1. HYPERLACTATEMIA Renie Traiforos, R3 Lab rounds August 28, 2008

2. OUTLINE Case Case Definitions – lactate, hyperlactatemia, lactic acidosis. Definitions – lactate, hyperlactatemia, lactic acidosis. Pathophysiology Pathophysiology Causes of elevated lactate/lactic acidosis. Causes of elevated lactate/lactic acidosis. Significance of elevated lactate Significance of elevated lactate Source of blood for sampling the lactate?? Source of blood for sampling the lactate?? Summary/take home message Summary/take home message

3. CASE 57 yr old female c/o difficulty breathing x 2 days. Hx of cough, sore throat & nasal congestion. 57 yr old female c/o difficulty breathing x 2 days. Hx of cough, sore throat & nasal congestion. Past med significant for smoking & ?COPD Past med significant for smoking & ?COPD Brought in by EMS – worsening SOB and chest pain. Brought in by EMS – worsening SOB and chest pain. Initial assessment: diaphoretic, appears slightly distressed. RR 22-24, HR 128, 113/79, T36.9 Initial assessment: diaphoretic, appears slightly distressed. RR 22-24, HR 128, 113/79, T36.9

4. CASE – cont’d Hgb 180, Wbc 37, bands 13, platelets 178, Hgb 180, Wbc 37, bands 13, platelets 178, creatinine 189, Na 128, K 4.9, Cl 90, CO2 20 creatinine 189, Na 128, K 4.9, Cl 90, CO2 20 ABG 7.26/46/90/20/-7. lactate 3.5 ABG 7.26/46/90/20/-7. lactate 3.5 CXR – large LLL consolidation CXR – large LLL consolidation

5. CASE – cont’d Worsens in the ED (Incr RR, then fatigued, more tachycardic, developed hypotension) Worsens in the ED (Incr RR, then fatigued, more tachycardic, developed hypotension) Rpt ABG: 7.17/53/92/19/-11. lactate 5 Rpt ABG: 7.17/53/92/19/-11. lactate 5 Intubated for impending respiratory failure. ICU admission. Intubated for impending respiratory failure. ICU admission.

6. DEFINITIONS LACTATE: A three carbon intermediary of carbohydrate metabolism, generated from pyruvate with lactate dehydrogenase as a catalyst. LACTATE: A three carbon intermediary of carbohydrate metabolism, generated from pyruvate with lactate dehydrogenase as a catalyst. Under normal circumstances, it made in skeletal muscle, brain, skin & erythrocytes and it metabolized in the liver & kidney. Under normal circumstances, it made in skeletal muscle, brain, skin & erythrocytes and it metabolized in the liver & kidney. N levels: <2 mmol/L (various cutoffs reported) N levels: <2 mmol/L (various cutoffs reported)

7. HYPERLACTATEMIA then is a blood lactate level greater than 2 mmol/L. HYPERLACTATEMIA then is a blood lactate level greater than 2 mmol/L. Sometimes see this subdivided into Sometimes see this subdivided into “mild to moderate” is 2-4 mmol/L and “severe” hyperlactatemia is > 4 mmol/L

8. DEFINITIONS LACTIC ACIDOSIS : LACTIC ACIDOSIS : [lactate] >4 mmol/L + metabolic acidosis [lactate] >4 mmol/L + metabolic acidosis Occurs when lactate production exceeds lactate use or metabolism Occurs when lactate production exceeds lactate use or metabolism Classically seen as a wide anion gap metabolic acidosis Classically seen as a wide anion gap metabolic acidosis

9. LACTATE FORMATION Glycolysis converts glucose into pyruvate. Glycolysis converts glucose into pyruvate. Pyruvate may be transported across mitochondrial membranes and metabolized in Krebs cycle (aerobic cond’ns). Pyruvate may be transported across mitochondrial membranes and metabolized in Krebs cycle (aerobic cond’ns). Or under anaerobic conditions, pyruvate is oxidized to lactate by lactate dehydrogenase. This is a reversible reaction within the liver & kidney, requiring the coenzyme NAD+ (the Cori cycle) Or under anaerobic conditions, pyruvate is oxidized to lactate by lactate dehydrogenase. This is a reversible reaction within the liver & kidney, requiring the coenzyme NAD+ (the Cori cycle)

10. LACTATE FORMATION

11. The Cori Cycle

12. Causes of Hyperlactatemia Elevated lactate can occur due to: excessive tissue lactate production excessive tissue lactate production impaired hepatic metabolism of lactate impaired hepatic metabolism of lactate In most clinical cases it is probable that both processes are contributing. Almost always discussed in the texts as a differential for lactic acidosis. But just remember that depending on buffer reserves and concurrent acid-base disturbances, hyperlactatemia may or may not be associated with acidemia.

13. CLASSIFICATION of LACTIC ACIDOSIS Cohen – Woods classification system Cohen – Woods classification system Type A: Due to tissue hypoxia Type A: Due to tissue hypoxia Tissue hypoperfusion (global – shock, hypotension, cardiac arrest. regional – mesenteric ischemia) Tissue hypoperfusion (global – shock, hypotension, cardiac arrest. regional – mesenteric ischemia) Reduced tissue 02 delivery (hypoxemia, severe anemia, CO poisoning) Reduced tissue 02 delivery (hypoxemia, severe anemia, CO poisoning) Anaerobic muscular activity (seizures, extreme exercise ) Anaerobic muscular activity (seizures, extreme exercise )

14. LACTIC ACIDOSIS – classification Type B: Not due to tissue hypoxia. 3 subtypes: Type B: Not due to tissue hypoxia. 3 subtypes: B1- is due to systemic disorders (note – can lead to Type A) Eg, renal or hepatic dysfunction, sepsis, DM, neoplasms, severe malnutrition B1- is due to systemic disorders (note – can lead to Type A) Eg, renal or hepatic dysfunction, sepsis, DM, neoplasms, severe malnutrition B2- is due to medications/intoxications. Eg, cyanide, salicylates, methanol, ethanol, ethylene glycol, anti-retrovirals, INH, nitroprusside, biguanides. B2- is due to medications/intoxications. Eg, cyanide, salicylates, methanol, ethanol, ethylene glycol, anti-retrovirals, INH, nitroprusside, biguanides. B3 - is due to hereditary inborn errors of metabolism. Eg, G-6-PD, biotin deficiency, mitochondrial disorders. B3 - is due to hereditary inborn errors of metabolism. Eg, G-6-PD, biotin deficiency, mitochondrial disorders.

15. Significance of elevated lactate In a recent paper on severe sepsis and septic shock by Talan et al (Infec Dis Clin North America 2008), it states that elevated lactate levels in sepsis “are associated with poor prognosis”… and “hyperlactatemia is not always accompanied by a low bicarb level and/or elevated AG and thus, a lactate level should be considered if severe sepsis is suspected.”

16. Significance of elevated lactate Studies have shown that anion gap does NOT accurately screen for either lactic acidosis or hyperlactatemia in critically ill patients (Adams et al, Emerg Med J 2006, and Iberti et al, Crit Care Med 1990) Studies have shown that anion gap does NOT accurately screen for either lactic acidosis or hyperlactatemia in critically ill patients (Adams et al, Emerg Med J 2006, and Iberti et al, Crit Care Med 1990) ie – can see a clinically significant rise in lactate without a wide anion gap metabolic acidosis and potentially even with no acidosis. ie – can see a clinically significant rise in lactate without a wide anion gap metabolic acidosis and potentially even with no acidosis. Lactic acidosis or lactate > 4 mmol/L has often been regarded as a sign of poor prognosis (in trauma, sepsis and other shock states) Lactic acidosis or lactate > 4 mmol/L has often been regarded as a sign of poor prognosis (in trauma, sepsis and other shock states)

17. Significance of elevated lactate Not all high lactate levels predict poor outcome though. Keep clinical setting in mind. Eg: elevated lactate in setting of seizure – can be high (30 mmol/L!) but clear within few hrs - likely b/c problem only d/t excess production not impaired lactate metabolism.

18. Drawing a lactate level any evidence for arterial vs central venous vs venous sampling??? any evidence for arterial vs central venous vs venous sampling??? Good correlation b/t arterial & central venous samples (Middleton et al, Emerg Med J, 2006) – this was true for pH, bicarb, BE & lactate values. Good correlation b/t arterial & central venous samples (Middleton et al, Emerg Med J, 2006) – this was true for pH, bicarb, BE & lactate values. One study (Gallagher et al, Ann of Emerg Med 1997) studied the agreement between peripheral venous and arterial lactate levels and concluded “caution should be used in substitution of V-LACT for A- LACT”. In particular found that N venous lactate closely correlate with arterial lactate but that elevated venous levels did not. One study (Gallagher et al, Ann of Emerg Med 1997) studied the agreement between peripheral venous and arterial lactate levels and concluded “caution should be used in substitution of V-LACT for A- LACT”. In particular found that N venous lactate closely correlate with arterial lactate but that elevated venous levels did not.

19. Drawing a lactate level Another study (Lavery et al, J Am Coll Surg 2000) found that in trauma patients venous lactate is “an excellent approximation for” arterial lactate. Another study (Lavery et al, J Am Coll Surg 2000) found that in trauma patients venous lactate is “an excellent approximation for” arterial lactate. It is suggested that in the setting of resuscitating a shock patient in the ED, better to follow central venous or arterial lactate levels. Do we do this? It is suggested that in the setting of resuscitating a shock patient in the ED, better to follow central venous or arterial lactate levels. Do we do this?

20. TAKE HOME POINTS Elevated levels of lactate – many causes. Often a sign of hypoxia. Often associated with bad outcomes. Elevated levels of lactate – many causes. Often a sign of hypoxia. Often associated with bad outcomes. Recognize that patient does not have to have wide AG acidosis or acidosis at all to have a significant hyperlactatemia. Espec true in early sepsis. Recognize that patient does not have to have wide AG acidosis or acidosis at all to have a significant hyperlactatemia. Espec true in early sepsis. It may matter where you draw your lactate level from. ABG/CVBG often considered better than VBG. VBG okay if N level. It may matter where you draw your lactate level from. ABG/CVBG often considered better than VBG. VBG okay if N level.

21. QUESTIONS?????? QUESTIONS??????