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Metabolic Acidosis
c h a p t e r
3
Metabolic Acidosis: Clinical Approach
Introduction����������������������������������������������������������������������������������������� 60 Objectives��������������������������������������������������������������������������������������������� 60 Case 3-1: The truth will be told in the end������������������������������������� 61 Case 3-2: Stick to the facts����������������������������������������������������������������� 61 P A R T A CLINICAL APPROACH������������������������������������������������������������������� 62 Emergencies in the patient with metabolic acidosis������������������� 63 Risks prior to therapy������������������������������������������������������������������������� 64 Dangers to anticipate after commencing therapy���������������������������� 65 Assess the effectiveness of the bicarbonate buffer system�������� 67 Determine the basis of metabolic acidosis����������������������������������� 68 Detect addition of acids by finding new anions�������������������������������� 69 Detect conditions with fast addition of H+��������������������������������������� 69 Assess the renal response to metabolic acidosis����������������������������� 69
P A R T B Discussions����������������������������������������������������������������������������������� 70 Discussion of cases����������������������������������������������������������������������������� 70 Discussion of questions�������������������������������������������������������������������� 73
Introduction
In this chapter, our goal is to provide a bedside approach to the patient with metabolic acidosis. This approach focuses not only on diagnosis but also on identifying and handling emergencies while anticipating and preventing risks that are likely to develop during therapy. An important component of our approach is to deduce whether there is a risk of excessive binding of H+ to intracellular proteins in vital organs (e.g., the brain and the heart). We discuss how this may occur and how it can be reversed. OBJECTIVES n To emphasize the following issues in the approach to the patient with metabolic acidosis: 1. Treat emergencies first: The first step is to recognize and deal with threats to the patient’s life and to anticipate and prevent risks that may arise owing to therapy.
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2. Assess the effectiveness of the bicarbonate buffer system: The brachial or femoral venous Pco2 is needed to evaluate the effectiveness of the bicarbonate buffer system in skeletal muscle, where the bulk of this buffer system exists. When the bicarbonate buffer system is compromised, more H+ bind to proteins in cells of vital organs (e.g., brain and heart). n To illustrate how to determine whether the basis of the meta bolic acidosis is due to added acids and/or a deficit of sodium bicarbonate: Look for new anions in plasma and urine, and assess the rate of excretion of NH4+.
Case 3-1: The Truth Will Be Told in the End (Case discussed on page 70) A 25-year-old man was perfectly healthy until he developed diarrhea 24 hours ago (see margin note). He has had no intake of food or water and currently has no urine output. His blood pressure is 90/60 mm Hg, his pulse rate is 110 beats per minute, and his jugular venous pressure is low. Acid-base measurements in arterial blood reveal pH of 7.39, PHCO3 of 24 mmol/L, and Pco2 of 39 mm Hg. He has lost 5 L of diarrhea fluid, which contained Na+ 140 mmol/L, K+ 15 mmol/L, Cl− 115 mmol/L, and HCO3− 40 mmol/L. On admission, his hematocrit is 0.60, PAlbumin is 8.0 g/dL (80 g/L), and PK is 4.8 mmol/L.
This case is also presented in Chapter 2 with a different title; the points emphasized there are how the diagnostic tests should be interpreted. In this chapter, the major emphasis is to recognize current threats to the patient and anticipate those that may develop during therapy. A more detailed description of the biochemistry and pathophysiology of cholera is provided in Chapter 4, Part D, page 106.
Questions Is there a major threat to life on admission? What dangers might be created by therapy? Why is his PHCO3 24 mmol/L in the face of such a large loss of NaHCO3?
ABBREVIATION PAlbumin, [albumin] in plasma
Case 3-2: Stick to the Facts (Case discussed on page 71) A 28-year-old man had been sniffing glue on a chronic but intermittent basis. Over the past 3 days, he had become profoundly weak and had a very unsteady gait. On physical examination, his blood pressure was 100/60 mm Hg and his pulse rate was 110 beats per minute while lying flat. When he sat up, his blood pressure fell to 80/50 mm Hg and his pulse rate rose to 130 beats per minute. His arterial blood pH was 7.20, Pco2 was 25 mm Hg, and PHCO3 was 10 mmol/L. His PGlucose was 3.5 mmol/L (63 mg/dL), his PAlbumin was 6.0 g/dL (60 g/L), and his hematocrit was 0.50. VENOUS BLOOD pH Pco2 HCO3− Na+ K+ Cl− Creatinine BUN (urea) Osmolality
mm Hg mmol/L mmol/L mmol/L mmol/L mg/dL (μmol/L) mg/dL (mmol/L) mOsm/kg H2O
7.00 60 15 120 2.3 90 1.7 (150) 14 (5.0) 250
URINE 6.0 — <5 50 30 0 3.0 mmol/L 150 mmol/L 500
ABBREVIATION PGlucose, concentration of glucose in plasma
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Questions Is metabolic acidosis present? What dangers are present before therapy begins? What dangers might be created by therapy? What is the basis of the metabolic acidosis?
PART A
CLINICAL APPROACH • The first step in the approach to the patient with metabolic acidosis is to identify threats for that patient. • The next two steps are as follows: (1) Determine whether H+ were buffered appropriately by the bicarbonate buffer system. (2) Determine whether the basis of the metabolic acidosis is due to added acids and/or a deficit of NaHCO3. Our initial approach to the patient with metabolic acidosis is provided in Flow Chart 3-1. Metabolic acidosis must be present to enter this flow chart. This diagnosis is based on one of the following criteria: (1) a low plasma pH and PHCO3; (2) an increase in the anion gap in plasma (PAnion gap) corrected for the PAlbumin; or (3) an appreciable decrease in the content of HCO3− in the extracellular fluid (ECF) compartment in the patient who has a history suggesting that the ECF volume may be contracted. For the third criterion, a quantitative estimate of the ECF volume is needed. Because one
METABOLIC ACIDOSIS Is there a major threat for the patient?
YES
NO
Proceed to the right side after this evaluation
Before therapy • Hemodynamic emergency • Cardiac arrhythmia • Respiratory failure • Toxins • Metabolic/nutrition issues
Is buffering adequate by the BBS?
During therapy • Shift of K+ into cells • Pulmonary edema • Cerebral edema in DKA • Thiamin deficiency • Rapid correction of chronic hyponatremia
Ventilation • Assess with the arterial PCO2
In muscle • Assess with the brachial venous PCO2
FLOW CHART 3-1 Initial steps in the evaluation of the patient with metabolic acidosis. One must use a definition of metabolic acidosis that is based not only on the PHCO3 but also on the content of HCO3− in the ECF compartment if its volume is significantly contracted. The initial step is to determine threats for the patient that may be present and anticipate those that may develop during therapy (left side of the flow chart). The next step is to assess buffering by the bicarbonate buffer system (BBS) in the ECF and ICF of skeletal muscle to deduce whether more H+ are bound to brain proteins (right side of the flow chart). DKA, diabetic ketoacidosis.
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cannot obtain accurate quantitative data about the ECF volume with the physical examination, we recommend using the hematocrit or total protein level in plasma to obtain this information (see the discussion of Case 2-1, page 57). 1. Identify threats. The first step is to identify and deal with threats that are present before therapy begins and anticipate and prevent dangers that may develop during the course of the illness or with therapy. 2. Determine whether H+ are removed appropriately by HCO3−. After the emergencies are considered and dealt with, the arterial Pco2 and the brachial (or femoral) venous Pco2 should be assessed, as the latter helps reveal to the effectiveness of the bicarbonate buffer system in the ECF and ICF compartments in skeletal muscle. If the brachial venous Pco2 is high, the bicarbonate buffer system in skeletal muscle is compromised. Hence, more of the H+ load binds to intracellular proteins in vital organs (e.g., brain cells). If autoregulation of cerebral blood flow fails, more H+ will bind to intracellular proteins in the brain because of a marked decrease in the effective arterial blood volume.
EMERGENCIES IN THE PATIENT WITH METABOLIC ACIDOSIS Although it is common practice to begin the assessment of a patient with metabolic acidosis with an emphasis on diagnosis, we recommend a different approach for the critically ill patient with metabolic acidosis—begin with data that are most important to answer the question “How can I prevent this patient from dying?” The risks to the patient can be divided into those that are present when the patient seeks medical attention and those that may develop during therapy (Table 3-1). TABLE 3-1 THREATS TO LIFE ASSOCIATED WITH
METABOLIC ACIDOSIS
On admission • Hemodynamic instability • Marked decrease in myocardial contractility (e.g., cardiogenic shock) • Very low intravascular volume (e.g., NaCl loss, hemorrhage) • Decreased peripheral vascular resistance (e.g., sepsis) • Cardiac arrhythmia • Most frequently seen in patients with hyperkalemia or hypokalemia • Failure of ventilation (e.g., respiratory muscle weakness due to hypokalemia) • Presence of toxins (e.g., methanol, ethylene glycol) • Presence of reactive oxygen species (e.g., pyroglutamic acidosis) • Nutritional deficiency (especially B vitamins) During therapy • Development of cerebral edema during therapy of diabetic ketoacidosis in children • Overly rapid infusion of isotonic saline • Failure to prevent a fall in the effective plasma osmolality during therapy • Pulmonary edema (e.g., in patients with severe diarrhea if the ECF volume is expanded, but NaHCO3 is not given) • Too rapid a rise in PNa in patients with chronic hyponatremia • Development of a severe degree of acidemia in a patient with metabolic acidosis (see discussion of Case 3-1, page 70) • Acute shift of K+ into cells (e.g., administration of glucose to patients with hypokalemia, administration of insulin to patients with DKA and hypokalemia, administration of NaHCO3 to patients with a low PK) • Wernicke’s encephalopathy due to failure to give thiamin (vitamin B1) to chronic alcoholics with alcoholic ketoacidosis
Abbreviations ECF, extracellular fluid ICF, intracellular fluid
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The diagnostic category of metabolic acidosis is made up of two major subgroups, one where the basis of the disorder is the addition of acids and the other where the basis is a major loss of NaHCO3. Although the emergencies may be different within each of the causes for the disorder, nevertheless, we start this discussion by emphasizing the importance of detecting, anticipating, and dealing with threats to life. Risks prior to therapy Hemodynamic emergency • The most common example is a patient with l-lactic acidosis owing to cardiogenic shock (e.g., myocardial infarction) because survival at this point depends on whether the cardiac output can be improved very quickly. In most of the other settings of metabolic acidosis due to added acids, true hemodynamic emergencies are not common, with the possible exception of some patients with sepsis and others with alcoholic or diabetic ketoacidosis. Although a significant degree of contraction of the effective arterial blood volume is usually present in children with diabetic ketoacidosis (i.e., caused by the glucose-induced osmotic diuresis) a true hemodynamic emergency is usually not present. Hence, overly rapid and excessive administration of saline should be avoided because of the risk of inducing cerebral edema (see Chapter 5, page 128 for more discussion). Conversely, patients with a very significant degree of contraction of the effective arterial blood volume that causes an inadequate delivery of oxygen to tissues and the production of an appreciable quantity of l-lactic acid require the urgent administration of a large volume of isotonic saline. In contrast, if the patient is not hemodynamically compromised, aggressive therapy is not warranted because, at times, serious complications related to this infusion might arise (see the discussion of Case 3-1, page 70). Cardiac arrhythmia Patients with metabolic acidosis may develop a cardiac arrhythmia when there is a severe degree of hyperkalemia (e.g., owing to renal failure) or hypokalemia (e.g., certain patients with distal renal tubular acidosis, patients with metabolic acidosis due to glue sniffing). In addition, hypokalemia may develop after therapy is initiated (see Cases 3-1 and 3-2). The emergency treatment of hypokalemia and of hyperkalemia is discussed in Chapters 14 and 15. Failure of adequate ventilation Respiratory muscle weakness due to a severe degree of hypokalemia could lead to respiratory failure and a more severe degree of acidemia in patients with metabolic acidosis. Enough KCl should be given to raise the PK to 3.0 mmol/L in this setting; mechanical ventilation might also be needed. Toxin-induced metabolic acidosis Ingestion of methanol or ethylene glycol should always be suspected in a patient with metabolic acidosis, an elevated PAnion gap, and
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no obvious cause for these findings, especially if the ECF volume is not significantly contracted (see Chapter 6, page 178). Failing to make this diagnosis can be devastating. If ingestion of these alcohols is suspected, one must calculate the POsmolal gap (see Chapter 2, page 48). If the POsmolal gap is considerably greater than 10 mOsm/kg H2O, the diagnosis should be confirmed by direct measurements of methanol and of ethylene glycol in plasma because ethanol also contributes to the POsmolal gap. Because it is the products of the metabolism of these toxic alcohols that create the danger rather than the parent compounds, administer ethanol to prevent their metabolism until the facts become clear.
abbreviation POsmolal gap, osmolal gap in plasma
Dangers to anticipate after commencing therapy Several threats are anticipated in a patient with metabolic acidosis. Dangers related to overly aggressive administration of saline Although enough saline should be given if there is evident hemodynamic instability, an excessive rate of administration of saline has its dangers. In absence of hemodynamic instability, we use the brachial venous Pco2 and the hematocrit to guide decisions about intravenous fluid therapy (see margin note). If oliguria develops during therapy, a more vigorous restoration of intravascular volume may be needed. Several complications may arise from overly aggressive administration of saline. A very severe degree of acidemia. There is a fall in the PHCO3 when a large volume of saline without NaHCO3 is given to a patient who has a severe degree of ECF volume contraction (e.g., the patient with a large loss of NaHCO3 and saline in diarrhea fluid; see Case 3-1, page 70). When saline is infused very rapidly, some patients with metabolic acidosis caused by NaHCO3 loss due to diarrhea and a severe degree of contraction of the effective arterial blood volume develop pulmonary edema before their ECF volume is sufficiently reexpanded. This may be the result of the severe degree of acidemia that develops, which leads to the redistribution of blood from the peripheral to the central circulating blood volume. It is important to recognize this complication, because pulmonary edema can be prevented and/or treated successfully with an infusion of fluid that contains NaHCO3 (or an anion that can be metabolized to produce HCO3− [e.g., l-lactate−]). See the discussion of Case 3-1, page 70. Three mechanisms may lead to a more severe degree of acidemia with the infusion of a large amount of saline in these patients. 1. Dilution of the HCO3− in the ECF compartment: These patients have metabolic acidosis with a large deficit of HCO3− even though their PHCO3 might not be very low because of the marked degree of contraction of their ECF volume. Hence, the concentration of HCO3− in the ECF compartment declines when a large volume of saline is infused because of the rise in the denominator of the HCO3−:ECF volume ratio. 2. Loss of more NaHCO3 in diarrhea fluid: Reexpansion of the effective arterial blood volume increases splanchnic blood flow. This permits a much larger quantity of Na+ and Cl− to be secreted in the small intestine. When a large volume of luminal fluid containing Na+ and Cl− reaches the colon, more Cl− is reabsorbed in exchange for HCO3− compared with the absorption of Na+ in exchange for secreted H+; hence, the loss
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CAUTION The hematocrit on admission is not useful in patients who have anemia.
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of NaHCO3 in diarrhea fluid may rise markedly (see Fig. 4-4, page 82). 3. Back-titration of HCO3− by H+ that were bound to intracellular proteins: Assume that muscle cells have a constant consumption of oxygen and production of CO2. Now when the blood flow rate rises, the same amount of oxygen is consumed, but less oxygen is extracted from each liter of blood. Because almost the same amount of CO2 is produced as O2 consumed, less CO2 is added per liter of blood. Hence, the venous Pco2 and the tissue Pco2 decline. As a result of the decline in Pco2, the concentra tion of H+ in cells falls and fewer H+ are bound to proteins in cells. Many of these H+ that are released combine with HCO3− in the ICF and ECF compartments; hence, the concentration of HCO3− in the ECF compartment declines (Fig. 3-1).
Abbreviation PEffective osm, effective osmolality in plasma = 2 PNa + PGlucose in mmol/L terms
Cerebral edema in children with diabetic ketoacidosis. Children with diabetic ketoacidosis, especially those with a long delay before arriving in hospital for therapy, are prone to develop cerebral edema during therapy (see Chapter 5, page 127 for more details). One of the factors that might predispose a patient to this dreaded complication is the administration of a large volume of saline. Enough saline should be given to restore systemic hemodynamics if there is evident hemodynamic instability. Conversely, in the absence of hemodynamic instability, one should avoid giving too much saline or giving it too quickly. The brachial venous Pco2, hematocrit, and urine flow rate are parameters that can be used to guide the decision concerning the rate of administration of saline. Measures must also be taken to prevent a fall in the PEffective osm (see margin note). Rapid correction of chronic hyponatremia. Another important risk factor for the patient with a markedly contracted effective arterial blood volume is removal of the stimulus for the release of vasopressin and an increase in the distal delivery of filtrate once the effective arterial blood volume is reexpanded. If that patient has chronic hyponatremia, the ensuing water diuresis may lead to a rapid rise in PNa and thereby increase the risk for developing osmotic demyelination, especially in the patient with poor nutrition and/or hypokalemia.
Diarrhea or DKA Venous PCO2 Low ECFV
H + + HCO32
CO 2 Protein
H•Protein +
HCO32 to body PHCO3
FIGURE 3-1 Fall in the PHCO3 when the venous Pco2 declines in a patient with metabolic acidosis. The oval represents a muscle cell with membrane containing its HCO3− and protein buffer systems. Owing to the diarrhea or DKA, the effective arterial blood volume is very contracted and the rate of blood flow to muscle is reduced. The subsequent enhanced O2 extraction from each liter of blood flowing through the capillaries raises both the capillary and the ICF Pco2. The higher Pco2 in the interstitial fluid and in these cells drives the synthesis of H+ and HCO3; the H+ bind to intracellular proteins while the HCO3− is exported to the ECF. The net result is a rise in the PHCO3. After the infusion of a large volume of saline and a decline in the Pco2, in capillaries and in cells, these events are reversed, and this contributes to the fall in the PHCO3. DKA, diabetic ketoacidosis; ECFV, extracellular fluid volume.
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Administering dDAVP at the outset should be considered to prevent a water diuresis and minimize the risk of developing this devastating complication. Hypokalemia. A sudden shift of K+ into cells causes hypokalemia and thus an increased risk of developing a cardiac arrhythmia and/ or respiratory muscle weakness. Risk factors are the administration of insulin, a stimulator of its release (glucose), removal of the α-adrenergic–induced inhibition of the release of insulin (e.g., reexpanding the effective arterial blood volume by infusing saline), and/or adminis tration of drugs that may increase β2-adrenergic activity (see Chapter 14, page 477 for more discussion). Metabolic or nutritional issues One must always suspect a deficiency of vitamin B family embers in patients who have metabolic acidosis who are malnour m ished. Thiamin (vitamin B1) deficiency is not uncommon in chronic alcoholics; these patients need therapy with this vitamin at the outset to prevent the development of Wernicke-Korsakoff enceph alopathy (see Chapter 6, page 172). Other patients may have l-lactic acidosis if they are deficient in riboflavin (vitamin B2). Patients who take isoniazid to treat tuberculosis are at risk for mini-seizures and l-lactic acidosis; these patients should be given vitamin B6 (pyridoxine). Another example of a metabolic threat is in patients with pyroglutamic acidosis (see Chapter 6, page 183). In this disorder, the threat to life is due to depletion of reduced glutathione and thus compromised ability to detoxify reactive oxygen species. Metabolic acidosis is a “red flag” that warns the physician about this pathophysiology.
ASSESS THE EFFECTIVENESS OF THE BICARBONATE BUFFER SYSTEM There must be a low Pco2 to ensure that HCO3− remove H+. • The arterial Pco2 must be low. • The Pco2 in venous blood draining skeletal muscle must be low. The arterial Pco2 reflects the physiologic respiratory response to metabolic acidosis. It is also similar to the Pco2 in brain cells because the metabolic rate in the brain is virtually constant; hence, there is little change in its rate of oxygen consumption and CO2 production. In addition, its blood supply is autoregulated. The arterial Pco2 sets the lower limit for the capillary Pco2 in other organs. Because most of the bicarbonate buffer system in the ECF and ICF compartments is in skeletal muscle, we use the Pco2 in the brachial or femoral venous blood to indicate whether the bicarbonate buffer system in this location is effective in buffering the H+ load (see Fig. 1-8, page 14). The bicarbonate buffer system in skeletal muscle is ineffective if the brachial or femoral venous Pco2 is too high; hence, acidemia is more pronounced and more of the H+ load is titrated in vital organs (e.g., brain and heart). Furthermore, if autoregulation of the blood supply to the brain fails because of a marked degree of contraction of the effective arterial blood volume,
Abbreviation dDAVP, desmopressin, or desamino, d-arginine vasopressin
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the brain venous Pco2 rises and more H+ bind to intracellular proteins in brain cells. The major clinical setting for failure of the bicarbonate buffer system in muscle is a low blood flow rate owing to a contracted effective arterial blood volume. At the usual blood flow rates at rest, the brachial venous Pco2 is 46 mm Hg, whereas the arterial Pco2 is 40 mm Hg. Hence, enough saline should be administered to restore the effective arterial blood volume and ensure that the brachial venous Pco2 remains less than 10 mm Hg above the arterial Pco2.
DETERMINE THE BASIS OF METABOLIC ACIDOSIS Three steps remain in the clinical approach: 1. Detect added acids by finding new anions in plasma or in excreted fluids. 2. If acids were added very rapidly, suspect hypoxia or ingestion of an acid. 3. Assess the renal response by estimating the rate of excretion of NH4+. The basis of metabolic acidosis could be a gain of an acid or the loss of NaHCO3 (Flow Chart 3-2). There are three important additional
METABOLIC ACIDOSIS Is the PAnion gap increased?
YES
NO Is the PAlbumin increased?
Is ammonium excretion high?
YES
NO
NO
YES
• Very low ECF volume and a deficit of NaHCO3
• Excess added acids • Very low GFR
• Added acid with new anions in urine • GI loss of NaHCO3
• Very low GFR • Distal RTA • Proximal RTA (see Chapter 4)
FLOW CHART 3-2 Basis of metabolic acidosis. Metabolic acidosis is a process that leads to a rise in the H+ concentration in plasma and a fall in the PHCO3. The goal for this flow chart is to identify whether its cause is the net addition of acids and/or the net loss of Na+ (or K+) plus HCO3−. Hence, the first step is to identify whether the footprints of added acids (the anions that accompany the H+) are present in plasma and thereby in the ECF compartment (detected by finding a high PAnion gap; see the left portion of the flow chart). Be careful if the concentration of albumin is low. Notwithstanding, if there is a higher negative charge associated with the PAlbumin, there will be an increased PAnion gap that may not reflect added acids (e.g., a patient with a marked degree of contraction of the ECF volume owing to severe diarrhea with large losses of NaCl and NaHCO3 in diarrhea fluid). As shown in the right portion of the flow chart, a net loss of NaHCO3 is present if the PAnion gap is not increased. If the rate of excretion of NH4+ is high along with an anion other than Cl−, suspect that the cause of metabolic acidosis is the addition of an acid that has an accompanying anion that is excreted rapidly in the urine. If the rate of excretion of NH4+ is low, on the other hand, seek the basis for the renal defect that compromises the rate of excretion of NH4+. ECF, extracellular fluid; GFR, glomerular filtration rate; GI, gastrointestinal; RTA, renal tubular acidosis.
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considerations that improve the diagnostic approach to the patient with metabolic acidosis. Detect addition of acids by finding new anions • Search for new anions in plasma, in urine, and at times in diarrhea or drainage fluids. An increase in the PAnion gap is used to detect the addition of new acids. Nevertheless, there are two pitfalls to avoid in this context. First, the baseline value for the PAnion gap should be lower if the PAlbumin is reduced; the converse is also true (see margin note). Second, there is a much smaller rise in the PAnion gap if the anions of the added acids are excreted in the urine at a rapid rate (e.g., hippurate anions in a patient with metabolic acidosis due to glue sniffing; see the discussion of Case 3-2, page 71). To detect new anions in the urine, we calculate the urine anion gap (UNa + UK + UNH4 − UCl). The concentration of NH4+ in the urine is estimated from the UOsmolal gap. Detect conditions with fast addition of H+ • If metabolic acidosis develops over a short period of time, the likely causes are overproduction of l-lactic acid (e.g., shock) or ingested acids. The first one is obvious: hypoxic l-lactic acidosis (i.e., when the supply of oxygen is too low to match the demand for ATP regeneration by aerobic fuel oxidation). The other setting where H+ input can be very fast is the ingestion of a large quantity of an acid (e.g., metabolic acidosis due to ingestion of citric acid; see Chapter 6, page 184). Assess the renal response to metabolic acidosis The expected renal response to chronic metabolic acidosis is the excretion of 200 to 250 mmol of NH4+ per day in an adult. The calculation of the UOsmolal gap provides the most reliable indirect estimate of the concentration of NH4+ in the urine (see Chapter 2, page 48). This UNH4 can be converted to an excretion rate by dividing the UNH4 by UCreatinine and multiplying this ratio by expected rate of excretion of creatinine.
QUESTIONS (Discussions on pages 73 and 74) 3-1 In a patient with cholera and metabolic acidosis due to the loss of NaHCO3 in diarrhea fluid, the ECF volume is contracted by close to 50%, yet O2 delivery to tissues is adequate to avoid anaerobic metabolism. Should this patient have an elevated value for the PAnion gap? 3-2 Why might pulmonary edema develop before the ECF volume is fully reexpanded in this patient with cholera?
ADJUST PAnion gap FOR PAlbumin As a rough approximation, the PAnion gap should decrease by 4 mEq/L for each 1.0-g/dL (10-g/L) decrease in the PAlbumin. The converse is also true.
abbreviations UOsmolal gap, osmolal gap in the urine UNH4, concentration of NH4+ in the urine UCreatinine, concentration of creatinine in the urine
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PART B
Discussions DISCUSSION OF CASES Case 3-1: The Truth Will Be Told in the End (Case presented on page 61) Is there a major threat to life on admission? The following threats are present: Low effective arterial blood volume: There is a very severe degree of plasma volume contraction (∼ 60%) as judged from the hematocrit (0.60). The decision that the clinician must make in this context is how fast saline should be administered. On one hand, there are potential dangers from such a severe degree of effective arterial blood volume contraction, including acute tubular necrosis, venous thrombosis due to high blood viscosity because of slow blood flow rate, and a “tissue” form of respiratory acidosis. On the other hand, this patient does not have a significant degree of decreased tissue perfusion because there is no appreciable rise in the Pl-lactate; thus, one need not reexpand the ECF volume with very great haste if there is a potential danger in doing so (see the discussion of the next question). High venous Pco2, a tissue form of respiratory acidosis: This is particularly relevant when dealing with a patient with poor tissue perfusion due to either severe cardiac disease or ECF volume contraction. The very low ECF volume in this patient suggests that a “tissue” form of respiratory acidosis might be present; this was confirmed by the high Pco2 in brachial venous blood (69 mm Hg) compared with the arterial Pco2 (39 mm Hg). This high venous Pco2 indicates that the buffering by the bicarbonate buffer system in skeletal muscles is compromised and thus that there is a more severe degree of acidemia and more H+ binding to intracellular protein in vital organs (e.g., brain, especially if the autoregulation of its blood flow is compromised; see Fig. 1-8, page 14). The venous Pco2 should fall once tissue perfusion improves; this provides the clinician with a tool to guide the rate of administration of saline. As a rough guide, enough saline should be given to lower brachial venous Pco2 to a value that is less than 10 mm Hg higher than the arterial Pco2. What dangers might be created by therapy? These dangers should be anticipated and prevented: A more severe degree of acidemia: Reexpanding his ECF volume by infusing a saline solution that does not contain HCO3− might cause a severe degree of acidemia because this patient has a large deficit of HCO3− and little opportunity to add new HCO3− to the body (no available anions that can be converted into HCO3−). The other mechanisms that would cause a fall in the PHCO3 when saline is administered include accelerated loss of NaHCO3 in diarrhea fluid and titration of HCO3− with H+ that are bound to intracellular proteins and are released from cells when the venous Pco2 falls (see Fig. 3-1, page 66). The administration of saline to
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such patients and development of a severe degree of acidemia are associated with the appearance of pulmonary edema (see the discussion of Question 3-2, page 74 for more information). Hypokalemia: Despite an important degree of K+ depletion, hypokalemia was not present on admission, presumably because K+ had shifted out of cells. The mechanism for this K+ shift is probably a deficiency of insulin, which is the result of inhibition of its release by the α-adrenergic surge in response to the very contracted effective arterial blood volume. Hence, one should expect a significant drop in the PK with reexpansion of the ECF volume because this leads to a fall in circulating α-adrenergic hormone, which causes a rise in the PInsulin. One should also be aware that the degree of hypokalemia may become more severe with the infusion of NaHCO3 and thus more aggressive therapy with KCl may be needed. If a severe degree of K+ depletion with hypokalemia develops, bowel motility may diminish to a degree such that intestinal secretions are pooled in the gut and diarrhea is no longer observed; this serious complication is called cholera sicca. Why is his PHCO3 24 mmol/L in the face of such a large loss of NaHCO3? • The concentration of HCO3− in the ECF compartment is equal to its content divided by the ECF volume. First, this patient had a very severe degree of contraction of his ECF volume, as reflected by the hematocrit of 0.60; this raises his PHCO3 2.5-fold compared with the value if his ECF volume were normal. Second, there is added HCO3− to his ECF compartment because of the very high venous Pco2 draining muscle (see Fig. 3-1, page 66). Of interest, the high value for his PAnion gap may suggest that there were added acids, which would lower his PHCO3. In this context, the acid to suspect is L-lactic acid due to the very markedly contracted effective arterial blood volume. Nevertheless, the fact that the high PAnion gap is due to a very high PAlbumin secondary to the profoundly contracted ECF volume and not to the addition of new acids was confirmed by failing to find an appreciably elevated Pl-lactate. In addition, PKetoacid anions and Pd-lactate were not elevated. At this point, our attention turns to the need to reexpand his effective arterial blood volume despite an ongoing and increasing volume of diarrhea fluid because expansion of his effective arterial blood volume results in a marked increase in the secretion of Na+ and Cl− in the small intestine. Notwithstanding, the positive balance for Na+ and Cl− can be maintained by promoting the absorption of Na+ and Cl− in the intestinal tract by giving large volumes of a solution containing equimolar amounts of glucose and Na+ with Cl− plus some citrate anions by the oral route (this is called oral rehydration therapy; see Fig. 4-6, page 83). Case 3-2: Stick to the Facts (Case presented on page 61) Is metabolic acidosis present? Yes, he has metabolic acidosis because his arterial pH is 7.20, PHCO3 is 10 mmol/L, and arterial Pco2 is 25 mm Hg.
71
abbreviation PInsulin, concentration of insulin in plasma
72 ACID-BASE
What dangers are present before therapy begins? Cardiac arrhythmia and/or hypoventilation: The low PK can cause both of these complications. The K+ deficit is due to an excessive excretion of K+ in the urine in this patient because the urine contains a large quantity of the organic anion, hippurate, which is excreted at a faster rate than NH4+. Because of the danger of causing a shift of K+ into cells that would aggravate an already severe degree of hypokalemia, one should not administer NaHCO3 or give glucose (unless the patient also has hypoglycemia) until the PK is raised to a safe level. Treatment of hypokalemia is discussed in detail in Chapter 14, page 500. Binding of more H+ to proteins in cells: His brachial venous Pco2 is 60 mm Hg and the arterial Pco2 was 25 mm Hg; this Pco2 difference suggests that there was a significantly reduced blood flow rate to muscle owing to the very contracted effective arterial blood volume. This high brachial venous Pco2 suggests that the buffering by the bicarbonate buffer system in muscles is compromised and thus there is a risk of binding of more H+ to intracellular proteins in vital organs (e.g., brain and heart; see Fig. 1-8, page 14). What dangers might be created by therapy?
DISTAL RENAL TUBULAR ACIDOSIS This diagnosis is excluded because the rate of excretion of NH4+ is not low. This information is deduced using the UOsmolal gap as follows: • Calculated UOsm = 2 (UNa [60 mmol/L] + UK [20 mmol/L])+ (UUrea [100 mOsm/L]) = 260 mOsm/L • UNH4 = ½ (Measured UOsm − calculated UOsm) (i.e., [0.5 (566 − 260 mOsm/L)]) = 153 mmol/L • Because the UCreatinine is 8 mmol/L, the UNH4/UCreatinine is close to 20. If we assume that the urine creatinine excretion is 10 mmol/day, this represents a 24-hour NH4+ excretion of 200 mmol.
These are listed with a few comments because most of the dangers were discussed in Case 3-1. The dangers to anticipate are a fall in the PK, a further fall in the PHCO3, and too rapid a rise in the PNa. There could also be nutritional issues. Further fall in the PK: Just as in the previous case, reexpansion of the effective arterial blood volume can lead to a fall in α-adrenergics and thereby to a rise in insulin levels. In addition, as renal perfusion improves, the excretion of hippurate at a rate faster than NH4+ could lead to very high rates of excretion of K+. Again, if HCO3− and/or glucose is administered, this could further aggravate the degree of hypokalemia owing to a shift of K+ into cells. Further fall in the PHCO3: Just as in the previous case, the PHCO3 falls for a number of reasons when isotonic saline is administered. The dilemma is balancing the need for giving exogenous HCO3− versus the danger of causing an acute fall in the PK. In the opinion of the authors, K+ replacement should take precedence. If there is a need to administer HCO3− early on, give NaHCO3 with sufficient KCl to prevent a fall in the PK; this should be done in a setting where cardiac and respiratory monitoring can be carried out. Too rapid a rise in the PNa: This is very important in a patient who is poorly nourished and/or K+ depleted, because these are risk factors for the development of osmotic demyelination during therapy. Our rationale for administering dDAVP at the outset of therapy is discussed in Chapter 10, page 331. What is the basis of the metabolic acidosis? Because the PAnion gap is in the normal range, one might have thought that the metabolic acidosis was not due to a gain of acids. Nevertheless, the rate of excretion of NH4+ was high (see margin note), and the accompanying anions were not Cl−. This case represents the overproduction of an organic acid with the rapid excretion of its anion in the urine. Metabolic acidosis develops because some of the anions are excreted in the urine with Na+ and K+ (not NH4+ or
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73
Toluene 1 Hippuric acid
HCO 3
–
2 H
H 2O + CO 2
+
+ Hippurate
–
3
4 Hippurate– + NH4+
5 Hippurate– + Na+ + K+
FIGURE 3-2 Metabolic acidosis due to the metabolism of toluene. The metabolism of toluene occurs in the liver, where benzoic acid is produced via alcohol and aldehyde dehydrogenases. Conjugating benzoic acid with glycine produces hippuric acid (all represented as site 1 for simplicity). The H+ are titrated by HCO3− for the most part (site 2). The hippurate anions are filtered and also secreted in the proximal convoluted tubule (site 3). Therefore, instead of accumulating in blood and increasing the PAnion gap, they are excreted in the urine. Some of the hippurate anions are excreted in the urine with NH4+ (site 4) and others with Na+ and K+ (site 5), when the capacity to excrete NH4+ is exceeded. The excretion of hippurate anions with Na+ and/or K+ (and not NH4+) leads to the persistence of the metabolic acidosis, extracellular fluid volume contraction, and hypokalemia.
H+), and hence there is an indirect loss of NaHCO3 (see Fig. 4-2, page 78). The most likely basis for the metabolic acidosis in this patient is glue sniffing with the production of hippuric acid and the excretion of hippurate anions in the urine at a rate that exceeds that of NH4+ (Fig. 3-2). DISCUSSION OF QUESTIONS 3-1 In a patient with cholera and metabolic acidosis due to the loss of NaHCO3 in diarrhea fluid, the ECF volume is contracted by close to 50%, yet O2 delivery to tissues is adequate to avoid anaerobic metabolism. Should this patient have an elevated value for the PAnion gap? The oversimplified and incorrect answer is that there is no change in the PAnion gap when there is a net loss of Na+ and HCO3−. Notwithstanding, because most of the PAnion gap is due to the net negative charge on albumin, the value for this gap would be higher if the PAlbumin were to rise because of a contracted plasma volume. In quantitative terms, the net valence on albumin is close to 16 mEq/L per 4.0 g albumin/dL. When the PAlbumin is 8.0 g/dL, the expected rise in the PAnion gap is close to 16 mEq/L above the usual 12 ± 2 mEq/L (see margin note). Moreover, there appears to be a rise in value for the negative valence on albumin when the effective arterial blood is contracted. Therefore, the rise in PAnion gap in this setting does not represent the addition of new acids.
PAnion gap In this calculation for the rise in the PAnion gap, we assumed that the PK did not change.
74 ACID-BASE
3-2 Why might pulmonary edema develop before the Ecf volume is fully reexpanded in this patient with cholera? The clinicians who treated severely ill patients with cholera were very surprised when 5 of their first 40 patients developed pulmonary edema when they received isotonic saline at a rapid rate. In fact, the positive balance of saline was significantly less than what would be needed to fully reexpand the ECF volume. Even more surprising was the fact that pulmonary edema was ameliorated when isotonic NaHCO3 was infused at a rapid rate, whereas other treatments for pulmonary edema were not successful. One speculation to explain these observations was that the more severe degree of acidemia that developed following partial reexpansion of the ECF volume with isotonic saline led to a more intense constriction of the peripheral venous capacitance vessels and thus a larger increase in the central blood volume. Because pulmonary edema could be reversed by the administration of a solution that contains HCO3−, these patients should receive an isotonic solution (to the patient) that contains close to 40 mmol NaHCO3 or its equivalent (e.g., sodium l-lactate) to match the concentration of HCO3− in diarrhea fluid. As men tioned previously, one must be extremely cautious if the patient has hypokalemia.
3
Metabolic Acidosis: Clinical Approach
Introduction����������������������������������������������������������������������������������������� 60 Objectives��������������������������������������������������������������������������������������������� 60 Case 3-1: The truth will be told in the end������������������������������������� 61 Case 3-2: Stick to the facts����������������������������������������������������������������� 61 P A R T A CLINICAL APPROACH������������������������������������������������������������������� 62 Emergencies in the patient with metabolic acidosis������������������� 63 Risks prior to therapy������������������������������������������������������������������������� 64 Dangers to anticipate after commencing therapy���������������������������� 65 Assess the effectiveness of the bicarbonate buffer system�������� 67 Determine the basis of metabolic acidosis����������������������������������� 68 Detect addition of acids by finding new anions�������������������������������� 69 Detect conditions with fast addition of H+��������������������������������������� 69 Assess the renal response to metabolic acidosis����������������������������� 69
P A R T B Discussions����������������������������������������������������������������������������������� 70 Discussion of cases����������������������������������������������������������������������������� 70 Discussion of questions�������������������������������������������������������������������� 73
Introduction
In this chapter, our goal is to provide a bedside approach to the patient with metabolic acidosis. This approach focuses not only on diagnosis but also on identifying and handling emergencies while anticipating and preventing risks that are likely to develop during therapy. An important component of our approach is to deduce whether there is a risk of excessive binding of H+ to intracellular proteins in vital organs (e.g., the brain and the heart). We discuss how this may occur and how it can be reversed. OBJECTIVES n To emphasize the following issues in the approach to the patient with metabolic acidosis: 1. Treat emergencies first: The first step is to recognize and deal with threats to the patient’s life and to anticipate and prevent risks that may arise owing to therapy.
60
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61
2. Assess the effectiveness of the bicarbonate buffer system: The brachial or femoral venous Pco2 is needed to evaluate the effectiveness of the bicarbonate buffer system in skeletal muscle, where the bulk of this buffer system exists. When the bicarbonate buffer system is compromised, more H+ bind to proteins in cells of vital organs (e.g., brain and heart). n To illustrate how to determine whether the basis of the meta bolic acidosis is due to added acids and/or a deficit of sodium bicarbonate: Look for new anions in plasma and urine, and assess the rate of excretion of NH4+.
Case 3-1: The Truth Will Be Told in the End (Case discussed on page 70) A 25-year-old man was perfectly healthy until he developed diarrhea 24 hours ago (see margin note). He has had no intake of food or water and currently has no urine output. His blood pressure is 90/60 mm Hg, his pulse rate is 110 beats per minute, and his jugular venous pressure is low. Acid-base measurements in arterial blood reveal pH of 7.39, PHCO3 of 24 mmol/L, and Pco2 of 39 mm Hg. He has lost 5 L of diarrhea fluid, which contained Na+ 140 mmol/L, K+ 15 mmol/L, Cl− 115 mmol/L, and HCO3− 40 mmol/L. On admission, his hematocrit is 0.60, PAlbumin is 8.0 g/dL (80 g/L), and PK is 4.8 mmol/L.
This case is also presented in Chapter 2 with a different title; the points emphasized there are how the diagnostic tests should be interpreted. In this chapter, the major emphasis is to recognize current threats to the patient and anticipate those that may develop during therapy. A more detailed description of the biochemistry and pathophysiology of cholera is provided in Chapter 4, Part D, page 106.
Questions Is there a major threat to life on admission? What dangers might be created by therapy? Why is his PHCO3 24 mmol/L in the face of such a large loss of NaHCO3?
ABBREVIATION PAlbumin, [albumin] in plasma
Case 3-2: Stick to the Facts (Case discussed on page 71) A 28-year-old man had been sniffing glue on a chronic but intermittent basis. Over the past 3 days, he had become profoundly weak and had a very unsteady gait. On physical examination, his blood pressure was 100/60 mm Hg and his pulse rate was 110 beats per minute while lying flat. When he sat up, his blood pressure fell to 80/50 mm Hg and his pulse rate rose to 130 beats per minute. His arterial blood pH was 7.20, Pco2 was 25 mm Hg, and PHCO3 was 10 mmol/L. His PGlucose was 3.5 mmol/L (63 mg/dL), his PAlbumin was 6.0 g/dL (60 g/L), and his hematocrit was 0.50. VENOUS BLOOD pH Pco2 HCO3− Na+ K+ Cl− Creatinine BUN (urea) Osmolality
mm Hg mmol/L mmol/L mmol/L mmol/L mg/dL (μmol/L) mg/dL (mmol/L) mOsm/kg H2O
7.00 60 15 120 2.3 90 1.7 (150) 14 (5.0) 250
URINE 6.0 — <5 50 30 0 3.0 mmol/L 150 mmol/L 500
ABBREVIATION PGlucose, concentration of glucose in plasma
62 ACID-BASE
Questions Is metabolic acidosis present? What dangers are present before therapy begins? What dangers might be created by therapy? What is the basis of the metabolic acidosis?
PART A
CLINICAL APPROACH • The first step in the approach to the patient with metabolic acidosis is to identify threats for that patient. • The next two steps are as follows: (1) Determine whether H+ were buffered appropriately by the bicarbonate buffer system. (2) Determine whether the basis of the metabolic acidosis is due to added acids and/or a deficit of NaHCO3. Our initial approach to the patient with metabolic acidosis is provided in Flow Chart 3-1. Metabolic acidosis must be present to enter this flow chart. This diagnosis is based on one of the following criteria: (1) a low plasma pH and PHCO3; (2) an increase in the anion gap in plasma (PAnion gap) corrected for the PAlbumin; or (3) an appreciable decrease in the content of HCO3− in the extracellular fluid (ECF) compartment in the patient who has a history suggesting that the ECF volume may be contracted. For the third criterion, a quantitative estimate of the ECF volume is needed. Because one
METABOLIC ACIDOSIS Is there a major threat for the patient?
YES
NO
Proceed to the right side after this evaluation
Before therapy • Hemodynamic emergency • Cardiac arrhythmia • Respiratory failure • Toxins • Metabolic/nutrition issues
Is buffering adequate by the BBS?
During therapy • Shift of K+ into cells • Pulmonary edema • Cerebral edema in DKA • Thiamin deficiency • Rapid correction of chronic hyponatremia
Ventilation • Assess with the arterial PCO2
In muscle • Assess with the brachial venous PCO2
FLOW CHART 3-1 Initial steps in the evaluation of the patient with metabolic acidosis. One must use a definition of metabolic acidosis that is based not only on the PHCO3 but also on the content of HCO3− in the ECF compartment if its volume is significantly contracted. The initial step is to determine threats for the patient that may be present and anticipate those that may develop during therapy (left side of the flow chart). The next step is to assess buffering by the bicarbonate buffer system (BBS) in the ECF and ICF of skeletal muscle to deduce whether more H+ are bound to brain proteins (right side of the flow chart). DKA, diabetic ketoacidosis.
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cannot obtain accurate quantitative data about the ECF volume with the physical examination, we recommend using the hematocrit or total protein level in plasma to obtain this information (see the discussion of Case 2-1, page 57). 1. Identify threats. The first step is to identify and deal with threats that are present before therapy begins and anticipate and prevent dangers that may develop during the course of the illness or with therapy. 2. Determine whether H+ are removed appropriately by HCO3−. After the emergencies are considered and dealt with, the arterial Pco2 and the brachial (or femoral) venous Pco2 should be assessed, as the latter helps reveal to the effectiveness of the bicarbonate buffer system in the ECF and ICF compartments in skeletal muscle. If the brachial venous Pco2 is high, the bicarbonate buffer system in skeletal muscle is compromised. Hence, more of the H+ load binds to intracellular proteins in vital organs (e.g., brain cells). If autoregulation of cerebral blood flow fails, more H+ will bind to intracellular proteins in the brain because of a marked decrease in the effective arterial blood volume.
EMERGENCIES IN THE PATIENT WITH METABOLIC ACIDOSIS Although it is common practice to begin the assessment of a patient with metabolic acidosis with an emphasis on diagnosis, we recommend a different approach for the critically ill patient with metabolic acidosis—begin with data that are most important to answer the question “How can I prevent this patient from dying?” The risks to the patient can be divided into those that are present when the patient seeks medical attention and those that may develop during therapy (Table 3-1). TABLE 3-1 THREATS TO LIFE ASSOCIATED WITH
METABOLIC ACIDOSIS
On admission • Hemodynamic instability • Marked decrease in myocardial contractility (e.g., cardiogenic shock) • Very low intravascular volume (e.g., NaCl loss, hemorrhage) • Decreased peripheral vascular resistance (e.g., sepsis) • Cardiac arrhythmia • Most frequently seen in patients with hyperkalemia or hypokalemia • Failure of ventilation (e.g., respiratory muscle weakness due to hypokalemia) • Presence of toxins (e.g., methanol, ethylene glycol) • Presence of reactive oxygen species (e.g., pyroglutamic acidosis) • Nutritional deficiency (especially B vitamins) During therapy • Development of cerebral edema during therapy of diabetic ketoacidosis in children • Overly rapid infusion of isotonic saline • Failure to prevent a fall in the effective plasma osmolality during therapy • Pulmonary edema (e.g., in patients with severe diarrhea if the ECF volume is expanded, but NaHCO3 is not given) • Too rapid a rise in PNa in patients with chronic hyponatremia • Development of a severe degree of acidemia in a patient with metabolic acidosis (see discussion of Case 3-1, page 70) • Acute shift of K+ into cells (e.g., administration of glucose to patients with hypokalemia, administration of insulin to patients with DKA and hypokalemia, administration of NaHCO3 to patients with a low PK) • Wernicke’s encephalopathy due to failure to give thiamin (vitamin B1) to chronic alcoholics with alcoholic ketoacidosis
Abbreviations ECF, extracellular fluid ICF, intracellular fluid
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64 ACID-BASE
The diagnostic category of metabolic acidosis is made up of two major subgroups, one where the basis of the disorder is the addition of acids and the other where the basis is a major loss of NaHCO3. Although the emergencies may be different within each of the causes for the disorder, nevertheless, we start this discussion by emphasizing the importance of detecting, anticipating, and dealing with threats to life. Risks prior to therapy Hemodynamic emergency • The most common example is a patient with l-lactic acidosis owing to cardiogenic shock (e.g., myocardial infarction) because survival at this point depends on whether the cardiac output can be improved very quickly. In most of the other settings of metabolic acidosis due to added acids, true hemodynamic emergencies are not common, with the possible exception of some patients with sepsis and others with alcoholic or diabetic ketoacidosis. Although a significant degree of contraction of the effective arterial blood volume is usually present in children with diabetic ketoacidosis (i.e., caused by the glucose-induced osmotic diuresis) a true hemodynamic emergency is usually not present. Hence, overly rapid and excessive administration of saline should be avoided because of the risk of inducing cerebral edema (see Chapter 5, page 128 for more discussion). Conversely, patients with a very significant degree of contraction of the effective arterial blood volume that causes an inadequate delivery of oxygen to tissues and the production of an appreciable quantity of l-lactic acid require the urgent administration of a large volume of isotonic saline. In contrast, if the patient is not hemodynamically compromised, aggressive therapy is not warranted because, at times, serious complications related to this infusion might arise (see the discussion of Case 3-1, page 70). Cardiac arrhythmia Patients with metabolic acidosis may develop a cardiac arrhythmia when there is a severe degree of hyperkalemia (e.g., owing to renal failure) or hypokalemia (e.g., certain patients with distal renal tubular acidosis, patients with metabolic acidosis due to glue sniffing). In addition, hypokalemia may develop after therapy is initiated (see Cases 3-1 and 3-2). The emergency treatment of hypokalemia and of hyperkalemia is discussed in Chapters 14 and 15. Failure of adequate ventilation Respiratory muscle weakness due to a severe degree of hypokalemia could lead to respiratory failure and a more severe degree of acidemia in patients with metabolic acidosis. Enough KCl should be given to raise the PK to 3.0 mmol/L in this setting; mechanical ventilation might also be needed. Toxin-induced metabolic acidosis Ingestion of methanol or ethylene glycol should always be suspected in a patient with metabolic acidosis, an elevated PAnion gap, and
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no obvious cause for these findings, especially if the ECF volume is not significantly contracted (see Chapter 6, page 178). Failing to make this diagnosis can be devastating. If ingestion of these alcohols is suspected, one must calculate the POsmolal gap (see Chapter 2, page 48). If the POsmolal gap is considerably greater than 10 mOsm/kg H2O, the diagnosis should be confirmed by direct measurements of methanol and of ethylene glycol in plasma because ethanol also contributes to the POsmolal gap. Because it is the products of the metabolism of these toxic alcohols that create the danger rather than the parent compounds, administer ethanol to prevent their metabolism until the facts become clear.
abbreviation POsmolal gap, osmolal gap in plasma
Dangers to anticipate after commencing therapy Several threats are anticipated in a patient with metabolic acidosis. Dangers related to overly aggressive administration of saline Although enough saline should be given if there is evident hemodynamic instability, an excessive rate of administration of saline has its dangers. In absence of hemodynamic instability, we use the brachial venous Pco2 and the hematocrit to guide decisions about intravenous fluid therapy (see margin note). If oliguria develops during therapy, a more vigorous restoration of intravascular volume may be needed. Several complications may arise from overly aggressive administration of saline. A very severe degree of acidemia. There is a fall in the PHCO3 when a large volume of saline without NaHCO3 is given to a patient who has a severe degree of ECF volume contraction (e.g., the patient with a large loss of NaHCO3 and saline in diarrhea fluid; see Case 3-1, page 70). When saline is infused very rapidly, some patients with metabolic acidosis caused by NaHCO3 loss due to diarrhea and a severe degree of contraction of the effective arterial blood volume develop pulmonary edema before their ECF volume is sufficiently reexpanded. This may be the result of the severe degree of acidemia that develops, which leads to the redistribution of blood from the peripheral to the central circulating blood volume. It is important to recognize this complication, because pulmonary edema can be prevented and/or treated successfully with an infusion of fluid that contains NaHCO3 (or an anion that can be metabolized to produce HCO3− [e.g., l-lactate−]). See the discussion of Case 3-1, page 70. Three mechanisms may lead to a more severe degree of acidemia with the infusion of a large amount of saline in these patients. 1. Dilution of the HCO3− in the ECF compartment: These patients have metabolic acidosis with a large deficit of HCO3− even though their PHCO3 might not be very low because of the marked degree of contraction of their ECF volume. Hence, the concentration of HCO3− in the ECF compartment declines when a large volume of saline is infused because of the rise in the denominator of the HCO3−:ECF volume ratio. 2. Loss of more NaHCO3 in diarrhea fluid: Reexpansion of the effective arterial blood volume increases splanchnic blood flow. This permits a much larger quantity of Na+ and Cl− to be secreted in the small intestine. When a large volume of luminal fluid containing Na+ and Cl− reaches the colon, more Cl− is reabsorbed in exchange for HCO3− compared with the absorption of Na+ in exchange for secreted H+; hence, the loss
65
CAUTION The hematocrit on admission is not useful in patients who have anemia.
66 ACID-BASE
of NaHCO3 in diarrhea fluid may rise markedly (see Fig. 4-4, page 82). 3. Back-titration of HCO3− by H+ that were bound to intracellular proteins: Assume that muscle cells have a constant consumption of oxygen and production of CO2. Now when the blood flow rate rises, the same amount of oxygen is consumed, but less oxygen is extracted from each liter of blood. Because almost the same amount of CO2 is produced as O2 consumed, less CO2 is added per liter of blood. Hence, the venous Pco2 and the tissue Pco2 decline. As a result of the decline in Pco2, the concentra tion of H+ in cells falls and fewer H+ are bound to proteins in cells. Many of these H+ that are released combine with HCO3− in the ICF and ECF compartments; hence, the concentration of HCO3− in the ECF compartment declines (Fig. 3-1).
Abbreviation PEffective osm, effective osmolality in plasma = 2 PNa + PGlucose in mmol/L terms
Cerebral edema in children with diabetic ketoacidosis. Children with diabetic ketoacidosis, especially those with a long delay before arriving in hospital for therapy, are prone to develop cerebral edema during therapy (see Chapter 5, page 127 for more details). One of the factors that might predispose a patient to this dreaded complication is the administration of a large volume of saline. Enough saline should be given to restore systemic hemodynamics if there is evident hemodynamic instability. Conversely, in the absence of hemodynamic instability, one should avoid giving too much saline or giving it too quickly. The brachial venous Pco2, hematocrit, and urine flow rate are parameters that can be used to guide the decision concerning the rate of administration of saline. Measures must also be taken to prevent a fall in the PEffective osm (see margin note). Rapid correction of chronic hyponatremia. Another important risk factor for the patient with a markedly contracted effective arterial blood volume is removal of the stimulus for the release of vasopressin and an increase in the distal delivery of filtrate once the effective arterial blood volume is reexpanded. If that patient has chronic hyponatremia, the ensuing water diuresis may lead to a rapid rise in PNa and thereby increase the risk for developing osmotic demyelination, especially in the patient with poor nutrition and/or hypokalemia.
Diarrhea or DKA Venous PCO2 Low ECFV
H + + HCO32
CO 2 Protein
H•Protein +
HCO32 to body PHCO3
FIGURE 3-1 Fall in the PHCO3 when the venous Pco2 declines in a patient with metabolic acidosis. The oval represents a muscle cell with membrane containing its HCO3− and protein buffer systems. Owing to the diarrhea or DKA, the effective arterial blood volume is very contracted and the rate of blood flow to muscle is reduced. The subsequent enhanced O2 extraction from each liter of blood flowing through the capillaries raises both the capillary and the ICF Pco2. The higher Pco2 in the interstitial fluid and in these cells drives the synthesis of H+ and HCO3; the H+ bind to intracellular proteins while the HCO3− is exported to the ECF. The net result is a rise in the PHCO3. After the infusion of a large volume of saline and a decline in the Pco2, in capillaries and in cells, these events are reversed, and this contributes to the fall in the PHCO3. DKA, diabetic ketoacidosis; ECFV, extracellular fluid volume.
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Administering dDAVP at the outset should be considered to prevent a water diuresis and minimize the risk of developing this devastating complication. Hypokalemia. A sudden shift of K+ into cells causes hypokalemia and thus an increased risk of developing a cardiac arrhythmia and/ or respiratory muscle weakness. Risk factors are the administration of insulin, a stimulator of its release (glucose), removal of the α-adrenergic–induced inhibition of the release of insulin (e.g., reexpanding the effective arterial blood volume by infusing saline), and/or adminis tration of drugs that may increase β2-adrenergic activity (see Chapter 14, page 477 for more discussion). Metabolic or nutritional issues One must always suspect a deficiency of vitamin B family embers in patients who have metabolic acidosis who are malnour m ished. Thiamin (vitamin B1) deficiency is not uncommon in chronic alcoholics; these patients need therapy with this vitamin at the outset to prevent the development of Wernicke-Korsakoff enceph alopathy (see Chapter 6, page 172). Other patients may have l-lactic acidosis if they are deficient in riboflavin (vitamin B2). Patients who take isoniazid to treat tuberculosis are at risk for mini-seizures and l-lactic acidosis; these patients should be given vitamin B6 (pyridoxine). Another example of a metabolic threat is in patients with pyroglutamic acidosis (see Chapter 6, page 183). In this disorder, the threat to life is due to depletion of reduced glutathione and thus compromised ability to detoxify reactive oxygen species. Metabolic acidosis is a “red flag” that warns the physician about this pathophysiology.
ASSESS THE EFFECTIVENESS OF THE BICARBONATE BUFFER SYSTEM There must be a low Pco2 to ensure that HCO3− remove H+. • The arterial Pco2 must be low. • The Pco2 in venous blood draining skeletal muscle must be low. The arterial Pco2 reflects the physiologic respiratory response to metabolic acidosis. It is also similar to the Pco2 in brain cells because the metabolic rate in the brain is virtually constant; hence, there is little change in its rate of oxygen consumption and CO2 production. In addition, its blood supply is autoregulated. The arterial Pco2 sets the lower limit for the capillary Pco2 in other organs. Because most of the bicarbonate buffer system in the ECF and ICF compartments is in skeletal muscle, we use the Pco2 in the brachial or femoral venous blood to indicate whether the bicarbonate buffer system in this location is effective in buffering the H+ load (see Fig. 1-8, page 14). The bicarbonate buffer system in skeletal muscle is ineffective if the brachial or femoral venous Pco2 is too high; hence, acidemia is more pronounced and more of the H+ load is titrated in vital organs (e.g., brain and heart). Furthermore, if autoregulation of the blood supply to the brain fails because of a marked degree of contraction of the effective arterial blood volume,
Abbreviation dDAVP, desmopressin, or desamino, d-arginine vasopressin
67
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the brain venous Pco2 rises and more H+ bind to intracellular proteins in brain cells. The major clinical setting for failure of the bicarbonate buffer system in muscle is a low blood flow rate owing to a contracted effective arterial blood volume. At the usual blood flow rates at rest, the brachial venous Pco2 is 46 mm Hg, whereas the arterial Pco2 is 40 mm Hg. Hence, enough saline should be administered to restore the effective arterial blood volume and ensure that the brachial venous Pco2 remains less than 10 mm Hg above the arterial Pco2.
DETERMINE THE BASIS OF METABOLIC ACIDOSIS Three steps remain in the clinical approach: 1. Detect added acids by finding new anions in plasma or in excreted fluids. 2. If acids were added very rapidly, suspect hypoxia or ingestion of an acid. 3. Assess the renal response by estimating the rate of excretion of NH4+. The basis of metabolic acidosis could be a gain of an acid or the loss of NaHCO3 (Flow Chart 3-2). There are three important additional
METABOLIC ACIDOSIS Is the PAnion gap increased?
YES
NO Is the PAlbumin increased?
Is ammonium excretion high?
YES
NO
NO
YES
• Very low ECF volume and a deficit of NaHCO3
• Excess added acids • Very low GFR
• Added acid with new anions in urine • GI loss of NaHCO3
• Very low GFR • Distal RTA • Proximal RTA (see Chapter 4)
FLOW CHART 3-2 Basis of metabolic acidosis. Metabolic acidosis is a process that leads to a rise in the H+ concentration in plasma and a fall in the PHCO3. The goal for this flow chart is to identify whether its cause is the net addition of acids and/or the net loss of Na+ (or K+) plus HCO3−. Hence, the first step is to identify whether the footprints of added acids (the anions that accompany the H+) are present in plasma and thereby in the ECF compartment (detected by finding a high PAnion gap; see the left portion of the flow chart). Be careful if the concentration of albumin is low. Notwithstanding, if there is a higher negative charge associated with the PAlbumin, there will be an increased PAnion gap that may not reflect added acids (e.g., a patient with a marked degree of contraction of the ECF volume owing to severe diarrhea with large losses of NaCl and NaHCO3 in diarrhea fluid). As shown in the right portion of the flow chart, a net loss of NaHCO3 is present if the PAnion gap is not increased. If the rate of excretion of NH4+ is high along with an anion other than Cl−, suspect that the cause of metabolic acidosis is the addition of an acid that has an accompanying anion that is excreted rapidly in the urine. If the rate of excretion of NH4+ is low, on the other hand, seek the basis for the renal defect that compromises the rate of excretion of NH4+. ECF, extracellular fluid; GFR, glomerular filtration rate; GI, gastrointestinal; RTA, renal tubular acidosis.
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69
considerations that improve the diagnostic approach to the patient with metabolic acidosis. Detect addition of acids by finding new anions • Search for new anions in plasma, in urine, and at times in diarrhea or drainage fluids. An increase in the PAnion gap is used to detect the addition of new acids. Nevertheless, there are two pitfalls to avoid in this context. First, the baseline value for the PAnion gap should be lower if the PAlbumin is reduced; the converse is also true (see margin note). Second, there is a much smaller rise in the PAnion gap if the anions of the added acids are excreted in the urine at a rapid rate (e.g., hippurate anions in a patient with metabolic acidosis due to glue sniffing; see the discussion of Case 3-2, page 71). To detect new anions in the urine, we calculate the urine anion gap (UNa + UK + UNH4 − UCl). The concentration of NH4+ in the urine is estimated from the UOsmolal gap. Detect conditions with fast addition of H+ • If metabolic acidosis develops over a short period of time, the likely causes are overproduction of l-lactic acid (e.g., shock) or ingested acids. The first one is obvious: hypoxic l-lactic acidosis (i.e., when the supply of oxygen is too low to match the demand for ATP regeneration by aerobic fuel oxidation). The other setting where H+ input can be very fast is the ingestion of a large quantity of an acid (e.g., metabolic acidosis due to ingestion of citric acid; see Chapter 6, page 184). Assess the renal response to metabolic acidosis The expected renal response to chronic metabolic acidosis is the excretion of 200 to 250 mmol of NH4+ per day in an adult. The calculation of the UOsmolal gap provides the most reliable indirect estimate of the concentration of NH4+ in the urine (see Chapter 2, page 48). This UNH4 can be converted to an excretion rate by dividing the UNH4 by UCreatinine and multiplying this ratio by expected rate of excretion of creatinine.
QUESTIONS (Discussions on pages 73 and 74) 3-1 In a patient with cholera and metabolic acidosis due to the loss of NaHCO3 in diarrhea fluid, the ECF volume is contracted by close to 50%, yet O2 delivery to tissues is adequate to avoid anaerobic metabolism. Should this patient have an elevated value for the PAnion gap? 3-2 Why might pulmonary edema develop before the ECF volume is fully reexpanded in this patient with cholera?
ADJUST PAnion gap FOR PAlbumin As a rough approximation, the PAnion gap should decrease by 4 mEq/L for each 1.0-g/dL (10-g/L) decrease in the PAlbumin. The converse is also true.
abbreviations UOsmolal gap, osmolal gap in the urine UNH4, concentration of NH4+ in the urine UCreatinine, concentration of creatinine in the urine
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PART B
Discussions DISCUSSION OF CASES Case 3-1: The Truth Will Be Told in the End (Case presented on page 61) Is there a major threat to life on admission? The following threats are present: Low effective arterial blood volume: There is a very severe degree of plasma volume contraction (∼ 60%) as judged from the hematocrit (0.60). The decision that the clinician must make in this context is how fast saline should be administered. On one hand, there are potential dangers from such a severe degree of effective arterial blood volume contraction, including acute tubular necrosis, venous thrombosis due to high blood viscosity because of slow blood flow rate, and a “tissue” form of respiratory acidosis. On the other hand, this patient does not have a significant degree of decreased tissue perfusion because there is no appreciable rise in the Pl-lactate; thus, one need not reexpand the ECF volume with very great haste if there is a potential danger in doing so (see the discussion of the next question). High venous Pco2, a tissue form of respiratory acidosis: This is particularly relevant when dealing with a patient with poor tissue perfusion due to either severe cardiac disease or ECF volume contraction. The very low ECF volume in this patient suggests that a “tissue” form of respiratory acidosis might be present; this was confirmed by the high Pco2 in brachial venous blood (69 mm Hg) compared with the arterial Pco2 (39 mm Hg). This high venous Pco2 indicates that the buffering by the bicarbonate buffer system in skeletal muscles is compromised and thus that there is a more severe degree of acidemia and more H+ binding to intracellular protein in vital organs (e.g., brain, especially if the autoregulation of its blood flow is compromised; see Fig. 1-8, page 14). The venous Pco2 should fall once tissue perfusion improves; this provides the clinician with a tool to guide the rate of administration of saline. As a rough guide, enough saline should be given to lower brachial venous Pco2 to a value that is less than 10 mm Hg higher than the arterial Pco2. What dangers might be created by therapy? These dangers should be anticipated and prevented: A more severe degree of acidemia: Reexpanding his ECF volume by infusing a saline solution that does not contain HCO3− might cause a severe degree of acidemia because this patient has a large deficit of HCO3− and little opportunity to add new HCO3− to the body (no available anions that can be converted into HCO3−). The other mechanisms that would cause a fall in the PHCO3 when saline is administered include accelerated loss of NaHCO3 in diarrhea fluid and titration of HCO3− with H+ that are bound to intracellular proteins and are released from cells when the venous Pco2 falls (see Fig. 3-1, page 66). The administration of saline to
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such patients and development of a severe degree of acidemia are associated with the appearance of pulmonary edema (see the discussion of Question 3-2, page 74 for more information). Hypokalemia: Despite an important degree of K+ depletion, hypokalemia was not present on admission, presumably because K+ had shifted out of cells. The mechanism for this K+ shift is probably a deficiency of insulin, which is the result of inhibition of its release by the α-adrenergic surge in response to the very contracted effective arterial blood volume. Hence, one should expect a significant drop in the PK with reexpansion of the ECF volume because this leads to a fall in circulating α-adrenergic hormone, which causes a rise in the PInsulin. One should also be aware that the degree of hypokalemia may become more severe with the infusion of NaHCO3 and thus more aggressive therapy with KCl may be needed. If a severe degree of K+ depletion with hypokalemia develops, bowel motility may diminish to a degree such that intestinal secretions are pooled in the gut and diarrhea is no longer observed; this serious complication is called cholera sicca. Why is his PHCO3 24 mmol/L in the face of such a large loss of NaHCO3? • The concentration of HCO3− in the ECF compartment is equal to its content divided by the ECF volume. First, this patient had a very severe degree of contraction of his ECF volume, as reflected by the hematocrit of 0.60; this raises his PHCO3 2.5-fold compared with the value if his ECF volume were normal. Second, there is added HCO3− to his ECF compartment because of the very high venous Pco2 draining muscle (see Fig. 3-1, page 66). Of interest, the high value for his PAnion gap may suggest that there were added acids, which would lower his PHCO3. In this context, the acid to suspect is L-lactic acid due to the very markedly contracted effective arterial blood volume. Nevertheless, the fact that the high PAnion gap is due to a very high PAlbumin secondary to the profoundly contracted ECF volume and not to the addition of new acids was confirmed by failing to find an appreciably elevated Pl-lactate. In addition, PKetoacid anions and Pd-lactate were not elevated. At this point, our attention turns to the need to reexpand his effective arterial blood volume despite an ongoing and increasing volume of diarrhea fluid because expansion of his effective arterial blood volume results in a marked increase in the secretion of Na+ and Cl− in the small intestine. Notwithstanding, the positive balance for Na+ and Cl− can be maintained by promoting the absorption of Na+ and Cl− in the intestinal tract by giving large volumes of a solution containing equimolar amounts of glucose and Na+ with Cl− plus some citrate anions by the oral route (this is called oral rehydration therapy; see Fig. 4-6, page 83). Case 3-2: Stick to the Facts (Case presented on page 61) Is metabolic acidosis present? Yes, he has metabolic acidosis because his arterial pH is 7.20, PHCO3 is 10 mmol/L, and arterial Pco2 is 25 mm Hg.
71
abbreviation PInsulin, concentration of insulin in plasma
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What dangers are present before therapy begins? Cardiac arrhythmia and/or hypoventilation: The low PK can cause both of these complications. The K+ deficit is due to an excessive excretion of K+ in the urine in this patient because the urine contains a large quantity of the organic anion, hippurate, which is excreted at a faster rate than NH4+. Because of the danger of causing a shift of K+ into cells that would aggravate an already severe degree of hypokalemia, one should not administer NaHCO3 or give glucose (unless the patient also has hypoglycemia) until the PK is raised to a safe level. Treatment of hypokalemia is discussed in detail in Chapter 14, page 500. Binding of more H+ to proteins in cells: His brachial venous Pco2 is 60 mm Hg and the arterial Pco2 was 25 mm Hg; this Pco2 difference suggests that there was a significantly reduced blood flow rate to muscle owing to the very contracted effective arterial blood volume. This high brachial venous Pco2 suggests that the buffering by the bicarbonate buffer system in muscles is compromised and thus there is a risk of binding of more H+ to intracellular proteins in vital organs (e.g., brain and heart; see Fig. 1-8, page 14). What dangers might be created by therapy?
DISTAL RENAL TUBULAR ACIDOSIS This diagnosis is excluded because the rate of excretion of NH4+ is not low. This information is deduced using the UOsmolal gap as follows: • Calculated UOsm = 2 (UNa [60 mmol/L] + UK [20 mmol/L])+ (UUrea [100 mOsm/L]) = 260 mOsm/L • UNH4 = ½ (Measured UOsm − calculated UOsm) (i.e., [0.5 (566 − 260 mOsm/L)]) = 153 mmol/L • Because the UCreatinine is 8 mmol/L, the UNH4/UCreatinine is close to 20. If we assume that the urine creatinine excretion is 10 mmol/day, this represents a 24-hour NH4+ excretion of 200 mmol.
These are listed with a few comments because most of the dangers were discussed in Case 3-1. The dangers to anticipate are a fall in the PK, a further fall in the PHCO3, and too rapid a rise in the PNa. There could also be nutritional issues. Further fall in the PK: Just as in the previous case, reexpansion of the effective arterial blood volume can lead to a fall in α-adrenergics and thereby to a rise in insulin levels. In addition, as renal perfusion improves, the excretion of hippurate at a rate faster than NH4+ could lead to very high rates of excretion of K+. Again, if HCO3− and/or glucose is administered, this could further aggravate the degree of hypokalemia owing to a shift of K+ into cells. Further fall in the PHCO3: Just as in the previous case, the PHCO3 falls for a number of reasons when isotonic saline is administered. The dilemma is balancing the need for giving exogenous HCO3− versus the danger of causing an acute fall in the PK. In the opinion of the authors, K+ replacement should take precedence. If there is a need to administer HCO3− early on, give NaHCO3 with sufficient KCl to prevent a fall in the PK; this should be done in a setting where cardiac and respiratory monitoring can be carried out. Too rapid a rise in the PNa: This is very important in a patient who is poorly nourished and/or K+ depleted, because these are risk factors for the development of osmotic demyelination during therapy. Our rationale for administering dDAVP at the outset of therapy is discussed in Chapter 10, page 331. What is the basis of the metabolic acidosis? Because the PAnion gap is in the normal range, one might have thought that the metabolic acidosis was not due to a gain of acids. Nevertheless, the rate of excretion of NH4+ was high (see margin note), and the accompanying anions were not Cl−. This case represents the overproduction of an organic acid with the rapid excretion of its anion in the urine. Metabolic acidosis develops because some of the anions are excreted in the urine with Na+ and K+ (not NH4+ or
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73
Toluene 1 Hippuric acid
HCO 3
–
2 H
H 2O + CO 2
+
+ Hippurate
–
3
4 Hippurate– + NH4+
5 Hippurate– + Na+ + K+
FIGURE 3-2 Metabolic acidosis due to the metabolism of toluene. The metabolism of toluene occurs in the liver, where benzoic acid is produced via alcohol and aldehyde dehydrogenases. Conjugating benzoic acid with glycine produces hippuric acid (all represented as site 1 for simplicity). The H+ are titrated by HCO3− for the most part (site 2). The hippurate anions are filtered and also secreted in the proximal convoluted tubule (site 3). Therefore, instead of accumulating in blood and increasing the PAnion gap, they are excreted in the urine. Some of the hippurate anions are excreted in the urine with NH4+ (site 4) and others with Na+ and K+ (site 5), when the capacity to excrete NH4+ is exceeded. The excretion of hippurate anions with Na+ and/or K+ (and not NH4+) leads to the persistence of the metabolic acidosis, extracellular fluid volume contraction, and hypokalemia.
H+), and hence there is an indirect loss of NaHCO3 (see Fig. 4-2, page 78). The most likely basis for the metabolic acidosis in this patient is glue sniffing with the production of hippuric acid and the excretion of hippurate anions in the urine at a rate that exceeds that of NH4+ (Fig. 3-2). DISCUSSION OF QUESTIONS 3-1 In a patient with cholera and metabolic acidosis due to the loss of NaHCO3 in diarrhea fluid, the ECF volume is contracted by close to 50%, yet O2 delivery to tissues is adequate to avoid anaerobic metabolism. Should this patient have an elevated value for the PAnion gap? The oversimplified and incorrect answer is that there is no change in the PAnion gap when there is a net loss of Na+ and HCO3−. Notwithstanding, because most of the PAnion gap is due to the net negative charge on albumin, the value for this gap would be higher if the PAlbumin were to rise because of a contracted plasma volume. In quantitative terms, the net valence on albumin is close to 16 mEq/L per 4.0 g albumin/dL. When the PAlbumin is 8.0 g/dL, the expected rise in the PAnion gap is close to 16 mEq/L above the usual 12 ± 2 mEq/L (see margin note). Moreover, there appears to be a rise in value for the negative valence on albumin when the effective arterial blood is contracted. Therefore, the rise in PAnion gap in this setting does not represent the addition of new acids.
PAnion gap In this calculation for the rise in the PAnion gap, we assumed that the PK did not change.
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3-2 Why might pulmonary edema develop before the Ecf volume is fully reexpanded in this patient with cholera? The clinicians who treated severely ill patients with cholera were very surprised when 5 of their first 40 patients developed pulmonary edema when they received isotonic saline at a rapid rate. In fact, the positive balance of saline was significantly less than what would be needed to fully reexpand the ECF volume. Even more surprising was the fact that pulmonary edema was ameliorated when isotonic NaHCO3 was infused at a rapid rate, whereas other treatments for pulmonary edema were not successful. One speculation to explain these observations was that the more severe degree of acidemia that developed following partial reexpansion of the ECF volume with isotonic saline led to a more intense constriction of the peripheral venous capacitance vessels and thus a larger increase in the central blood volume. Because pulmonary edema could be reversed by the administration of a solution that contains HCO3−, these patients should receive an isotonic solution (to the patient) that contains close to 40 mmol NaHCO3 or its equivalent (e.g., sodium l-lactate) to match the concentration of HCO3− in diarrhea fluid. As men tioned previously, one must be extremely cautious if the patient has hypokalemia.