g. excessive saline infusion).

• Cation loss (e.g. severe diarrhea, small bowel fistulae, large ileostomy losses).

Acute renal failure causes metabolic acidosis that is often mixed (increased anion gap and hyperchloremic; see below).

Step 2. Compare the standard base excess (SBE) to the cAG

The magnitude of a metabolic acid-base disturbance is quantified by the SBE while the amount of unmeasured anions is quantified by the cAG (or more accurately by the strong ion gap; see below). Thus it is possible to not only determine if a metabolic acid-base disorder exists but whether its magnitude can be explained by known or unknown acids. For example, if the SBE is -10 and the cAG is 10 mEq/L it is possible to say that 100% of the disturbance is due to unmeasured anions. By contrast, if the SBE were -16 and cAG were 8, only 50% of the acidosis would attributable to unmeasured anions and the rest to hyperchloremic acidosis.

Furthermore, lactic acid is a monovalent (single charge) ion, so that 1 mmol = 1 mEq. Thus, lactate will decrease the SBE and increase the AG by exactly 1 mEq/L for every mmol/L concentration. In a patient with SBE of -30 and 10 mmol/L of lactate, there would still be 20 mEq/L of unexplained acid. The cAG may also exceed the SBE. This may occur when there is an underlying metabolic alkalosis and pseudocorrection with acidosis (see mixed disorders below) or when the salt of an unmeasured anion is added (e.g. sodium lactate) in large quantities.

Metabolic alkalosis

An increased arterial blood pH with an increased strong ion difference and base excess >2 mEq/l caused either by loss of anions or gain of cations.

As the kidney is usually efficient at regulating the strong ion difference, persistence of a metabolic alkalosis usually depends on either renal impairment or a diminished extracellular fluid volume with severe depletion of K+ resulting in an inability to reabsorb Cl- in excess of Na+.

• The patient is usually asymptomatic though, if spontaneously breathing, will hypoventilate.

• A metabolic alkalosis will cause a left shift of the oxyhemoglobin curve, reducing oxygen availability to the tissues.

• If severe (pH > 7.6), may result in encephalopathy, seizures, altered coronary arterial blood flow and decreased cardiac inotropy.

Causes

Loss of total body fluid, Cl-, usually due to:

• diuretics

• large nasogastric aspirates, vomiting

• Secondary hyperaldosteronism with KCl depletion

• Use of hemofiltration replacement fluid containing excess buffer (e.g., lactate)

• Renal compensation for chronic hypercapnia. This can develop within 1–2 weeks. Although more apparent when the patient hyperventilates, or is hyperventilated to normocapnia, an overcompensated metabolic alkalosis can occasionally be seen in the chronic state (i.e., a raised pH in an otherwise stable long-term hypercapnic patient)

• Excess administration of sodium bicarbonate

• Excess administration of sodium citrate (large blood transfusion)

• Drugs, including laxative abuse, corticosteroids

• Rarely, Cushing’s, Conn’s, Bartter’s syndrome

Respiratory acidosis

Excess CO₂ production and/or inadequate excretion

Causes

• Central hypoventilation (e.g., decreased mental status, excess narcotic)

• Chronic obstructive lung disease, acute exacerbation

• Acute lung disease

• VQ mismatch (e.g., pulmonary embolism)

• Increased CO₂ production with fixed ventilation (e.g., fever, shivering, seizures).

Respiratory alkalosis

Reduction in pCO₂ due to increased ventilation relative to production

Causes

• hyperventilation with normal lungs (e.g., anxiety, salicylate intoxication)

• hyperventilation due to hypoxemia (e.g., asthma exacerbation)

• decreased CO₂ production with fixed ventilation (e.g., hypothermia, chemical paralysis on mechanical ventilation)

Once the acid-base disorder has been characterized (metabolic acidosis, metabolic alkalosis, respiratory acidosis, respiratory alkalosis, mixed acid-base disorders) the specific workup will be determined by the type of disorder and the history and physical exam.

Simple disorders will conform to the patterns shown in Table I.

Approach to mixed disorders: The first clue that a mixed disorder is present is that the abnormality does not conform to the patterns shown in Table I.

For example, a metabolic acidosis with a base excess of -10 should result in a pCO₂ of ~30 mmHg (40 – 10 = 30). Allowing for some variance related to measurement error, if the pCO₂>34 or < 26 a secondary (respiratory) disorder would be present (acidosis or alkalosis respectively). Similarly, in the case of chronic respiratory acidosis with a pCO₂ of 60, the SBE should 0.4 x (60 – 40) = 5 mEq/L. A SBE < 2 or > 8 would indicate a secondary (metabolic) disorder.

Once mixed respiratory and metabolic disorders have been excluded the next step is to examine the SBE and the cAG (or SIG). As discribed above, the SBE will reflect the total (net) acid-base disorder due to changes in (a) measured ions (e.g., Na+, Cl-) and (b) unmeasured ions (ketones, sulfate). Ions like lactate can be measured easily and their concentration included in the analysis. For example, a lactate of 5 mmol/L will result in a SBE of -5 assuming no other abnormalities. If the SBE was < -8 a secondary metabolic acidosis would be present. This condition could be explained by measured (e.g., Cl-) or unmeasured (e.g. ketones) ions.

Conversely, if a patient has evidence of acidosis (increased lactate or anion gap) and an SBE that is not consistent, there may be an underlying alkalosis. For example, a patient with an SBE of -5 and a lactate of 10 mmol/L either has a underlying metabolic alkalosis with a superimposed lactic acidosis or has received large quantities of sodium lactate. The latter will result in hyperlactatemia but the acidosis will be mild because lactic acid was not infused but rather the sodium salt.

Note that rarely a persistent metabolic acidosis (e.g., high lactate secondary to a metabolic defect) will result in a “compensatory” hypochloremic metabolic alkalosis as the body attempts to compensate for the persistent acidosis.

Examples of mixed disorders:

1. pH 7.25, SBE -15, PCO₂ 26, cAG 10, Lactate 5

This patient has triple metabolic acidosis: lactic, unmeasured anion, hyperchloremic, each contributing exactly a third of the total abnormality

2. pH 7.35, SBE -4, PCO₂ 38, cAG 10, Lactate 5

This patient also has a triple acid-base disorder: lactic acidosis, unmeasured anions, and an underlying metabolic alkalosis. The latter can be identified by the SBE -4 as opposed to -10 that should result from the unbalanced anions (5 lactate and 5 other anions leading to a cAG of 10 mEq/L).

Confirmatory tests

Laboratory findings suggestive of acid-base disorders include the following:

Serum bicarbonate concentration < 22 or > 26 mmol/L.

Standard base excess < -3 or > 3 mEq/L

Anion gap (Na + K – Cl – HCO₃) > 12 mEq/L

Corrected anion gap (cAG) = AG – (2 x Albumin) – (0.5 x Phosphate) [albumin in g/dl and phosphate in mg/dl]

Normal cAG = 0 +/- 5 mEq/L

The anion gap and the strong ion gap

For more than 30 years, the anion gap has been used by clinicians, and it has evolved into a major tool to evaluate acid-base disorders. The anion gap is estimated from the differences between the routinely measured concentrations of serum cations (Na+ and K+) and anions (Cl- and HCO₃-). Normally, this difference, or “gap,” is made up by albumin, and, to a lesser extent, by phosphate. Sulfate and lactate also contribute a small amount, normally <2 mEq/L. However, there are also unmeasured cations, such as Ca++ and Mg++, and these tend to offset the effects of sulfate and lactate, except when the concentration of sulfate or lactate is abnormally increased. Plasma proteins other than albumin can be positively or negatively charged, but in the aggregate tend to be neutral, except in rare cases of abnormal paraproteins, such as in cases of multiple myeloma. In practice, the anion gap (AG) is calculated as follows:

AG = (Na+ + K+) – (Cl- + HCO₃-)

Because of its low and narrow extracellular concentration range, K+ is often omitted from the calculation. The normal value for anion gap is 12 ± 4 (if K+ is considered) or 8 ± 4 mEq/L (if K+ is not considered). The normal range has decreased in recent years following the introduction of more accurate methods for measuring Cl- concentration. However, the various measurement techniques available mandate that each institution reports its own expected “normal anion gap.”

The anion gap is useful because this parameter can limit the differential diagnosis for patients with metabolic acidosis. If the anion gap is increased, the explanation almost invariably will be found among five disorders: ketosis, lactic acidosis, poisoning, renal failure, or sepsis. However, several conditions can alter the accuracy of anion gap estimation, and these conditions are particularly prevalent among patients with critical illness. Dehydration can widen the apparent anion gap by increasing the concentration of all the ions used for the calculation. Hypoalbuminemia decreases the anion gap and it has been recommended to “correct” the anion gap for changes in albumin concentration, because for every 1-g/dL decrease in serum albumin concentration, the apparent anion gap narrows by 2.5 to 3 mEq/L. Respiratory and metabolic alkaloses are associated with an increase of up to 3 to 10 mEq/L in the apparent anion gap. The basis for this effect is enhanced lactate production (from stimulated phosphofructokinase enzymatic activity), reduction in the concentration of ionized weak acids (A-), and, possibly, the additional effect of dehydration.

Other factors that can increase the anion gap are low Mg++ concentration and administration of the sodium salts of poorly reabsorbable anions (such as beta-lactam antibiotics). Certain parenteral nutrition formulations, such as those containing acetate, can increase the anion gap. Citrate-based anticoagulants rarely can have the same effect after administration of multiple blood transfusions. None of these rare causes, however, increases the anion gap significantly, and they are usually easily identified. In recent years, some additional causes of an increased anion gap have been reported. It is sometimes widened in patients with non-ketotic hyperosmolar states induced by diabetes mellitus; the biochemical basis for this effect remains unexplained. In recent years, unmeasured anions have been reported in the blood of patients with sepsis and liver disease and in experimental animals injected with endotoxin. These anions may be the source of much of the unexplained acidosis seen in patients with critical illness.

Additional doubt has been cast on the diagnostic value of the anion gap in certain situations, however. Salem and Mujais found routine reliance on the anion gap to be “fraught with numerous pitfalls.” The primary problem with the anion gap is its reliance on the use of a “normal” range that depends on normal circulating levels of albumin and to a lesser extent phosphate, as discussed earlier. Plasma concentrations of albumin or phosphate are often grossly abnormal in patients with critical illness, leading to changes in the “normal” range for the anion gap. Moreover, because these anions are not strong anions, their charge is affected by pH. These considerations have prompted some authors to adjust the “normal range” for the anion gap according to the albumin concentration or phosphate concentration. Each g/dL of albumin has a charge of 2.8 mEq/L at pH 7.4 (2.3 mEq/L at pH 7.0 and 3.0 mEq/L at pH 7.6). Each mg/dL of phosphate has a charge of 0.59 mEq/L at pH 7.4 (0.55 mEq/L at pH 7.0 and 0.61 mEq/L at pH 7.6). Thus, the “normal” anion gap can be estimated using this formula:

“normal” anion gap = 2 × [albumin] (g/dL) + 0.5 × [phosphate] (mg/dL)

Or for international units:

“normal” anion gap = 0.2 × [albumin] (g/L) + 1.5 × [phosphate] (mmol/L)

These formulas should be used only when the pH is less than 7.35, and even then they are only accurate within 5 mEq/L. When more accuracy is needed, a slightly more complicated method of estimating [A-] is required.

Another alternative to using the traditional anion gap is to use the strong ion difference. By definition, the strong ion difference must be equal and opposite to the negative charges contributed by [A-] and total CO₂. The sum of the charges from [A-] and total CO₂ concentration has been termed strong ion difference effective. The apparent strong ion difference is obtained by measurement of each individual ion. Both the apparent strong ion difference and the strong ion difference effective should equal the true strong ion difference. If the apparent strong ion difference and strong ion difference effective differ, unmeasured ions must exist. If the apparent strong ion difference is greater than the strong ion difference effective, these ions are anions, and if the apparent strong ion difference is less than strong ion difference effective, the unmeasured ions are cations. This difference has been termed the strong ion gap to distinguish it from the anion gap. Unlike the anion gap, the strong ion gap is normally zero and does not change with changes in pH or albumin concentration.

Pathophysiology

General Concepts

There are three widely accepted methods to analyze and classify acid-base disorders, yielding mutually compatible results. The approaches differ only in assessment of the metabolic component (i.e., all three treat PCO₂ as an independent variable): (1) HCO₃– concentration ([HCO₃-]); (2) standard base-excess; (3) strong ion difference. All three yield virtually identical results when used to quantify the acid-base status of a given blood sample. For the most part, the differences among these three approaches are conceptual; in other words, they differ in how they approach the understanding of mechanism.

There are three mathematically independent determinants of blood pH:

1. The difference between the sum of the concentrations of strong cations (e.g., Na+ and K+) and the sum of the concentrations of strong anions (e.g., Cl-, lactate); this difference is called the strong ion difference.

2. The total weak acid “buffers” concentration (ATOT), which is mostly composed of the concentrations of albumin and phosphate.

3. PCO₂.

Only these three variables (strong ion difference, ATOT, and PCO₂) can independently affect blood pH. [H+] and [HCO₃-] are dependent variables, being functions of strong ion difference, ATOT, and PCO₂. Changes in plasma [H+] result from dissociation of ATOT and ossibly, water itself. The standard base-excess is mathematically equivalent to the change in strong ion difference required to restore pH to 7.4 given a PCO₂ of 40 mm Hg and the prevailing ATOT. Thus, a standard base-excess of -10 mEq/L means that the strong ion difference is 10 mEq/L less than the strong ion difference that is associated with a pH of 7.4 when PCO₂ is 40 mm Hg.

Acid-base homeostasis is defined by the pH of blood plasma and by the conditions of the acid-base pairs that determine it. Because blood plasma is an aqueous solution containing both volatile (carbon dioxide) and fixed acids, its pH will be determined by the net effects of all these components. The determinants of blood pH can be grouped into two broad categories, respiratory and metabolic. Respiratory acid-base disorders are disorders of carbon dioxide (CO₂) tension, and metabolic acid-base disorders comprise all other conditions affecting the pH. This latter category includes disorders of both weak acids (often referred to as “buffers,” although the term is imprecise) and strong acids and bases (including both organic and inorganic acids). Acid-base disorders can be recognized by any of the following:

1. An alteration in the pH of the arterial blood (normally 7.35 to 7.45).

2. An arterial partial pressure of CO₂ (PaCO₂) outside the normal range (35 to 45 mm Hg).

3. A plasma bicarbonate concentration outside the normal range (22-26 mEq/L).

4. An arterial standard base-excess of >3 or < -3 mEq/L.

Although these criteria are useful in identifying an acid-base disorder, the absence of all four cannot exclude a mixed acid-base disorder, i.e., alkalosis and acidosis, which are completely matched. Fortunately, such conditions are quite rare.

Metabolic acid-base derangements are associated with a greater number of underlying conditions than are respiratory acid-base disorders and tend to be more difficult to treat. Metabolic acidosis is produced by a decrease in the strong ion difference, which, in turn, generates an electrochemical force that increases [H+]. The strong ion difference decreases when the concentration of organic anions (e.g., lactate or β-hydroxybutyrate) increases. The strong ion difference also decreases when there is a loss of sodium bicarbonate (e.g., due to diarrhea or renal tubular acidosis) or there is a gain of exogenous anions (e.g., iatrogenic acidosis or poisonings). Metabolic alkaloses occur when the strong ion difference is inappropriately wide, although it need not be greater than the “normal” 40 to 42 mEq/L. Widening of the strong ion difference can be brought about by the loss of strong anions in excess of strong cations (e.g., vomiting, diuretics), or, rarely, by administration of strong cations in excess of strong anions (e.g., transfusion of large volumes of banked blood containing sodium citrate).

Similarly, the treatment of metabolic acid-base disorders requires a change in the strong ion difference. Metabolic acidoses are repaired by increasing plasma Na+ concentration more than plasma Cl- concentration (e.g., by infusing NaHCO₃) and metabolic alkaloses are repaired by replacing Cl- as NaCl (large volumes), KCl, or even HCl. Note that so-called “chloride-resistant” metabolic alkaloses are resistant to chloride only because of ongoing renal losses that increase in response to increased Cl- replacement (e.g., hyperaldosteronism).

Pathophysiology of metabolic acid-base disorders

Disorders of metabolic acid-base balance occur as a result of

• Dysfunction of the primary regulating organs.

• Exogenous administration of drugs or fluids that alter the body’s ability to maintain normal acid-base balance.

• Abnormal metabolism that overwhelms the normal defense mechanisms.

The organs responsible for regulating the strong ion difference in both health and disease are the kidneys and, to a lesser extent, the gastrointestinal tract.

Pathophysiology of respiratory acid-base disorders

Normal CO₂ production by the body (about 220 mL/min) is equivalent to 15,000 mM/day of carbonic acid. This amount compares to less than 500 mM/day for all nonrespiratory acids that are handled by the kidney and gut. Pulmonary ventilation is adjusted by the respiratory center in response to changes in PCO₂, blood pH, and PO₂ as well as other factors (e.g., exercise, anxiety, wakefulness). Normal PCO₂ (40 mm Hg) is maintained by precise matching of alveolar minute ventilation to metabolic CO₂ production. PCO₂ changes in compensation for alterations in arterial pH produced by metabolic acidosis or alkalosis in predictable ways (see Table I).

Organ-based physiology and acid-base disorders

Lungs

Normal CO₂ production by the body (about 220 mL/min) is equivalent to 15,000 mM/day of carbonic acid. This amount compares to less than 500 mM/day for all nonrespiratory acids that are handled by the kidney and gut. Pulmonary ventilation is adjusted by the respiratory center in response to changes in PaCO₂, blood pH, and PaO₂ as well as other factors (e.g., exercise, anxiety, wakefulness). Normal PaCO₂ (40 mm Hg) is maintained by precise matching of alveolar minute ventilation to metabolic CO₂ production. PaCO₂ changes in compensation for alterations in arterial pH produced by metabolic acidosis or alkalosis in predictable ways (see Table I)

Kidneys

Normal plasma flow to the kidneys is approximately 600 mL/min in adults. The glomeruli filter the plasma to yield about 120 mL/min of filtrate. Normally, more than 99% of the filtrate is reabsorbed and returned to the plasma. Thus, the kidney can only excrete a very small amount of strong ions into the urine each minute, and several minutes to hours are required to achieve a significant impact on the strong ion difference. The handling of strong ions by the kidney is extremely important, because every Cl- ion that is filtered but not reabsorbed decreases the strong ion difference. Accordingly, “acid handling” by the kidney is generally mediated through changes in Cl- balance. The purpose of renal ammoniagenesis is to allow the excretion of Cl- without Na+ or K+. Viewed this way, renal tubular acidosis can be regarded as an abnormality of Cl- handling rather than of H+ or HCO₃– handling.

Renal-hepatic interaction

Ammonium ion (NH₄+) is important to systemic acid-base balance but not because it stores H+ or has a direct action in the plasma (normal plasma NH₄+ concentration is <0.01 mEq/L). NH4₄ is important because it is “co-excreted” with Cl-. Of course, NH₄+ is not only produced in the kidney. Hepatic ammoniagenesis (and, as we shall see, glutaminogenesis) is also important for systemic acid-base balance and is tightly controlled by mechanisms sensitive to plasma pH. This reinterpretation of the role of NH₄+ in acid-base balance is supported by the evidence that hepatic glutaminogenesis is stimulated by acidosis. Glutamine is used by the kidney to generate NH₄+ and thus facilitates the excretion of Cl-. The production of glutamine, therefore, can be seen as having an alkalinizing effect on plasma pH because of the way the kidney utilizes it.

The gastrointestinal tract

Different parts of the gastrointestinal tract handle strong ions in distinct ways. In the stomach, Cl- is pumped out of the plasma and into the lumen, thereby reducing the strong ion difference and pH of gastric juice. The pumping action of the gastric parietal cells increases the strong ion difference of the plasma by promoting the loss of Cl-; this effect produces the so-called “alkaline tide” at the beginning of a meal when gastric acid secretion is maximal. In the duodenum, Cl- is reabsorbed and the plasma pH is restored. Normally, only slight changes in plasma pH are evident because Cl- is returned to the circulation almost as soon as it is removed.

However, if gastric secretions are removed from the patient, either through a suction catheter or as a result of vomiting, Cl- is lost and the strong ion difference increases. It is important to realize that it is the Cl- loss, not the H+ loss, that is the cause for widening of the strong ion difference and the development of metabolic alkalosis. Although H+ is “lost” as HCl, it is also lost with every molecule of water removed from the body.

In contrast to the stomach, the pancreas secretes fluid into the small intestine that has a strong ion difference much greater than that of plasma; the [Cl-] of pancreatic secretions is quite low. Thus, the strong ion difference in the plasma perfusing the pancreas decreases, a phenomenon that peaks about an hour after a meal and helps counteract the alkaline tide. If large amounts of pancreatic fluid are lost, for example from surgical drainage, acidosis develops as a consequence of the decreased plasma strong ion difference. Fluid in the lumen of the large intestine has a wide strong ion difference because most of the Cl- has been removed in the small intestine and the remaining electrolytes are mostly Na+ and K+ and HCO₃-. The body normally reabsorbs much of the water and electrolytes from this fluid, but when there is severe diarrhea, large amounts of this HCO₃– -rich and Cl- -poor fluid can be lost. If these losses are persistent, the plasma strong ion difference decreases and acidosis results. In addition, the small intestine may contribute strong ions to the plasma. This effect is most apparent when mesenteric blood flow is compromised and lactate is produced, sometimes in large quantities, by the tissues of the small intestine.

Epidemiology

Little is know about the epidemiology of acid-base disorders in the critically ill and injured. These conditions are common and probably under-recognized as clinicians do not always obtain arterial blood gas measurements or work up abnormalities when found. Acid-base disorders are associated with adverse clinical outcomes and certainly should be avoided when possible. Indications for active treatment of these disorders is more controversial.

Special considerations for nursing and allied health professionals.

N/A

What's the evidence?

Kellum, JA. “Disorders of acid-base balance”. Crit Care Med. vol. 35. 2007 Nov. pp. 2630-6.

Kellum, JA, Elbers, PWG. 2009.

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