Nephrology Hypertension

Acid/Base Disorders: Metabolic Acidosis

Does this patient have metabolic acidosis?

  • Metabolic acidosis is defined as a low arterial pH (normal range 7.35-7.45) and a low serum bicarbonate (HCO3) concentration (normal range 22-28 meq/L)

  • Metabolic acidosis occurs when there is excess acid in the plasma. In the basal state, the body generates about 12,000 to 13,000 mmol of carbon dioxide (CO2), and 1-1.5 mmol per kilogram body weight of nonvolatile acid. The body has a large buffering capacity, with CO2-HCO3 as the major buffer system. The two major routes of acid excretion are the lungs (for CO2) and the kidneys (for nonvolatile acid)

  • Metabolic acidosis can be caused by three major mechanisms: 1) increased acid production; 2) bicarbonate loss; and 3) decreased renal acid excretion

  • Increased acid production leads to anion-gap (AG) metabolic acidosis, and involves a variety of different clinical processes, see Table 1

  • Both bicarbonate loss and decreased renal acid excretion lead to normal-anion gap (NG) metabolic acidosis. When there is HCO3 loss, chloride is retained to maintain electrical neutrality. The different clinical processes are summarized in Table 2

  • Toxic ingestions are common causes of AG metabolic acidosis. Both methanol and ethylene glycol intoxications are frequently encountered. Methanol and ethylene glycol are quickly aborbed from the GI tract. Peak serum levels are usually reached within 1-2 hours. As these parent alcohols go through a two-step metabolism (via alcohol dehydrogenase and aldehyde dehydrogenase), they first elicit a high serum osmolar gap (>10), followed by a high AG when the osmolar gap returning toward normal. The toxicities mainly come from their metabolites.

  • Formate is the final metabolite from methanol, and glycolate, glyoxylate and oxalate are end metabolites from ethylene glycol. They accumulate and cause end-organ damage once the parent alcohol reaches a critical serum level (~20 mg/dl). However, because of slow hepatic metabolism, there is usually a latent period of 24-48 hours before these toxicities manifest, especially if there is coningestion of alcohol. If treatment is not instituted, permanent damage may ensue. Both methanol and ethylene glycol are excreted primarily by the kidneys, though the lung contributes to some degree of methanol elimination

  • Salicylates can also cause AG metabolic acidosis. Salicylates are readily absorbed from the small intestine, and are metabolized in the liver through glycine conjugation. The amount of drug excreted unchanged in the urine is small, but can be dramamtically increased with alkalization of urine. The mechanism of AG metabolic acidosis in salicylate is still unclear, but is thought to be secondary to inhibition of the Krebs cycle and subsequent accumulation of organic acids, e.g., lactic acid and ketoacids. Salicylates also commonly cause respiratory alkalosis in adults due to respiratory center stimulation

  • Inhalation of toluene can lead to both AG and NG metabolic acidosis. The AG is caused by the metabolite of toluene, hippuric acid. Toluene may also cause renal tubular damage after longterm use, and lead to RTA and NG acidosis. Toluene toxicity is associated with profound hypokalemia

  • 5-oxoproline is a rare cause of AG metabolic acidosis, and it is usually seen in patients with a high accumulative acetaminophen intake. Risk factors include sepsis, liver and/or kidney dysfunction

  • Lactic acidosis caused by either lactic acid overproduction from tissue hypoxia or lactic acid underutilization from thiamine deficiency or liver diseases. D-lactic acidosis is unique, as it is not metabolized by L-lactate dehydrogenase in human. It occurs in patients with short-bowel syndrome. When the small bowel is bypassed, large amount of carbohydrates are delivered to the colon, where there is an abundance of gram-positive anaerobes (e.g., Lactobacilli). Carbohydrates are metabolized into D-lactate which are then absorbed. Since D-lactate is not measured routinely when serum lactate is ordered, it should be specifically requested if D-lactic acidosis is suspected

  • Ketoacidosis occurs when there is an increased conversion of fatty acids to ketoacids (acetoacetate, β-hydroxybutyrate) in several pathological conditions, espeically when insulin is lacking. In diabetic ketoacidosis, NG metabolic acidosis is often enountered later in the course due to renal excretion of ketoacids. The lost ketoacids are potential source of serum HCO3

  • Chronic kidney disease with decreased renal function is a common cause of metabolic acidosis. In the early phases with moderate functional decline (stage 3 & early stage 4), the kidney is still able to excrete organic acids, therefore AG acidosis is not common. Patients usually manifest NG metabolic acidosis due to decreased ammonium excretion. Once renal function declines to a critical level, usually at late stage 4, acids from protein metabolism are retained, resulting in AG metabolic acidosis

  • There are three major types of renal tubular acidosis (RTA): 1) type 1 (distal, RTA-1); 2) type 2 (proximal, RTA-2) and 3) type 4 (distal from low aldosterone or aldosterone resistnace, RTA-4). RTA-1 results from a defect in distal tubular acid excretion as a result of decreased H+ secretion or back leak of secreted hydrogen. It can be severe and results in progressive HCO3 loss (serum concentration <10 meq/L). Urine pH in these patients is typically above 5.5. It stimulates bone resorption, and results in hypercalciuria and nephrocalcinosis. Hypokalemia is also common secondary to renal K wasting, and muscle weakness is a common complaint. Occasionally, an incomplete form of RTA-1 may occur. Common findings include NG acidosis and alkaline urine with hypocitraturia. However, patients with this imcomplete form of RTA-1 are able to maintain serum bicarbonate levels unless stressed.

  • Type 2 RTA results from proximal tubule HCO3 wasting. The threshold for tubular HCO3 reaborption is likely reset in these cases since patients are able to maintain their serum bicarbonate levels between 12-20 meq/L, and the alkali therapy results in HCO3 wasting. Urine pH in these cases can be variable. Milder form of hypokalemia is common. Type 4 RTA results from decreased aldosterone action either due to reduced hormone level or functional resistance. Acidosis is often mild, with serum bicarbonate usually reaches 16-18 meq/L. Urine pH commonly falls below 5.5, and hyperkalemia is the most prominent abnormality. The etiologies of RTA are summarized in Table 3

  • The history is an essential part of initial evaluation, though oftentimes, it is not available or simply unreliable. Histories from relatives and prehospital caregivers are improtant. Old patient records as well as details of recent hospitalization should be thoroughly reviewed

Table I.

Table II.

Table III.

Causes or RTA

What tests to perform?

  • First, measure arterial pH, PCO2, and serum bicarbonate concentration

  • In cases of acidic pH and low serum bicarbonate, check 1) AG; 2) whether there is a superimposed respiratory acidosis or alkalosis. This can be ascertained by determining whether the degree of respiratory compensation is appropriate (Table 4)

  • Serum AG=serum Na - serum (Cl +HCO3); The measured rather than the corrected serum sodium is used for calculations. The AG is determined primarily by negative charges in serum proteins, in particular, serum albumin. Normal serum AG ranges from 6 to 12 meq/L, but varies between different laboratories. The normal AG decreases when the serum albumin is low or unmeasured serum cations are high (e.g., hypercalcemia). The AG typically decreases by 2.5 meq/L for every 1 g/dl reduction in serum albumin

  • In complicated mixed acid-base disorders, metabolic acidosis may be less obvious. It is important to establish the primary acid-base disorder first, then check the compensatory response to assess for superimposed acid-base disorders, see Table 4

  • To further assess metabolic acidosis, determine delta AG (ΔAG). ΔAG=AG(measured)-AG(normal). If ΔAG +serum HCO3 <20, then there is NG metabolic acidosis in addition to AG metabolic acidosis. If the delta gap plus serum HCO3 > 28 then there is a metabolic alkalosis as well.

  • If an AG metabolic acidosis is established, additional tests to determine the causes should be ordered based on the history and physical findings

  • The diagnosis of D-lactic acidosis should be entertained in patients with short bowel syndrome. These patients present with AG acidosis, negative ketones, and normal serum lactate level by routine lactate testing. The diagnosis is likely if the acidosis worsens with oral intake. It requires special testing for D-lactate

  • Since alcohol delays the metabolism of methanol and ethylene glycol, AG acidosis may not be present in patients co-ingesting significant amount of alcohol. In such cases, elevated serum osmolar gap may be helpful in establishing the diagnosis. The urinalysis may provide important clue to the presence of ethylene glycol. Calcium oxalate crystals is common in urine (though not specific) if sufficient ethylene glycol has been ingested. The definitive test to daignose toxic ingestion is to measure the levels of the toxin in the serum. However, the test may not be readily available when there is a need for urgent decision-making.

  • Since salicylate enhances uric acid excretion in the kidney by competing with the organic acid transporter, it may be helpful to measure serum uric acid level as well as urine uric acid to creatinine ratio. A decrease in serum uric acid along with an increase in urinary uric acid/creatinine suggests salicylate intoxication.

  • For NG metabolic acidosis, the urinary AG is often used to distinguish between renal and extra-renal HCO3 losses. Urinary AG= urine (Na +K -Cl). A negative value indicates extra-renal causes of acidosis, either from increased oral acid load or bicarbonate loss from the gastrointestinal tract. For example, severe diarrhea causing significant gastrointestinal HCO3 loss, results large amount of urinay NH4+ production as a compensatory response. The increased NH4+ excretion s lead to higher urine Cl losses and, therefore, a negative urinary AG

  • To distinguish between different types of RTA, both urine pH and serum K are helpful. Alkaline urine, hypokalemia and hypercalciuria with evidence of kidney stone formation suggest type 1RTA, whereas relative acidic urine with hyperkalemia suggests type 4 RTA. In addition, the acidosis in type 1 RTA is usually severe, compared to those in type 2 and 4

  • Once NG metabolic acidosis is confirmed, additional testing will be based on the suspected diagnoses. Radiological imaging has limited role in the acute management of metabolic acidosis, except in rare occasions, imagings may be helpful in establishing tissue/organ ischemia, nephrocalcinosis and other processes that are associated with a particular acid-base disorder

Table IV.

Compensation table.

How should patients with metabolic acidosis be managed?

  • pH <7.1 or severe acute acidosis with compromised hemodynamics is considered a medical emergency as there may be significant neurological complications and high risks of cardiac arrhythmia. Treatment with intravenous bicarbonate is warrented (Class IIa recommendation). The initial goal is to raise serum pH to 7.15, or serum HCO3 to 15. The initial dose will be based on the HCO3 deficit. Typically 50% of the deficit is given as an iv bolus, the rest is given over 6-12 hours. Occasionally, hemodialysis may be needed for bicarbonate repletion. Bicarbonate therapy may not be needed. In ketoacidosis (diabetic or alcoholic) since organic anions can be converted to HCO3 rapidly after administration of insulin (DKA) or glucose (AKA). Thus exogenous bicarbonate should be administered with caution in keto acidosis and lactic acidosis to prevent overshoot metabolic alkalosis.

  • Calculation of bicarbonate deficit. Terms: VOD=volume of distribution in liters; BW=body weight in Kg; HCO3 deficit=VOD for HCO3 x HCO3 deficit per liter. HCO3 VOD varies per serum HCO3 levels. In severe deficiency, the VOD increases significantly due to contributions from intracellular space and bone. Easy rule of thumb: if serum HCO3 >10 meq/L => VOD =0.5 x BW; if serum HCO3 between 5-10 meq/L => VOD =0.75 x BW; if serum HCO3 <5 meq/L => VOD=1 x BW. HCO3 deficit per liter =target HCO3 level - initial serum HCO3 level

  • Intravenous NaHCO3 comes as 8.4% (1N) solution.. To administer an isotonic solution, three amps (150ml) of NaHCO3 are mixed with 1 liter of D5W to get ~150 meq/L of NaHCO3. Oral NaHCO3: one tablet (650 mg) provides ~7.7 meq of HCO3

  • The potential complications of bicarbonate therapy are: 1) CO2 generation, leading to worsening intracellular acidosis; 2) reduction of ionized serum calcium, as Ca and H+ compete for albumin binding. Rapid increases of pH may lead to more Ca binding to albumin and reduction of ionized Ca; and 3) volume overload

  • The use of bicarbonate in cases of organic acidosis (e.g., ketoacidosis and L-lactic acidosis) is highly controversial. In patients with severe acidosis (pH<7.1) and compromised hemodynamics, bicarbonate therapy is warrented (class IIa recommendation), since severe acidemia may lead to continued tissue hypoperfusion from reduced cardiac function and impaired oxygen delivery. However, studies thus far fail to show any benefit in hemodynamic improvement or mortality

  • For lactic acidosis, it is most important to correct the underlying abnormalities, such as restroration of tissue perfusion and treatment of underlying malignancies

  • For diabetic ketoacidosis, insulin therapy needs to be started immediately. At the same time, aggressive fluid and electrolyte management should be instituted

  • For D-lactic acidosis, mild cases often do not require treatment except restriction of carbohydrate intake. In more severe cases or patients with symptoms, treatment typically involves administration of NaHCO3 (PO or iv) and oral antimicrobials including Metronidazole or Vancomycin

  • For methanol or ethylene glycol intoxication, the serum toxin level may not be readily available at the time of clinical decision-making. Treatment should not be delayed, as permanent end-organ demages may occur if left untreated. Patients should be monitored closely in an ICU setting and managed accordingly for airway, breathing and circulation.

  • The first step of therapy is to block the metabolism of these parent alcohols, An ethanol drip (iv, 5%-10% solution in D5W, and target serum alcohol concentration of 100 mg/dl) has been used with success. However, CNS sedation, difficulty in dosing and other complications have limited its use. Formepazole was approved in 1997 as an antidote for methanol and ethylene glycol intoxications. Its binding affinity for alcohol dehydrogenase is 8,000 times greater compared to alcohol and has been proven to be highly effective with minimal complications. It should be started immediately in cases of suspected ingestions.

  • The typical regimen includes initial loading of 15 mg/kg iv bolus, then 10 mg/kg (increase to 15 mg/kg after 48 hours) iv bolus every 12 hours, until the serum level of parent alcohol is undetectable or below 20 mg/dl and patient becomes asymptomatic with normal pH. The Fomepazole dosing regimen needs to be adjusted in patients receiving dialysis.

  • After the initiation of therapy with either ethanol or Formepazole, hemodialysis may be needed to facilitate the removal of the parent alcohol. Hemodialysis should be considered in cases of renal failure, significant or worsening metabolic acidosis, or measured parent alcohol level >50 mg/dl. Of note, thiamine and pyridoxine have been used in ethylene glycol intoxication, as they are involved in alternative elimination pathways of glyoxylate. To date, there is no data to prove their efficacy

  • Since urinary excretion of salicylate can be significantly increased in alkaline urine, it is a common practice to induce alkaline diuresis. NaHCO3 iv (150 mmol mixed in 1 liter of D5W) is used to raise urine pH to 7.5 or above. Typically, a rate of 0.5 mmol/kg/hr is initiated and titrated to the target urine pH. Importantly, KCl (usually starts at 40 meq iv) needs to be added to the regimen since body potassium depletion is invariably present and may be masked by acidosis.

  • It is important to monitor serum potassium and magnesium and replete aggressively. Hemodialysis is effective in removing salicylate and is indicated 1) in patients with serum salicylate level >90 mg/dl (regardless of renal function), or 2) in patients with reduced renal function and serum salicylate level >75 mg/dl, or 3) in those with severe metabolic acidosis (pH<7.1), or 4) in those with severe or progressive clinical decompensation

  • For Toluene toxicity, treatment is usually supportive, i.e., maintain hydration, replete potassium and other electrolytes, and use bicarbonate therapy in severe cases (pH<7.2). Recovery is usually rapid. Since Toluene is lipophilic and stored in body fat, dialysis is usually not effective.

  • In cases of RTA-1, alkali therapy with NaHCO3 is strongly indicated, to correct acidosis and maintain bone health. Bicarbonate therapy also effectively repletes intravascular volume (volume depletion is common in RTA-1). K supplementation is rarely needed, though K-citrate may be indicated in patients who have active kidney stone disease. In RTA-2, alkali therapy is generally not indicated except in pediatric patients, where it has been suggested that RTA-2 is associated with poor growth. If alkali therapy is used, expect a higher than usual dose due to high renal wasting. K wasting will become significant with alkali therapy, and supplementation is often required.

  • Of note, there is anecdotal success with thiazide diuretic in RTA-2. It causes slight intravascular volume depletion and therefore, stimulates HCO3 reabsorption. In RTA-4, dietary K restriction and diuretic for volume control are the mainstay of therapy. Fludrocortisone (at a dose of 0.05mg to 0.2mg PO daily) is commonly used in patients with primary adrenal insufficiency, though its use in secondary hypoaldosteronism is limited by hypertension and volume overload.

What happens to patients with metabolic acidosis?

  • Patients with metabolic acidosis often present with nonspecific symptoms, including headache, chest pain, palpitation, shortness of breath, nausea, vomiting, muscle weakness, and bone pain. In some patients, there may be rapid deep breathing, anxiety, and change in mental status. Severe acidosis can lead to seizure, coma, cardiac arrhythmia and arrest. If metabolic acidosis is recognized and treated promptly, patients may not experience any longterm complications

  • For patients with metabolic acidosis from methanol or ethylene glycol, central nervous system (CNS) sedation is a common manifestation. As mentioned earlier, the main toxicities come from metabolites of these parent alcohols. The final metabolite of methanol (formic acid) is highly toxic to the retina, and can lead to permanent blindness. The final metabolites of ethylene glycol target the kidney primarily, and lead to acute tubular injury and tubular obstruction from oxalate crystallization

  • In the early stage of methanol intoxication, patients may be relatively asymptomatic, but worsening CNS sedation and cardiopulmonary decompensation may develop soon after. Survivors have a high incidence of permanent blindness. Gastrointestinal symptoms are also common.

  • There are several stages of ethylene glycol intoxication. Stage 1 occurs up to 12 hours after ingestion. Patients present with acute alcohol-like intoxication. CNS sedation of varying degree is common, and in severe cases, arrthymia may occur as a result of decreased serum ionized calcium. Stage 2 occurs from 12 to 24 hours after ingestion. Patients experience cardiopulmonary symptoms, including tachycardia, tachypnea and in severe cases, shock. Stage 3 is usually the late stage, occurs 24 hours after the ingestion. Patients develop acute kidney injury, commonly, oligoanuric renal failure

  • Patients with significant salicylate overdose may present with coma, with or without hyperventilation. Prognosis is related to the serum salicylate level, age, comorbid illnesses and degree of clinical decompensation

  • Patients with RTA-1 typically experience progressive bone resorption from persistent acidosis if left untreated. They are also more likely to develop kidney stone disease due to high urinary calcium excretion and low urinary citrate excretion

How to utilize team care?

  • Specialty consultations: A multidisciplinary approach should be adopted to care for patients with severe metabolic acidosis. The Intensive Care Team should be involved if there is severe acidosis with compromised hemodynamics, as well as in patients with significant intoxication. The nephrology service should be consulted for acute management of acidosis, and in cases of life-threatening acidosis or significant toxic ingestion, hemodialysis may be indicated. The Poison Control Center should be contacted immediately if toxic ingestion or drug overdose is suspected. Oftentimes, patients will develop neurological and cardiac decompensation from severe acidosis, especailly in those with pre-existing neurological disorders and heart diseases, therefore neurology and cardiology services may also be involved

  • Nursing care: Intensive nursing care is important in patients with severe metabolic acidosis, patients should be monitored closely for vital signs, new physical findings as well as signs of new or ongoing organ dysfunction (e.g., low urine output, etc)

  • Pharmacists: Pharmacy service is an essential component of multidisciplinary team for management of metabolic acidosis. They can assist in identifying potential medications that contribute to the acidosis, as well as safe-guard against complications from incorrect drug dosing or drug interactions

  • Dietitians: Dieticians should be involved in cases of ketoacidosis from diabetes or starvation, in patients with short bowel syndrome, in patients with chronic kidney disease, as well as in patients who develop acidosis from TPN

Physiology

  • The kidney is a vital organ for maintaining normal physiological pH. It does so by 1) reabsorbing filtered HCO3 and 2) excreting excessive H+. The promixal tubule is responsible for reabsorbing the majority (~80%) of the filtered HCO3 load, whereas the distal nephron claims the rest. Excretion of acid occurs primarily via ammonium excretion (responsible for ~2/3 of acid load), titration by intraluminal weak acids (e.g., HPO42-)(responsible for ~1/3 of acid load), and to a much less extent, free H+ excretion.

  • An important part of renal compensation for acidosis is the enhanced production and excretion of ammonia. Ammonia buffers through the following reaction: NH3 + H+ <—> NH4+. It is produced by the proximal tubular cells via deamindation and deamination of glutamine. Ammonium is then secreted into the tubular lumen by the Na+/H+ antiporter. When it reaches the loop of Henle, NH4+ replaces K+ at the luminal NKCC2 transporter and is reabsorbed (and soon dissolves back into NH3 and H+). This results in a high concentration of ammonium in the medullary interstitium, which then drives diffusion of NH3 back into the lumen at the collecting duct (CD). In the CD, NH3 binds with the secreted H+ and is trapped inside the lumen due to its ionic charge. NH4+ is finally excreted as the chloride salt. Although approximately 30-80 mmol of NH3 are produced daily by the kidney, NH3 production can be up-regulated so that in severe acidosis, ammonium excretion can reach as much as 300 mmol per day in humans

  • In AG metabolic acidosis from organic acids, body will clear organic anions by 1) renal excretion; and 2) hepatic metabolism. In cases of DKA, aggressive hydration will lead to enhanced renal exretion of ketoacids if kidney function is preserved. It may result in NG metabolic acidosis. Insulin therapy, on the other hand, will lead to enhanced hepatic metabolism of ketoacids. It can lead to rapid regeneration of serum bicarbonate

Are there clinical practice guidelines to inform decision making?

  • No evidence-based clinical practice guidelines available at this time

What is the evidence?

Jacobsen, D. "Methanol and ethylene glycol poisonings. Mechanism of toxicity, clinical course, diagnosis and treatment". Med Toxicol. vol. 1. 1986. pp. 309.

Stacpoole, PW. "Lactic acidosis: the case against bicarbonate therapy". Ann Intern Med. vol. 105. 1986. pp. 276.

Morris, LR. "Bicarbonate therapy in severe diabetic ketoacidosis". Ann Intern Med. vol. 105. 1986. pp. 836.

Cooper, DJ. "Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective controlled clinical study". Ann Intern Med. vol. 112. 1990. pp. 492.

Rodríguez Soriano, J. "Renal tubular acidosis: the clinical entity". J Am Soc Nephrol. vol. 13. 2002. pp. 2160.

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