La2009

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Lactic Acidosis

Dr. tongjun Ma

Emergency department of Tianjin Medical University

General Hospital

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Introduction

LA are important in emergency medicine. common complication of many severe illness

including sepsis , cardiac failure, respiratory failure, hepatic failure, cancer, AIDS, seizure, poisoning and drug therapy

change into multiple organ dysfunction syndrome and the mortality rate is more than 75%

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Content

1. Definition2. Pathophysiology3. Etiology and categories4. Manifestation5. Diagnosis6. Treatment7. Prognosis8. D-Lactic Acidosis

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1. Definition

LA is a metabolic acidosis caused by lactic acid accumulation, pH ↓+ Lactate↑

plasma lactate concentration Normal: 0.5~1.5 mmol/L, average: 1 mmol/L Hyperlactatemia: 2~5 mmol/L Lactic acidosis: >5 mmol/L

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2. Pathophysiology(1) Lactic acid production

Lactate is a key substrate which is simultaneously produced and used by the body tissues All tissues can produce lactic acid, brain, erythrocytes and

skeletal muscle are the main organs Basal lactate production is high, about 1 mmol/kg per

hour(15~20 mmol/kg•d, or 1400 mmol per day for a 70 kg person)

Under some conditions, the production rate can increase 50 times. In severe exercise, lactate levels can rise to very high levels eg up to 30 mmol/L.

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•Main pathways of lactate metabolism.•lactic acid is a metabolic dead-end

•Pyruvate is the sole immediate precursor•Pyruvate is the only route of metabolic transformation

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•There is a balance between pyruvate and lactic acid•catalyzed by LDH (lactate dehydrogenase)•When concentration of pyruvate or NADH increase , the concentration of lactic acid will increase•Under normal conditions, the lactate/pyruvate ratio ranges from 4:1 to 10:1

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•From glucose and alanine •The largest part originates from glucose (or glycogen) via the reactions of glycolysis•A smaller part originates from transamination of alanine

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•Pyruvate can have several metabolic fates•oxidation in the tricarboxylic acid cycle for energy production•transformation into glucose via the gluconeogenesis pathways

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Under aerobic conditions, pyruvate change into acetyl CoA. Acetyl CoA change into CO2 and NADH through the tricarboxylic acid cycle in the matrix of the mitochondria.Under anaerobic conditions, pyruvate change into lactic acid in the cellular cytosol.

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2. Pathophysiology(1) Lactic acid production

Pathological lactate production occurs when – inadequate tissue oxygen supply– defective pyruvate clearance – increased pyruvate or NADH production

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2. Pathophysiology(2) Lactic acid destruction

The half-life of serum lactate is about 60 minutes

Cleared in three ways Gluconeogenesis Oxidation Excretion

renal threshold is 6~10 mmol/L

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2. Pathophysiology(2) Lactic acid destruction

Lactate is utilized mainly by the liver and kidney. About 65% of lactate was cleared by liver. The kidneys can remove 10~20% of the total lactate.

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2. Pathophysiology(3) Mechanisms

Lactic acidosis can occur due toexcessive tissue lactate productionimpaired hepatic metabolismIn most clinical cases both processes

are contributing to the development of the acidosis.

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3. Etiology and Categories

Two types Type A

obvious tissue hypoxiaCommon

Type B tissue hypoxia is not apparentRare Three subtypes: B1, B2, B3

developed by Cohen and Woods in 1976 and it is widely accepted now

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3. Etiology and Categories: type A

Tissue hypoxaemiasevere anemiacarbon monoxide poisoning

Tissue hypoperfusionwith clinical evidence

Hypotension cyanosiscool and clammy extremities

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3.Etiology and Categories

• 76 years old, female• chief complain: sudden severe pain across her mid-abdomen

after dinner and moved to her left flank, vomiting• past history: hypertension, kidney stone• Laboratory data: WBC count 11000 , sodium 140 mEq/L,

serum creatinine 1mg/dl, urine WBC +, urine ketones “trace”

• Ultrasound: hydronephrosis• After admission, she developed shaking chills, T 39℃ ，

blood pressure became progressively lower and was hard to detect several hours later

• serum lactate level was 7.4 , pH 7.24• Diagnosis: Urinary tract infection, septic shock, LA

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3. Etiology and Categories(2) type B1

B1:with underlying disease liver diseases, renal failure ( glyconeogenesis) malignancy (eg, leukemia, lymphoma, lung cancer)

Malignant cells produce more lactate Seizures, severe asthma (enhanced metabolic rate ,

increased Oxygen Consumption )

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B1:with underlying disease thiamine deficiency

coenzyme of pyruvate dehydrogenase, can lead to defective pyruvate metabolism

Patients receiving total parenteral nutrition (TPN) without intravenous multivitamins (MVIs) supplementation are at risk for thiamine deficiency and life-threatening complications associated with severe deficiency of thiamine

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a 32-year-old man underwent a total coloproctectomy with ileostomy as treatment for fulminant ulcerative colitis.

TPN was initiated immediately postoperatively and included 2087 ml per day of amino acids (92 g) and dextrose (382.5 g) with 21 g fat emulsion, electrolytes, and minerals per day; however, no MVIs were added to the solution.

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Attempts to introduce clear liquids orally on 4th and fifth days after operation were unsuccessful because of persistent severe anorexia, nausea, and vomiting.

7 days after operation ,an upper gastrointestinal barium imaging study revealed delayed transit time, but no mechanical obstruction.

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19 days after operation, TPN was continued without MVIs. the patient was lethargic and weak, and abnormal laboratory findings included severe acidosis :pH 6.87 ; HCO3, 5 mEq/L ; pCO2, 28 mm Hg pO2, 131 mm Hg ; and serum lactic acid of 16 mmol/L serum ketones were negative.

Lactic acidosis of unknown etiology was diagnosed.

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During the next 8 hours, 600 mEq/L of bicarbonate was administered with only modest elevation of pH (to 7.20) .

Because the patient's clinical condition continued to deteriorate, an exploratory laparotomy was performed; however, no focus of infection or bowel necrosis was found.

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An analysis for serum thiamine measured the lowest detectable level of 0.2 mg/dL (normal: 1.1-1.6 mg/dL), and 400 mg of thiamine was administered intravenously.

Two hours later, a blood gas specimen contained a serum pH of 7.50 and an HCO3 of 11.3 mEq/L. Acid/base and clinical status improved; a second dose of 400 mg thiamine was administered intravenously, and pH, pCO2, and HCO3 levels returned to normal.

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3.Etiology and Categories (3)type B2

B2: drugs and toxins Biguanides

phenformin, metforminAntihyperglycemic agent, used to treat type 2

diabetes (overweight, obesity)decrease gluconeogenesisprobably interferes with mitochondrial

function

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B2: drugs and toxins biguanides

The estimated rate of phenformin-associated lactic acidosis ranged from 40 to 64 cases per 100,000 person-years, which has a 50% fatality rate.

In 1977, phenformin was banned by the FDA. With the Cessation of phenformin therapy,

lactic acidosis in diabetes become uncommon

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The lactic acidosis rate in metformin users is much lower, 9 cases per 100,000 person-years.

Metformin is contraindicated because of an increased risk of lactic acidosis :

elevated serum creatinine levels (> 1.5 mg/dl for males and > 1.4 mg/dl for females)

hepatic impairmenthypoxic states (shock, severe heart failure)excessive alcohol intake

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Special X-ray tests that require the injection of contrast media often cause kidneys to be temporarily less efficient in clearing lactic acid

To lessen the risk for lactic acidosis, metformin is stopped before the examination and restarted about 48 hours afterwards if the renal function is normal.

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B2: drugs and toxinsanti-retrovirus drugs

In 1996, AIDS patients were treated with anti-retrovirus drugs.

shortly thereafter, reports of fatal lactic acidosis began to appear.

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20%~80% of individuals develop some metabolic abnormalities

Changes in body habitus( Central obesity)increased plasma lipidsglucose intolerance and insulin resistancehyperlactatemia and lactic acidosis

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mitochondrial toxicitymitochondria has his own DNA and have

their own DNA replicating enzymeincidence rate: Stavudine(d4T) >

zidovudine(AZT)/ didanosine (ddI)> lamivudine (3TC)

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B2: drugs and toxins alcohols and glycols (methanol, propylene glycol)

Overproduction of NADH in the liver Acetaminophen intoxication

inhibiting mitochondrial respiration Cocaine intoxication

seizures or other violent muscle activity , systemic hypoxia

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B3: inborn errors of metabolism Glyconeogenesis enzyme deficiency

glucose-6-phosphatase fructose-1,6-diphosphatasepyruvate carboxylasepyruvate dehydrogenase

MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes)

mutation in mitochondrial DNA gene

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4.Manifestation

Hyperventilation ,dyspnea Cardiovascular compromise is a frequent finding

explaining many of the associated signs, which include cyanosis, cold extremities, tachycardia, hypotension,

lethargy, stupor or coma pH , HC03

- ,AG , lactate

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5.Diagnosis

History Manifestation Laboratory test Exclude:

DKAUremiaIntoxication: such as salicylates , by

toxicology screen

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5.Diagnosis- Laboratory test

In critically ill patients, arterial lactate concentrations are essentially equivalent to those measured in blood sampled from central venous or from pulmonary artery catheter.

This is however not true for lactate measurements performed during cardiopulmonary resuscitation, where arterial concentrations are less than venous concentrations.

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5.Diagnosis- Laboratory test Serial determinations of lactate plasma

concentration give useful information on the evolution of the

metabolic processes more powerful predictors of clinical outcome than a

single determination of lactatemia. blood lactate must be measured as quickly as

possibleshould be brought to the lab on ice

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6.Treatment(1) type A

improve tissue oxygenation is the only effective treatment

Maintenance of airway patency and oxygen delivery100% oxygen by maskIntubate if the patient is unconscious, in

severe shock, or otherwise in unstable condition.

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6.Treatment(1) type A

restoration of the circulating fluid volumeEstablish an intravenous line, Give a fluid

bolus if the patient has tachycardia, hypotension or other signs of poor tissue perfusion

improve cardiac function, such dobutamine Monitor the cardiac rhythm

Acidosis may predisposes to dysrhythmias Empirical antibiotic

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6. Treatment(2) Type B

B1: identification of the primary illness and correctionthiamine (50~100 mg IV followed by 50

mg/d orally for 1~2 wk) may be dramatic and potentially life saving

chemotherapy for malignant disorders B2: discontinuation of causative drugs

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6.Treatment(3) Alkalinization

ControversialNo Prospective studies have shown

improved hemodynamics or outcomes The hydrogen ion may be produced at 72

mmol/ min, alkaline therapy ’s value is doubtful (need 120ml/min 5%HCO3)

Most studies show no change or decrease in intracellular pH

Carbon dioxide leads to subsequent intracellular acidosis

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Controversialmay cause respiratory failure Metabolic alkalosisThe administration of HCO3

- has been observed to reduce cardiac performance in patients with cardiac arrest, CHF, and AMI.

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Conclusion In cardiopulmonary resuscitation, sodium

bicarbonate generally is not recommended Toxic etiologies of lactic acidosis may use intravenous NaHCO3

- to keep the pH above 7.2

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6.Treatment(4) Hemodialysis

Dialysis or continuous hemofiltration Consider hemodialysis in association with

ethylene glycol and methanol poisoning. useful mode of therapy when severe lactic

acidosis exists in conjunction with renal failure or congestive heart failure.

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7. Prognosis

the primary disorder is determinant mortality rates may be 60%~80%,. arterial lactate values of more than 5 mmlo/l on

admission to ICU were associated with a mortality rate exceeding 80% at 30 days

lactate concentration >15 mmol/l, patients rarely survive

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8. D-8. D-Lactic AcidosiLactic Acidosiss

RareD-Lactate made by bacteria from glucose and carbohydrate

L-Lactate normally produced in human beingsLactate dehydrogenase can effectively metabolize only L-lactate, so if D-Lactate was absorbed, it will accumulate in bloodoccur in patients with small bowel resections•Unexplained metabolic acidosis, AG increased •TreatmentTreatment

•fluid resuscitationfluid resuscitation•restriction of simple sugarsrestriction of simple sugars•NaHCONaHCO33 administration as necessary administration as necessary

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Thank youThank you

Health & Medicine

La2009