Lactic Acidosis — Type A, B & D, MALA, and Lactate Clearance

Overview & definition

The lactic acidosis is the high-anion-gap metabolic acidosis from the accumulation of the lactate. The lactate is the product of the anaerobic glycolysis — the pyruvate is converted to the lactate (by the LDH) when the oxygen is scarce or the mitochondria are overwhelmed. The lactate is normally cleared by the liver (the Cori cycle — the lactate to the glucose) and the kidney. The accumulation causes the high-AG acidosis, and the lactate level and the clearance are the prognostic markers in the critical illness.[1]

The classification (the Cohen and Woods)

Type A — the tissue hypoxia (the commonest)

The Type A is the impaired oxygen delivery. Causes:[1]

• The shock — the septic, the hypovolaemic, the cardiogenic, the obstructive.[1]
• The severe hypoxaemia, the carbon monoxide, the severe anaemia.[1]
• The mesenteric ischaemia (the bowel hypoperfusion).[1]
• The seizures, the severe exercise, the shivering.[1]

Type B — no overt tissue hypoxia

• B1 — the underlying disease: the liver failure (the impaired clearance), the malignancy (the Warburg effect, the leukaemia, the lymphoma), the diabetes, the renal failure, the sepsis (a B-component, though it overlaps the A).[1]
• B2 — the drugs and the toxins: the metformin (the biguanide inhibits the mitochondrial complex I), the linezolid, the propofol infusion syndrome (the PRIS), the NRTIs (the mitochondrial toxicity), the salicylate, the ethylene glycol, the cyanide (the mitochondrial poisoning), the isoniazid, the beta-agonists.[1]
• B3 — the inborn errors of metabolism (the mitochondrial disorders, the glycogen storage diseases).[1]

Type D — the D-lactic acidosis

A special form: the D-lactate produced by the gut bacteria in the short-bowel syndrome (or the blind-loop). The D-lactate is absorbed and causes the high-AG acidosis with the neurological features (the confusion, the ataxia). The D-lactate is NOT measured by the standard L-lactate assay — a special D-lactate assay is required. The treatment: the antibiotics (to reduce the bacterial load), the low-carbohydrate diet, the thiamine.[1]

The pathophysiology and the prognostic

• The pyruvate → lactate (the LDH) in the anaerobic conditions; the lactate-to-pyruvate ratio rises.[1]
• The lactate is cleared by the liver (the Cori cycle) and the kidney. The liver failure impairs the clearance and worsens the accumulation.[1]
• The lactate over 4 mmol/L is the severe lactic acidosis; over 2 is the hyperlactataemia.[1]
• The lactate clearance of over 10 per cent per hour in the sepsis correlates with the better survival (the Jansen 2010; the lactate-guided resuscitation). The rising or the persistent lactate is the poor prognostic sign.[1]

The management

1. Treat the underlying cause (the cornerstone)

• The Type A — restore the oxygen delivery: the fluids, the blood, the inotropes, the vasopressors, the source control (the mesenteric ischaemia, the sepsis), the oxygen, the seizure control.[1]
• The Type B1 — the liver failure (the supportive, the transplant), the malignancy (the chemotherapy).[1]
• The Type B2 — stop the offending drug (the metformin, the linezolid, the propofol); the specific antidote where applicable (the hydroxocobalamin or the sodium thiosulfate for the cyanide, the fomepizole for the ethylene glycol).[1]
• The Type D — the antibiotics, the low-carbohydrate diet.[1]

2. The supportive care

• The ventilation and the haemodynamic support.[1]
• The renal replacement therapy — clears the lactate and the metformin; the high-flux haemodialysis for the MALA.[1]
• The bicarbonate — controversial; the pH under 7.1 (the severe acidosis with the haemodynamic compromise) may benefit transiently, but the bicarbonate generates the CO2 and worsens the intracellular acidosis. Use selectively, not routinely.[1]
• The thiamine for the suspected deficiency (the alcoholism, the malnutrition).[1]

3. The emerging and the specific

• The methylene blue — the mitochondrial electron carrier; emerging for the vasoplegic/septic lactic acidosis (the mitochondrial dysfunction). Controversial.[1]
• The MALA (the metformin-associated lactic acidosis) — the high-flux haemodialysis to clear the metformin and the lactate. The high mortality; the early recognition and the dialysis are the key.[1]

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Exam practice

[1] [1]

Red flags

The Cohen and Woods classification — the deep dive

The Cohen and Woods (1976) classification is the framework the examiners expect — it divides the lactic acidosis by the aetiology rather than the biochemistry.[1] The Type A is the tissue hypoxia (the impaired oxygen delivery or the impaired oxygen utilisation); the Type B is the no overt tissue hypoxia (sub-divided into the B1 — the underlying disease, the B2 — the drugs and the toxins, the B3 — the inborn errors of the metabolism); the Type D is the D-lactate from the gut bacteria. The reality in the ICU is that most of the critically ill have a mixed picture — the sepsis, for example, has the Type A component (the hypoperfusion) AND the Type B1 component (the mitochondrial dysfunction, the impaired clearance) at the same time.[1]

The Cohen and Woods — the comparison table

[1]

The pathophysiology — the anaerobic glycolysis, the pyruvate-to-lactate, and the Cori cycle

The lactate is produced from the pyruvate by the lactate dehydrogenase (the LDH). In the normal aerobic metabolism, the pyruvate enters the mitochondria and is converted to the acetyl-CoA (by the pyruvate dehydrogenase, PDH) → the Krebs cycle → the oxidative phosphorylation → 36 ATP. When the oxygen is scarce (the anaerobic conditions) OR the mitochondrial function is impaired, the pyruvate cannot enter the mitochondria and is shunted to the lactate (by the LDH) → only 2 ATP per glucose (the anaerobic glycolysis is energetically inefficient).[1]

The biochemical pathway

flowchart LR
    A[Glucose] -->|glycolysis| B[Pyruvate]
    B -->|aerobic: PDH| C[Acetyl-CoA]
    C -->|Krebs cycle + OxPhos| D[36 ATP + CO2 + H2O]
    B -->|anaerobic: LDH| E[Lactate + 2 ATP]
    E -->|Cori cycle: liver/kidney| F[Gluconeogenesis]
    F --> A
    E -.->|impaired clearance: liver failure| G[Accumulation → acidosis]

The key enzymes and the rate-limiting steps

• The pyruvate dehydrogenase (PDH) — the gatekeeper. The PDH converts the pyruvate to the acetyl-CoA (the aerobic path). The PDH is inhibited by the NADH (the high NADH/NAD ratio pushes the pyruvate to the lactate). The thiamine is the cofactor for the PDH — the thiamine deficiency impairs the PDH and causes the lactic acidosis.[8]
• The lactate dehydrogenase (LDH) — converts the pyruvate ↔ the lactate (reversible). The equilibrium favours the lactate when the NADH is high.
• The pyruvate carboxylase — the alternative aerobic path; converts the pyruvate to the oxaloacetate (the gluconeogenesis). Requires the biotin.

The lactate-to-pyruvate ratio — the diagnostic clue

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The clearance — the liver and the kidney

The lactate is cleared at approximately 0.5–1.0 mmol/L/hour in the healthy adult. The liver handles about 50–70 per cent of the clearance (the Cori cycle — the gluconeogenesis); the kidney handles the rest (the gluconeogenesis and the oxidation). The liver can clear the lactate up to a maximum of about 4 mmol/L/hour before it is overwhelmed. The hepatic clearance is impaired by the liver failure, the hypoperfusion (the liver ischaemia), the hypoxia, and the severe acidosis (the pH under 7.1 inhibits the hepatic gluconeogenesis — a vicious cycle).[1]

The D-lactic acidosis — the short-bowel syndrome and the gut bacteria

The D-lactic acidosis is the special form. The mammalian tissues produce ONLY the L-lactate (the L-isomer). The D-lactate is produced by the bacteria in the colon. In the short-bowel syndrome (or the jejuno-ileal bypass, or the blind-loop syndrome), the unabsorbed carbohydrates reach the colon in excess; the bacteria (the lactobacilli, the bifidobacteria, the eubacteria) ferment the carbohydrates to the D-lactate; the D-lactate is absorbed and causes the high-AG acidosis.[1]

The clinical features — the neurological and the acidotic

The D-lactate crosses the blood-brain barrier (the D-lactate is a neuromodulator) and causes the neurological features: the encephalopathy, the confusion, the ataxia, the slurred speech, the nystagmus, the irritability — these can mimic the alcohol intoxication. The picture: the short-bowel patient with the unexplained high-AG acidosis + the neurological features + the normal L-lactate.[1]

The KEY — the D-lactate is NOT measured by the standard assay

The standard point-of-care and the laboratory lactate assays use the L-lactate oxidase (or the L-LDH), which is specific for the L-isomer and does NOT detect the D-lactate. The D-lactate requires a special D-lactate assay (the D-LDH enzymatic assay). This is the classic exam trap: the high-AG acidosis with the normal L-lactate in the short-bowel patient → order the D-lactate assay.[1]

The MALA — the metformin-associated lactic acidosis

The metformin (the biguanide) is the first-line oral hypoglycaemic for the type 2 diabetes. The metformin inhibits the mitochondrial complex I → the impaired oxidative phosphorylation → the increased anaerobic glycolysis → the lactic acidosis. The metformin is renally cleared; in the renal failure (the AKI, the CKD) the metformin accumulates and the lactic acidosis supervenes. The MALA is uncommon but the high mortality (the reported mortality of 30–50 per cent).[5]

The MALA — the risk factors

The MALA occurs almost exclusively in the setting of the accumulated metformin — the precipitating factor is usually the acute kidney injury (the AKI from any cause — the sepsis, the dehydration, the contrast, the surgery) in the patient taking the metformin. The other risk factors: the liver failure, the heart failure, the sepsis, the hypoperfusion, the chronic kidney disease, the age over 80, and the iodinated contrast (the held before the contrast). The metformin itself is rarely the sole cause in the patient with the normal renal function — the Cochrane review found no increased risk of the lactic acidosis with the metformin versus the other oral hypoglycaemics in the well-selected patients.[5]

The MALA — the management

• The stop the metformin — the first step.
• The supportive care — the ventilation, the haemodynamics, the correction of the acidosis.
• The high-flux haemodialysis — clears BOTH the metformin (the MW 129, the small, the water-soluble, the low protein binding — the highly dialysable) AND the lactate. The bicarbonate-based dialysate corrects the acidosis. The CVVHDF is the alternative if the haemodynamically unstable. The indications for the dialysis: the lactate over 20 mmol/L, the pH under 7.0–7.1, the metformin level over 5–10 mg/L, the failure of the standard therapy, or the severe AKI.[5]
• The bicarbonate — the controversial; the MALA is the severe acidosis and the bicarbonate (the high-flux bicarbonate dialysate) is used to correct the pH to over 7.1 to support the haemodynamics while the metformin clears. Avoid the over-correction (the sodium overload, the hypernatraemia, the alkalaemia).[5]

The PRIS — the propofol infusion syndrome

The propofol infusion syndrome (the PRIS) is the rare but the fatal complication of the prolonged, the high-dose propofol infusion. The PRIS is a Type B2 lactic acidosis (the mitochondrial toxicity). The pathophysiology: the propofol impairs the mitochondrial fatty-acid oxidation and the oxidative phosphorylation → the lactic acidosis, the rhabdomyolysis, the myocardial failure, the hepatomegaly, the lipaemia.[6]

The PRIS — the risk factors and the threshold

• The high dose — over 4 mg/kg/hour (the infusions over 5 mg/kg/hour for over 48 hours are the high risk).
• The prolonged duration — over 48 hours.
• The concurrent catecholamines (the vasopressors) and the corticosteroids — the additive mitochondrial toxicity.
• The severe head injury, the severe sepsis, the paediatric patient, the poor nutrition — the higher susceptibility. [1]

The PRIS — the clinical features

The PRIS presents with the metabolic acidosis (the high lactate), the rhabdomyolysis (the rising CK), the cardiac failure (the bradycardia, the low-output, the arrhythmias — the classical the Brugada-like ECG), the hepatomegaly (the fatty liver), the lipaemia (the milky serum), the hyperkalaemia, and the renal failure. The mortality is the high (over 50 per cent).[6]

The PRIS — the management

The stop the propofol — the first and the most important step. The supportive care — the ventilation, the haemodynamics (avoid the high-dose catecholamines — they worsen the mitochondrial toxicity), the haemodialysis for the AKI and the acidosis. The carbohydrate replacement (the dextrose — to suppress the lipolysis and the fatty-acid overload). The alternative sedation — the midazolam, the dexmedetomidine, the volatile anaesthetic. The avoid the propofol re-challenge.[6]

The thiamine deficiency and the lactic acidosis

The thiamine (the vitamin B1) is the cofactor for the pyruvate dehydrogenase (the PDH) and the alpha-ketoglutarate dehydrogenase. The PDH converts the pyruvate to the acetyl-CoA. The thiamine deficiency → the impaired PDH → the pyruvate cannot enter the Krebs cycle → the pyruvate is shunted to the lactate → the lactic acidosis. This is a Type B lactic acidosis (the impaired aerobic metabolism — the pyruvate accumulates and becomes the lactate).[8]

The thiamine deficiency — the ICU population

The thiamine deficiency is under-recognised in the ICU. The risk factors: the chronic alcoholism (the poor intake AND the impaired absorption — the Wernicke encephalopathy), the malnutrition, the refeeding syndrome (the thiamine is consumed in the refeeding), the hyperemesis gravidarum, the bariatric surgery, the chronic diuretic use (the loop diuretics increase the thiamine excretion), the dialysis (the thiamine is lost in the dialysate), the sepsis (the Donnino study — over 20 per cent of the septic patients at the ICU admission had the thiamine deficiency).[8]

The thiamine deficiency — the clinical features

The thiamine deficiency causes the Wernicke encephalopathy (the triad — the confusion, the ataxia, the ophthalmoplegia — though only about 10 per cent have the full triad), the high-output cardiac failure (the wet beriberi), the lactic acidosis, and the refeeding syndrome (the thiamine is consumed in the refeeding; the lactic acidosis worsens). The Donnino study found the thiamine supplementation in the thiamine-deficient septic patients improved the lactate and the mortality.[8]

The beta-hydroxybutyrate and the DKA — the ketoacidosis and the lactate

The diabetic ketoacidosis (the DKA) is a ketoacidosis — the high-AG acidosis from the ketone bodies (the beta-hydroxybutyrate, the acetoacetate, the acetone). The DKA also causes the lactic acidosis in about 30–50 per cent of the cases (the volume depletion, the impaired tissue perfusion, and the impaired lactate clearance from the insulin deficiency).[9]

The beta-hydroxybutyrate — the dominant ketone in the DKA

The beta-hydroxybutyrate (the BOHB) is the dominant ketone body in the DKA — the ratio of the beta-hydroxybutyrate to the acetoacetate is approximately 3:1 in the DKA (and rises to 7:1 or higher in the severe DKA or the lactic acidosis). The reason: the beta-hydroxybutyrate is produced from the acetoacetate (by the beta-hydroxybutyrate dehydrogenase) and the equilibrium favours the beta-hydroxybutyrate when the NADH is high (the high NADH/NAD ratio pushes the acetoacetate to the beta-hydroxybutyrate).[9]

The nitroprusside test and the beta-hydroxybutyrate trap

The classical ketone test (the nitroprusside / the Acetest) detects the acetoacetate (and the acetone) but NOT the beta-hydroxybutyrate. This is the classic exam trap: the severe DKA with the minimal or the absent ketones on the nitroprusside because the ketones are predominantly the beta-hydroxybutyrate (the nitroprusside-negative). The treatment (the insulin) shifts the beta-hydroxybutyrate BACK to the acetoacetate → the nitroprusside may transiently turn MORE positive (the "paradoxical" rise in the ketones during the treatment). The bedside beta-hydroxybutyrate meters are now the preferred test.[9]

The lactate clearance as the resuscitation marker — the Jansen 2010 and the ANDROMEDA-SHOCK

The serial lactate measurement is the cornerstone of the goal-directed resuscitation. The lactate falls when the tissue perfusion is restored; the lactate clearance (the percentage fall in the lactate over the time) is the surrogate marker of the adequate resuscitation. The two landmark trials: [1]

The Jansen 2010 — the lactate-guided therapy in the ICU

The Jones 2010 — the lactate clearance vs the ScvO2

The Hernandez 2019 — the ANDROMEDA-SHOCK (the capillary refill vs the lactate)

The methylene blue — the emerging therapy for the vasoplegic lactic acidosis

The methylene blue is the mitochondrial electron carrier — it bypasses the inhibited complex IV and the cytochrome c oxidase (the cyanide, the CO, the sepsis-induced mitochondrial dysfunction). The methylene blue also inhibits the inducible nitric oxide synthase (the iNOS) and the soluble guanylate cyclase → the reduced nitric-oxide-mediated vasoplegia → the increased the SVR and the MAP.[7]

The methylene blue — the indications and the dose

The methylene blue is the salvage therapy for the refractory vasoplegic shock (the septic shock, the post-cardiac-surgery vasoplegia, the anaphylaxis) with the high lactate. The dose: the 1–2 mg/kg IV over 20–30 minutes (the bolus), the repeated as needed, or the 0.25–0.5 mg/kg/h infusion. The onset is the rapid (the minutes). The Zhao 2022 meta-analysis found the increased MAP and the reduced vasopressor requirements but the no clear mortality benefit.[7]

The methylene blue — the cautions

• The serotonin syndrome — the methylene blue is the monoamine oxidase inhibitor (the MAOI); the avoid the SSRIs, the SNRIs, the TCAs, the linezolid, the tramadol, the pethidine (the serotonin syndrome).
• The methaemoglobinaemia paradox — the methylene blue (at the low dose) reduces the methaemoglobinaemia (it is the treatment), but at the high dose (over 7 mg/kg) it can oxidise the haemoglobin to the methaemoglobin.
• The haemolysis in the G6PD deficiency — the screen the G6PD if possible.
• The pulse oximetry artefact — the methylene blue (the blue dye) spuriously lowers the SpO2 (the 85–90 per cent) for the 1–2 minutes after the bolus.
• The urine and the skin discolouration (the blue-green urine, the blue skin) — the benign but the alarming. [1]

The FlowSteps — the structured approach to the lactic acidosis

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The lactate in the specific clinical scenarios — the comparison

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The high-yield exam summary

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References

1. [1]Kraut JA, Madias NE Lactic acidosis N Engl J Med, 2015.PMID 25760366
2. [2]Jansen TC, van Bommel J, Schoonderbeek FJ, et al Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial Am J Respir Crit Care Med, 2010.PMID 20463176
3. [3]Jones AE, Shapiro NI, Trzeciak S, et al Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial JAMA, 2010.PMID 20179283
4. [4]Hernandez G, Ospina-Tascon GA, Damiani LP, et al Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial JAMA, 2019.PMID 30772908
5. [5]Salpeter SR, Greyber E, Pasternak GA, Salpeter EE Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus Cochrane Database Syst Rev, 2010.PMID 20091535
6. [6]Kam PC, Cardone D Propofol infusion syndrome Anaesthesia, 2007.PMID 17567345
7. [7]Zhao CC, Zhai YJ, Hu ZJ, et al Efficacy and safety of methylene blue in patients with vasodilatory shock: A systematic review and meta-analysis Front Med (Lausanne), 2022.PMID 36237547
8. [8]Donnino MW, Carney E, Cocchi MN, et al Thiamine deficiency in critically ill patients with sepsis J Crit Care, 2010.PMID 20646908
9. [9]Dhatariya KK, Umpierrez GE Guidelines for management of diabetic ketoacidosis: time to revise? Lancet Diabetes Endocrinol, 2017.PMID 28372975