Acute Diabetes Case Acute Diabetes Case Study EStudy E

Ainsley McDonald

Veronica Nou

Poonam Shrestha

Mary Tormey

What is Lactic Acidosis?What is Lactic Acidosis?

What is LactateWhat is Lactate

Formed from:Formed from:

Pyruvate + NADH + HPyruvate + NADH + H++ <-> Lactate + NAD <-> Lactate + NAD++

All tissues produce lactate under anaerobic All tissues produce lactate under anaerobic conditions.conditions.

Lactate is metabolised predominately in the Lactate is metabolised predominately in the liver (60%) and kidney (30%).liver (60%) and kidney (30%).

Half is converted to glucose and half is further Half is converted to glucose and half is further metabolised to C0metabolised to C022 and water in the citric acid and water in the citric acid

cycle.cycle.

Mechanisms involved in Lactic Mechanisms involved in Lactic AcidosisAcidosis

Lactic Acidosis is due to:Lactic Acidosis is due to:1.1. Excessive tissue lactate productionExcessive tissue lactate production

2.2. Impaired hepatic metabolism of lactateImpaired hepatic metabolism of lactate

In most cases In most cases both both processes are often processes are often contributing.contributing.

DefinitionsDefinitions

Hyperlactaemia:Hyperlactaemia: a level from 2 mmols/L to 5 a level from 2 mmols/L to 5 mmol/Lmmol/L

Severe Lactic Acidosis:Severe Lactic Acidosis: when levels are when levels are greater than 5 mmols/Lgreater than 5 mmols/L

Acidosis:Acidosis: Arterial Blood pH of less than 7.35 Arterial Blood pH of less than 7.35 with a plasma bicarbonate concentration of with a plasma bicarbonate concentration of less than 22 mmol/Lless than 22 mmol/L

Types of Lactic AcidosisTypes of Lactic Acidosis

Type A:Type A:

- Tissue oxygen delivery is inadequate.- Tissue oxygen delivery is inadequate.

Inadequate 02 -> slowing of mitochrondrial Inadequate 02 -> slowing of mitochrondrial metabolism -> pyruvate is converted into metabolism -> pyruvate is converted into lactate.lactate.

Anaerobic MetabolismAnaerobic Metabolism

Types of Lactic Acidosis Types of Lactic Acidosis Ctd.Ctd.

Type B:Type B:

- No clinical evidence of a reduction in - No clinical evidence of a reduction in tissue oxygen perfusion.tissue oxygen perfusion.

- Carbohydrate metabolism is - Carbohydrate metabolism is disordered and excess lactic acid is disordered and excess lactic acid is produced.produced.

Sub- Categories of BSub- Categories of B

Type B1:Type B1: Associated with underlying diseases Associated with underlying diseases eg. Ketoacidosiseg. Ketoacidosis

Type B2:Type B2: Associated with drugs and toxins eg. Associated with drugs and toxins eg. Phenformin and Biguanide hypoglycaemicPhenformin and Biguanide hypoglycaemic

Type B3:Type B3: Inborn errors of metabolism eg. Inborn errors of metabolism eg. Congentital enzyme defects (Pyruvate Congentital enzyme defects (Pyruvate dehydrogenase deficiency.)dehydrogenase deficiency.)

Signs and Symptoms of Lactic Signs and Symptoms of Lactic AcidosisAcidosis

Initially:Initially:

- - Nausea, vomiting, bloating, abdominal pain Nausea, vomiting, bloating, abdominal pain and lack of appetite, difficulty breathing and and lack of appetite, difficulty breathing and diarrhea.diarrhea.

Other signs include:Other signs include:

- - Hepatomegaly, Elevated Liver enzymes, low Hepatomegaly, Elevated Liver enzymes, low bicarbonate, raised lactate and deteriorating bicarbonate, raised lactate and deteriorating

kidney function.kidney function.

Mary’s HistoryMary’s History• 70 years of age, 60kg, BMI of 22kg/m2

• Serum creatinine of 0.15mmol/L (normal range 0.05-0.12mmol/L)

• Creatinine Clearance = [(140-age)*weight]/815*serum creatinine = 34mmol/L

• Medications include: gliclazide 160mg BD, metformin 850mg TDS, glyceryl trinitrate 600mcg PRN, simvastatin 40mg N

• Stable angina for previous 10 months following MI

• Angioplasty for occluded right coronary artery

• Diffuse coronary artery disease not amenable to angioplasty or bypass grafting

• Diabetes (well controlled) – microvascular complications include stable background diabetic retinopathy, minor renal impairment, and reduced peripheral sensation

• Admitted to A&E with severe chest pain – died 10 hours later from lactic acidosis complicating MI.

• So why lactic acidosis?

Mary’s MedicationsMary’s Medications Metformin 850mg TDS – Metformin 850mg TDS –

BiguanideBiguanide indicated for Type 2 Diabetes. indicated for Type 2 Diabetes. Max recommended doseMax recommended dose, (max dose 3g). , (max dose 3g). Metformin accumulation causes the rare adverse Metformin accumulation causes the rare adverse

effect of lactic acidosis effect of lactic acidosis WHICH IS OFTEN WHICH IS OFTEN FATAL.FATAL.

Should be replaced with insulin if possible in cases Should be replaced with insulin if possible in cases of renal impairmentof renal impairment

Contraindicated when creatinine clearance less Contraindicated when creatinine clearance less than 50mL/min as there is a risk of lactic acidosis.than 50mL/min as there is a risk of lactic acidosis.

Mary’s MedicationsMary’s Medications

Gliclazide 160mg BDGliclazide 160mg BD – sulfonylurea indicated for – sulfonylurea indicated for Type 2 Diabetes. On max dose.Type 2 Diabetes. On max dose.

Simvastatin 40mg NSimvastatin 40mg N – rare adverse effects include – rare adverse effects include hepatitis and liver failure, the risk of which is hepatitis and liver failure, the risk of which is increased by pre-existing liver function abnormalities. increased by pre-existing liver function abnormalities. Liver function should be monitored before starting Liver function should be monitored before starting treatment, at 3 months and then at 6 month intervals. treatment, at 3 months and then at 6 month intervals.

Glyceryl Trinitrate 600mcg PRNGlyceryl Trinitrate 600mcg PRN – for treatment of – for treatment of acute angina. BUT there seems to be no long acting acute angina. BUT there seems to be no long acting nitrate for prevention of anginal attacks.nitrate for prevention of anginal attacks.

Management of Lactic AcidosisManagement of Lactic Acidosis

Generally supportiveGenerally supportive Isolate cause of increased lactate production or Isolate cause of increased lactate production or

decreased lactate clearance and treatdecreased lactate clearance and treat Sodium bicarbonate (NaHCOSodium bicarbonate (NaHCO33) used to treat acid ) used to treat acid

base disturbancebase disturbance Role controversial as treats only acidaemia and Role controversial as treats only acidaemia and

not underlying cause, and use may result in not underlying cause, and use may result in sodium and fluid overload, hypokalaemia, CNS sodium and fluid overload, hypokalaemia, CNS acidosis, hypercapnia, and alkalosis as a result of acidosis, hypercapnia, and alkalosis as a result of overshoot.overshoot.

NaHCONaHCO33 required (mEq) = [(HCO required (mEq) = [(HCO33-)-)desireddesired – – (HCO(HCO33-)-)observedobserved * 0.4 * body weight (kg)] * 0.4 * body weight (kg)]

• If patient renally insufficient or there is a threat of hypervolaemia, the Merck Manual 2000 recommends hemofiltration or hemodialysis.

• Another proposed alternative is the use of dichloroacetate, as it enhances the oxidation of lactic acid, but clinical trials so far have shown little benefit.

Clinical chemistry test for Clinical chemistry test for Myocardial InfarctionMyocardial Infarction

Cardiac Enzyme in the bloodCardiac Enzyme in the blood

Cardiac MarkersCardiac Markers Most conclusive evidence for infraction is an Most conclusive evidence for infraction is an

increase in CARDIAC ENZYMESincrease in CARDIAC ENZYMES Specific patterns of enzyme release are Specific patterns of enzyme release are

sensitive and specific markers for acute MIsensitive and specific markers for acute MI Cardiac MarkersCardiac Markers --aspartate transaminase(AST)aspartate transaminase(AST) -Lactate dehydrogenase(LDH) -Lactate dehydrogenase(LDH) -creatinine kinase (CK)-creatinine kinase (CK) - - troponintroponin

CK, CK-MB and CK-MB indexCK, CK-MB and CK-MB index

Creatinine Kinase(CK)Creatinine Kinase(CK)

-rises -rises 4 to 6 hours after M.I., peaks at 12 4 to 6 hours after M.I., peaks at 12 to 24 hours and returns to normal by 3 to to 24 hours and returns to normal by 3 to 4 days4 days

CK-MBCK-MB is more specific than total CK is more specific than total CK CK-MB indexCK-MB index is only calculated when is only calculated when

CK-MB is elevatedCK-MB is elevated

-CK-MB index >2.5-CK-MB index >2.5cardiac damagecardiac damage

Lactase dehydrogenaseLactase dehydrogenase

Specific to heart and changes during MISpecific to heart and changes during MI Rise above the reference range within 24 Rise above the reference range within 24

hours of an AMIhours of an AMI Reaches the peak within 3-6 daysReaches the peak within 3-6 days Returns to baseline within 8-12 daysReturns to baseline within 8-12 days

Troponin in AMITroponin in AMI Troponin level will rise at the same time Troponin level will rise at the same time

as CK,CK-MB but continues to rise for a as CK,CK-MB but continues to rise for a longer periods. longer periods.

Troponin would have risen 4 to 6 hours Troponin would have risen 4 to 6 hours after M.I., after M.I., and its level remains elevated and its level remains elevated for 14 days.for 14 days.

They are very specific for cardiac muscle, They are very specific for cardiac muscle, not elevated with skeletal muscle damage not elevated with skeletal muscle damage or in renal failure as with CK and CK-MB.or in renal failure as with CK and CK-MB.

Lactic acidosisLactic acidosis

A lactate concentration of 5 mEq/L or greater A lactate concentration of 5 mEq/L or greater & arterial pH of 7.35 or less identify & arterial pH of 7.35 or less identify significant lactic acidosissignificant lactic acidosis

Although by definition: a lactate level greater Although by definition: a lactate level greater than 2, levels of 2-5 represent gray areas & are than 2, levels of 2-5 represent gray areas & are of questionable clinical significance of questionable clinical significance (Mizock, 2001, 1997) (Mizock, 2001, 1997)

Lactic acidosisLactic acidosis

Lactate levels of > 5 mM have been associated Lactate levels of > 5 mM have been associated with 30 day mortality of 83% with 30 day mortality of 83% USA study 1994USA study 1994

the higher the blood lactate level the worse the the higher the blood lactate level the worse the prognosis, survival is unlikely at levels >25prognosis, survival is unlikely at levels >25

If the level falls 5-10% within an hour of If the level falls 5-10% within an hour of starting resus - prognosis is fairly goodstarting resus - prognosis is fairly good

? Lactic acidosis in the diabetic? Lactic acidosis in the diabetic

Most diabetics with lactic acidosis are in shock Most diabetics with lactic acidosis are in shock or have severe underlying disorders associated or have severe underlying disorders associated with the syndrome with the syndrome Mizock 1992 1989 Mizock 1992 1989

Usually present with ketoacidosisUsually present with ketoacidosis The incidence of lactic acidosis in patients The incidence of lactic acidosis in patients

with ketoacidosis is low - probably < 10% with ketoacidosis is low - probably < 10% Strangaard 1971Strangaard 1971

Lactate is not elevated well in controlled Lactate is not elevated well in controlled diabetics unless they are acutely ill diabetics unless they are acutely ill Mizock 1989 1992Mizock 1989 1992

Lactic acidosis -ABGsLactic acidosis -ABGs

Acidosis metabolic- caused by the generation Acidosis metabolic- caused by the generation of lactic acid, pCO2 is subnormal if respiratory of lactic acid, pCO2 is subnormal if respiratory compensation occurs & pH varies from normal compensation occurs & pH varies from normal to significantly lowered (guide < 7.35)to significantly lowered (guide < 7.35)

Alkalosis respiratory- there is an antecedent or Alkalosis respiratory- there is an antecedent or coexistent respiratory alkalosis in many coexistent respiratory alkalosis in many conditions associated with LD- a mixed AB conditions associated with LD- a mixed AB disorder is frequently presentdisorder is frequently present

LA-ABGsLA-ABGs

Acute hypoxia is associated with an MIAcute hypoxia is associated with an MI When arterial pO2 was 26-32 mmHg lactate When arterial pO2 was 26-32 mmHg lactate

rose 3-4 mmol/L rose 3-4 mmol/L Huckabee 1958Huckabee 1958 However:However: HyperlacteamiaHyperlacteamia . . Is Is notnot a reliable indicatora reliable indicator of of tissue tissue

perfusionperfusion or or O2 debtO2 debt because multiple mechanisms contribute because multiple mechanisms contribute to the lactate level eg hypoxia, ^aerobic metabolism, to the lactate level eg hypoxia, ^aerobic metabolism, endotoxins & catecholamines endotoxins & catecholamines

LA or DKA or both?LA or DKA or both?

Hyperglyceamia not associated with LA but Hyperglyceamia not associated with LA but with DKAwith DKA

Ketonuria strongly associated with DKAKetonuria strongly associated with DKA Hyperosmolality is associated with DKAHyperosmolality is associated with DKA Suspect LA if level of anion gap high & Suspect LA if level of anion gap high &

ketonuria lowketonuria low

BUNBUN

RF is frequently associated with LA either in RF is frequently associated with LA either in Type a due to poor tissue perfusion or type b Type a due to poor tissue perfusion or type b for which the MOA is unclearfor which the MOA is unclear

Measuring anion gapMeasuring anion gap

Na - (Cl + HCO3-)Na - (Cl + HCO3-) normal was 12 +/- 4 mEq/Lnormal was 12 +/- 4 mEq/L now due to new techniques of measurement in now due to new techniques of measurement in

labs, normal has decreased may be as low as 5 labs, normal has decreased may be as low as 5 to 12 to 12 Merck manual p157 17th edMerck manual p157 17th ed

Anion gap - increased in lactic Anion gap - increased in lactic acidosisacidosis

The decrease in bicarbonate is approximately The decrease in bicarbonate is approximately equal to the increase in the anion gapequal to the increase in the anion gap

It may be an unreliable indicator of LA It may be an unreliable indicator of LA because of hyperchloreamia by N/S IVIs, because of hyperchloreamia by N/S IVIs, hypoalbuminemia, & mixed AB disordershypoalbuminemia, & mixed AB disorders

0.25 x normal - observed albumin + AG = 0.25 x normal - observed albumin + AG = adjusted AG in presence of hypoalbuminemiaadjusted AG in presence of hypoalbuminemia

Other serum levels which may be seen with Other serum levels which may be seen with LALA

phosphatephosphate + in tissue hypoxia with shock+ in tissue hypoxia with shock lower levels- associated with DKAlower levels- associated with DKA CalciumCalcium low Ca possibly due to chelation of free low Ca possibly due to chelation of free

calcium by lactate ions or admin of sodium calcium by lactate ions or admin of sodium bicarbonatebicarbonate

Uric acid high competes with lactate for Uric acid high competes with lactate for excretion excretion

potassiumpotassium

Increased in severe acidosis because hydrogen Increased in severe acidosis because hydrogen cations enter cells and K ions exit to maintain cations enter cells and K ions exit to maintain neutrality, also often due to renal failure neutrality, also often due to renal failure

Normal serum K - may be due to H & lactate Normal serum K - may be due to H & lactate moving into cells together & so not requiring moving into cells together & so not requiring r/o cation out of cellr/o cation out of cell

LFTsLFTs

The liver is the main route for lactate disposal The liver is the main route for lactate disposal by gluconeogenesis or oxidation of lactateby gluconeogenesis or oxidation of lactate

In acidosis gluconeogenesis in the liver is In acidosis gluconeogenesis in the liver is decreased so lactate accumulatesdecreased so lactate accumulates

at pH < 7.0 the liver will actually generate at pH < 7.0 the liver will actually generate lactate.lactate.