Metabolic acidosis

• Metabolic acidosis – a primary decrease in serum HCO3

• HCO3 also low in respiratory alkalosis

• Metabolic acidosis without a low serum pH can occur if there is another acid-base disturbance that increases the serum HCO3 e.g. metabolic alkalosis from vomiting

Renal control of serum pH

• Serum pH is maintained in a tight range via lung control of pCO2 and renal control of HCO3

• The kidneys control HCO3 by 1) reabsorbing all filtered HCO3 (about 4000 mEq/day); defect in: proximal RTA 2) excreting acid produced from diet (about 70 meq/day) primarily as NH4+ and HPO4; defect in: distal RTA

Respiratory compensation in metabolic acidosis

• The change in pCO2 is 1.2 times the change in HCO3 or alternatively put a thumb over the 7 in the pH

• If is adequate respiratory compensation is simple metabolic acidosis

• If inadequate respiratory compensation is a mixed disorder – combined metabolic and respiratory acidosis

Anion Gap

• Na+ - (Cl- + HCO3) = 12 +/- 4 meq/L• Outside of USA most countries exclude the K+ • Another way of thinking of this formula is as

unmeasured anions – unmeasured cations• Unmeasured anions - mostly albumin,

phosphorous, and sulfate• For each 1 gm decrease in serum albumin the

expected anion gap would go down by 2.3• Unmeasured cations - Mg, Ca, paraproteins

Anion gap (AG) interpretation

• Normal initially described as 12 +/-4 but with new ion selective electrodes normal in some hospitals significantly lower

• An insensitive screen for mild to moderate deviations from normal

• Pronounced elevations (e.g. >30) - the identity of the anion is usually obvious

• Less pronounced elevations – the unmeasured anions identity often not clear

delta HC03/delta AG ratio

• Typically is a 1:1 ratio between increase in anion gap and a decrease in HCO3

• If the change in HCO3 exceeds the change in anion gap by 3 mEq/L this suggests that both a high and normal anion gap acidosis are present

• If the change in anion gap is more than the change in HCO3 probably both a metabolic acidosis and metabolic alkalosis are present

• Conversion of high anion gap to normal anion gap can occur if patient excretes the anion from the acid but retains the H+

High AG metabolic acidosis

• Glycols - ethylene and propylene• Oxoproline – pyroglutamic acid• L - lactic acid• D - lactic acid• Methanol – formic acid• Aspirin – multiple organic acids• Renal failure – multiple organic and inorganic

acids• Ketoacidosis – B-OH butyric and acetoacidic

acids

Hyperlactatemia

• Elevated serum lactate without acidosis

• Normal lactate level in critical care patient <2 mm/L

• Minor elevations (as low as 0.75 mm/L) correlate with mortality in patients in ER, ICU, or with sepsis

• Lactate-based therapies in Rx of sepsis

Lactic Acid

• Lactic acid can exist in two forms: L-lactate and D-lactate. In mammals, only L-lactate is a product of metabolism.

• The lab measures only L-lactate• Normal daily production of lactate 15 to 30

mmol/kg per day• All of this lactic acid is converted to CO2

and water with no net acid-base effect

Type A lactic acidosis

• Mechanism – overproduction of lactic acid due to shock, hypoxemia, profound anemia, carbon monoxide, seizures (transient)

• Anaerobic glycolysis of 1 mole of glucose generates ATP but only about 10% of that generated with aerobic glycolysis

• With marked anoxia body can generate 12 mm/min of lactic acid or 12 meq/min of H+

Anaerobic lactate metabolism

• Glucose enters glycolytic cycle in cytoplasm to form pyruvate.

• Since no 02 for oxidative phosphorylation pyruvate can not enter the mitochondria to generate ATP but is converted to lactate

• Lactate generated in muscle goes to liver which converts it to glucose which can be cycled back to muscle (Cori cycle)

Type B lactic acidosis

• Mechanism – not due to overproduction of lactic acid but usually due to decreased liver utilization from genetic defects, drugs, vitamin deficiencies, toxins

• In comparison to type A - much less common, in some cases due to a genetic defect only manifested by a drug or toxin, the acidosis not as severe, since acidosis not as severe may be easier to treat with HCO3

• Causes - congenital defects in glucose and lactate metabolism especially in genetic mitochondrial diseases, liver disease, diabetes, neoplasms, vitamin deficiencies, toxins, drugs

Drugs associated with lactic acidosis

• highly active retroviral agents• ethylene glycol, methanol, propylene glycol• salicylate• metformin, phenformin• clenbuterol - beta-blocker contaminant in heroin• linezolid• propofol – propofol infusion syndrome• propylene glycol solvent - lorazepam• nitroprusside – cyanide formation

Metformin and lactic acidosis

• Package insert – do not give if creatinine >1.4 in female or >1.5 in male

• Precipitated by worsening of CKD via NSAIDs, ACE inhibitors, or contrast

• OD or therapeutic dosage

• Reports of 30-50% mortality

• CRRT can remove the metformin and also help correct the lactic acidosis

Metformin-induced lactic acidosis (MALA) recent article titles

• Does metformin increase risk of fatal or nonfatal lactic acidosis?

• Metformin associated lactic acidosis - is it really just an association?

• Metformin - potential benefits and use in chronic kidney disease

• Metformin does not increase risk for lactic acidosis in type 2 diabetes mellitus

D-Lactic acidosis

• Certain bacteria in the GI tract may convert carbohydrate (cellulose) into organic acids – primarily D-lactic acid which when absorbed is very slowly metabolized

• Most patients who develop D-lactic acidosis have slow GI transit as with blind loops, obstruction, drugs decreasing GI motility

• Often exacerbated by increased carbohydrate intake or antibiotics allowing for overgrowth of lactobacilli

• CNS findings – usually is associated with confusion, dysarthria, ataxia (due to other toxins made by the bacteria)

• D-lactate is not measured when order lactic acid level • Treatment - restrict carbohydrates, hydrate, give bicarbonate

MELAS

• Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes

• Usually presents with seizures

• Almost always diagnosed in childhood

• Diagnosis usually made by molecular genetic testing of mitochondrial DNA

• Adults – case reports, suspect if seizures worsened by valproic acid

Alcoholic ketosis

• Usually a history of long-term alcohol use, reduced food intake, nausea and vomiting

• Starvation ketosis – similar but less severe• Ketone measurement may be normal since beta

hydroxybutyric acid may be 90% of acid present• Increased incidence of sudden death• Treatment – glucose (increases insulin), normal

saline to correct volume loss, thiamine to prevent Wernicke’s encephalopathy, do not need to give HCO3 since as the abnormality corrects the ketoacids are converted to HCO3

Pyroglutamic acidosis

• Consider if unexplained AG acidosis and acetaminophen ingestion - either OD or therapeutic dose

• Some studies have found a high incidence of this if unexplained AG acidosis and CNS changes

• Glutathione levels reduced due to the oxidative stress of an acute illness and suppression from acetaminophen

• Reduced glutathione levels lead to increased pyroglutamic acid levels (oxoproline)

Osmolar Gap

• Serum Osm = 2 (Na) + BUN/2.8 + glc/18• Calculated and determined Osm should

agree within 10 to 15 mOsm/kg. • If not, then serum Na may be spuriously

low OR osmolytes other then Na, glc or urea have accumulated.

• The osmolar gap is a reliable and helpful tool when screening for toxin-associated high AG acidosis

• Must correct for ETOH if present.

Etylene glycol and methanol metabolism

• The major toxicities of these agents are not from the agents themselves but from metabolites

• Methanol produces formic acid & formaldehyde and ethylene glycol produces glycolic acid

• Both are metabolized by alcohol dehydrogenase so if the patient has consumed ETOH this would slow formation of the lethal metabolites

• Alcohol dehydrogenase much more avidly binds to ETOH than to methanol or ethylene glycol

• Fomepizole – alcohol dehydrogenase specific inhibitor, much more effective than ETOH

Ethylene glycol poisoning

• Suicide attempt, substitute for alcohol, homicidal • antifreeze• 3-phase clinical picture

1) 4-12 hrs - CNS/GI phase: inebriation, mimics EtOH intoxication 2) 12-24 hrs - worse acidosis, cardiopulmonary dysfunction, increased HR, increased BP, myocarditis, pneumonia, pulmonary edema, myositis 3) 36-72 hrs - oliguric renal failure

• Clues for this diagnosis - crystals in the urine (due to calcium oxalate formation from the ethylene glycol)

• MW of ethylene glycol=46 so a level of 20 mg/dl would increase AG by 4 and a level of 100 by 16

Methanol poisoning

• Methyl alcohol or wood alcohol• Can be from bootleg alcohol unknowingly

contaminated• As a thinner for shellac and varnish, windscreen

and gasoline antifreeze, fuel for alcohol burning devices

• No symptoms for the first 12 hours• 1 ounce can produce a blood level of 100 mg/dL• Toxicity primarily CNS and optic nerve damage• Molecular weight is 32 so a level of 20 mg/dl

produces an AG of 6 and 100 an AG of 31

Crtieria for Rx in methanol or ethylene glycol poisoning

• plasma concentration >20 mg/dl OR

• documented recent history of ingestion of toxic amounts and osmolal gap >10 OR

• at least 3 of the following – arterial pH<7.3, serum HCO3<20, osmolal gap >10, oxalate crystalluria (with ethylene glycol)

• Unexplained anion gap: NEJM 2009:2216

Hemodialysis for methanol or ethylene glycol

• Goal – to prevent end organ toxicity

• Mechansim – corrects metabolic abnormalities and eliminates nonmetabolized methanol or EG

• Indications – level>50 mg/dL, HCO3<15 or pH<7.3, optic injury from methanol

Propylene Glycol Toxicity

• An alcohol used to enhance water solubility of many hydrophobic IV medications (lorazepam, diazepam, esmolol, nitroglycerin)

• Propylene glycol toxicity from solvent accumulation has been reported in 19%-66% of ICU patients receiving high dose lorazepam or diazepam >2 days.

• Signs of toxicity—agitation, coma, seizures, tachycardia, hypotension

Salicylate intoxication

• Respiratory alkalosis usually accompanies ASA intoxication, but metabolic acidosis may be prominent in children

• The toxicity is primarily due [ASA] in tissues

• The uncharged form HASA crosses cell membranes easily so a primary goal is to prevent metabolic acidosis since would increase conversion of ASA to HASA

ASA intoxication Rx

• Reduction of HASA movement into cells (especially brain cells) – NaHCO3

• Excretion of ASA in urine by alkalination - NaHCO3, acetazolamide (but competes with protein binding of ASA and may increase free levels, if not carefully monitored can cause metabolic alkalosis)

• Hemodialysis – consider: ASA >60 mg/dl, institute >90 mg/dL

Normal anion gap metabolic acidosis

• Gastrointestinal HCO3 loss – diarrhea, loss of pancreatic or biliary secretions, ureteroileostomy or ureterosigmoidostomy, sevelamer

• Renal acidification defects – RTA, CKD, hypoaldosteronism; drugs (Topamax, acetazolamide, spironolactone, amiloride , trimethoprim, cyclosporine, pentamidine, toluene from glue sniffing)

• Administration of acid – cationic aminoacids in TPN

Estimation of urine NH4+

• The acid excreted by the kidney each day is excreted primarily in the form of NH4+

• Acidotic patient with normal AG a decrease in the urine NH4+ suggests a defect in renal acid excretion – distal RTA

• Estimation of urine NH4+ can be done by measuring urine AG (urine Na + K – Cl)

• Negative value suggests high urine NH4+

Adverse consequences of severe acidemia

• Cardiovascular – impaired contractility, vasodilatation, venoconstriction, sensitization to arrhythmias, reduced response to pressors.

• Respiratory - hyperventilation, respiratory muscle fatigue, dyspnea

• Metabolic -- insulin resistance, inhibition of anaerobic glycolysis, protein degradation, decreased ATP synthesis, hyperkalemia

Complications of bicarbonate therapy

• Overshoot alkalosis – due to conversion of lactate or acetate to HC03

• Increase in lactate generation in lactic acidosis• Volume expansion• Increased CO2 production• Hypocalcemia• Hypernatremia – IV NaHCO3 (8.5%) • Cardiac depression

NaHCO3 dose estimation

• Volume of distribution of HCO3 is ½ of the body weight, may be higher with severe acidosis

• To correct the serum HCO3 from 5 to 10 meq/L in a 100 kg man would be 5 x 50 or 250 meq which is about 5 amps of NaHCO3

• 1 amp IV NaHCO3 = 48 meq in 50 cc• 1 gram po NaHCO3 = 12 meq