Lactate Flashcards

1
Q

Plasma lactate is a late but quantitative indicator of tissue hypoperfusion and can be used as a prognostic indicator and a treatment guide.

Lactate is an intermediary metabolite of glucose oxidation that serves as

Lactate production is an adaptive and protective response to cellular energy deficiency that allows

A

a carbohydrate energy substrate reservoir

continued energy production when cellular energy requirements exceed the capacity of cellular aerobic respiration

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2
Q

Lactate and lactic acid are not synonymous

Lactic acid, CH3CH(OH)COOH

lactate ion is conjugate base to lactic acid C3CH(OH)COOH

As the pKa of lactic acid is 3.8, at physiologic pH, lactic acid is essentially fully dissociated into lactate anions and protons

Increased plasma lactate concentration is termed hyperlactatemia, which may or may not be associated with a net acidemia depending

A

Lactate and lactic acid are not synonymous

is a strong acid that at physiologic pH is almost completely dissociated to the lactate anion CH3CH(OH)COO- and H+

cause of the increased lactate, concurrent acid/base disturbances, and buffer reserves

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3
Q

Glycolysis is the cytosolic process by which
1 mole of glucose is oxidized to

Pyruvate enters the mitochondria and is converted into

under normal aerobic conditions only a small quantity of pyruvate is converted into lactate

catalyzed by

Lactate may then be either transported out of the cell or used within the same cell. Ultimately lactate is either converted back into

A

2 moles of pyruvate
2ATP
2NADH

undergoes decarboxylation to produce acetyl‐CoA
acetyl CoA
proceeds through tricarboxylic acid (TCA) cycle
NADH and FADH2 - supply proton
electron transport chain
oxidative phosphorylation
produce 36 moles of ATP

lactate dehydrogenase (LDH)

pyruvate in local or distant tissues
oxidized to produce energy or converted back into glucose by gluconeogenesis

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4
Q

Glycolysis consumes NAD+ and produces

If there is a cellular oxygen deficiency, the TCA cycle and oxidative phosphorylation are slowed so NAD+ falls and

To allow glycolysis to continue, pyruvate converted into lactate and NADH looses H

Although glycolysis produces only 2 moles of ATP, it is very

A

NADH and pyruvate

pyruvate and NADH build up, thereby hindering ongoing glycolysis

conversion of pyruvate to lactate

fast and so can temporarily satisfy energy demands

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5
Q

Contrary to popular belief, the metabolic acidosis associated with lactate production is due to

Glycolysis produces the lactate ion rather than lactic acid. When the ATP made by glycolysis is utilized, H+ is released into the cytosol. This proton would usually enter the mitochondrion and be used to maintain the proton gradient required for the electron transport chain and oxidative phosphorylation. When oxygen supplies are insufficient this cannot happen and H+ ions accumulate and are then transported out of the cell. Hence, the acidosis from increased lactate production mostly is due to

Nevertheless, stoichiometrically, in acute anaerobic states, 1 mmol/L of lactate is associated with an equimolar production of H+ ions and a concomitant reduction of the standardized base excess of 1 mmol/

There are clinical states in which increased lactate production occurs while H+ consumption by the mitochondria in maintained. The result will be

A

ATP use, not lactate production

reduced H+ consumption, not increased lactate production per se

hyperlactatemia without concurrent acidosis

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6
Q

Lactate is produced in the cytosol and then either

predominant lactate-consuming organs

hepatic metabolism accounts for

renal cortex metabolizes

keeping with its role as a carbohydrate energy substrate (essentially half a glucose molecule), lactate is not excreted in the urine until its plasma concentration is high. It is reabsorbed by the proximal convoluted tubule

renal threshold

A

converted back to pyruvate to proceed through local aerobic cellular metabolism or exported out of the cell and transported to distant tissues in the bloodstream

liver and renal cortex

50% to 70% of lactate consumption, and the liver is capable of metabolizing markedly increased lactate loads

25% to 30% of circulating lactate

6 to 10 mmol/L

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7
Q

Tissue lactate production, distribution, metabolism, consumption, and excretion are different in disease states

dogs with hypovolemia what produces majority of lactate

During hyperlactatemia, some tissues, such as ____ increase their lactate uptake

liver continues to extract lactate until hepatic blood flow is less than

once in plasma lactate equilibrates with

whole blood lactate refers to the sum of

almost all analyzers measure lactate from plasma even though whole blood is aspirated by the machine

A

splanchnic circulation, skin, subcutaneous tissue, and skeletal muscle

skeletal muscle, cardiac muscle, and brain tissue, increase their lactate uptake

less than 30% of normal
it can actually become a net lactate producer with poor perfusion, severe hypoxia, or hepatic failure

intracellular space of erythrocytes

intraerythrocytic and plasma lactate

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8
Q

“Lactic acidosis”

A

hyperlactatemia with a concurrent metabolic acidosis

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9
Q

1961 Huckabee divided hyperlactatemia into
type I vs II:
type A vs B
Type II hyperlactatemia (lactic acidosis) was further classified into two categories: type A and type B

A

type I increased lactate without metabolic acidosis
type II w metabolic acidosis

Type A tissue oxygen deficiency
Type B occurs in the absence of clinical evidence of decreased oxygen delivery
may exist concurrently

type B usually results in a mild to moderate increase in lactate (3 to 6 mmol/L. Conversely, severe hyperlactatemia (>6 mmol/L) usually is due to global hypoperfusion. type A

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10
Q

Type A Hyperlactatemia
Increased Oxygen Demand (5)
Decreased Oxygen Delivery (5)

A
Exercise
Trembling/shivering
Muscle tremors
Seizure activity
Struggling

hypoperfusion
Severe anemia
Severe hypoxemia
Carbon monoxide poisoning

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11
Q

Type B Hyperlactatemia
B1:
B2:
B3:

A
B1: Associated with Underlying Disease	
Sepsis/SIRS*
Neoplasia
Diabetes mellitus
Severe liver disease
Thiamine deficiency
Pheochromocytoma
B2: Associated with Drugs or Toxins	
Acetaminophen
Activated charcoal
β2 Agonists
Bicarbonate
Catecholamines
Corticosteroids*
Cyanide
Ethanol
Ethylene glycol
Propofol
Propylene glycol
Glucose
Halothane
Insulin
Lactulose
Methanol
Morphine
Nitroprusside
Salicylates
Strychnine
Terbutaline
Theophylline
TPN
Xylitol
B3: Inborn Errors in Metabolism
Mitochondrial myopathies
Enzymatic deficiencies
MELAS(mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes)
d-lactic acidosis
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12
Q

Exercise-related hyperlactatemia ranges from

resolves:

A

4.5 mmol/L- 30 mmol/L in racing Greyhound

T1/2 30 to 60 min

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13
Q

hypoperfusion grading

cats

A

mild 3 to 4 mmol/
moderate with 4 to 6 mmol/L
severe >6 mmol/L

Anecdotal clinical experience suggest that cats demonstrate an exponential increase with a lesser increase in mild and moderate hypoperfusion, then a rapid rise when it is severe.

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14
Q

Why is lactate a late indicator:

A

lactate production does not occur until oxygen extraction has been maximized

just as we recognize that falling blood pressure is a late indicator of hypovolemia

.:. corollary being that subclinical hypoperfusion may exist with a normal blood lactate concentration.

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15
Q

Hyperlactatemia in normotensive, normovolemic patients caused by decreased oxygen content and oxygen delivery as a result of anemic or hypoxic hypoxia is ____

hyperlactatemia does not develop until the packed cell volume (PCV) drops below ___

hypoxemia must also be severe ____before pure hypoxemia-related hyperlactatemia develops

.:. hypoxia should only rarely be considered as a sole diagnosis for increased lactate.

A

rare

15%
Dogs and cats with chronic, euvolemic anemia may remain eulactatemic with a PCV of 10% or less

PaO2 25 to 40 mm Hg

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16
Q

local hypoperfusion
organ torsion such as lung lobes, liver lobes, or spleens do not release much lactate and the systemic lactate concentration actually reflects the global perfusion status.

A

little washout

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17
Q

which isomer predominates

A

L‐lactate and D‐lactate

L‐lactate accounts for >99% of total body lactate

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18
Q

is lactate strong ion per Stewart approach

A

yes acidifying effect in a manner similar to chloride as per Stewart’s physicochemical approach

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19
Q

every 1 mmol/L (9 mg/dL) increase in lactate, SBE will decrease by ___

A

1 unit

20
Q

For example, in one study investigating dogs with gastric dilatation and volvulus, 74% (23/31) of dogs with plasma lactate > (1999 study)

whereas in another, only 33% (8/24) of dogs with plasma lactate ≥ 6 mmol/L (54.0 mg/dL) had gastric necrosis (2011)

A

6.0 mmol/L (54.0 mg/dL) had gastric necrosis

21
Q

Carbon monoxide binds to hemoglobin with a greater affinity than oxygen - carboxyhemoglobin

shifts the oxyhemoglobin curve

A

left

22
Q

Warburg’s effect

lymphoma and hemangiosarcoma may exhibit hyperlactatemia despite apparently normal perfusion

A

malignant cells are known to exhibit atypical carbohydrate metabolism by preferentially utilizing glycolytic pathways for energy production despite oxygen availability (Warburg’s effect)

lactate may alter the tumor micro environment in a manner that inhibits destruction of neoplastic cells

23
Q

MoA DM and > lactate

DKA 2 mech:

Cats DKA which type of lactate

A

upregulated glycolysis
impaired glycogenesis
reduced pyruvate dehydrogenase (PDH) activity
reduced oxidative metabolism

dehyd./decreased tissue perfusion
impaired lactate

higher D‐lactate concentrations not L-lactate

24
Q

Liver is >lactate common?

no but severe hepatic dysfunction or failure, the liver can become a net lactate producer

A

severe liver disease is rarely associated with hyperlactatemia unless they are acutely challenged by a lactate load or are experiencing concurrent hypoperfusion

25
Q

Thiamine deficiency
uncommon but well‐doc cause of hyperlactatemia:
MoA:

Thiamine deficiency, also known as

Causes:

dogs and cats, thiamine deficiency has been reported in association with the ingestion of fish high in thiaminase
and sulfite‐preserved meat

Human CS of thiamine def.:

Dog and cat CS:

A

converted to thiamine pyrophosphate

  • Thiamine pyrophosphate is a cofactor TCA cycle
  • leads to accumulation of pyruvate and lactate

beriberi disease

diet def., malignancy, sepsis, critical illness, chronic malnutrition, chronic pyloric outflow obstruction, and hyperthyroidism

hyperlactatemia, vasodilation, peripheral edema, cardiac dysfunction, vomiting, peripheral neuropathy, and Wernicke’s encephalopathy

cervical ventroflexion, ataxia, mydriasis, depressed mentation, and seizure activity

26
Q

T4

A

upregulation of glycolysis and the hexose monophosphate pathway

hyperthyroidism and thyroid storm are considered risk factors for thiamine deficiency due to depletion of thiamine stores

27
Q

Microcirculatory dysfunction
most important cause of impaired oxygen extraction in:

Sepsis enhances nitric oxide production, alters the neurohormonal control of endothelial and smooth muscle cells, reduces erythrocyte flexibility, and activates leukocytes resulting in marked ….

list 2 other contributors to microcirc. dysfunction:

One of the most important features of microcirculatory dysfunction is that it can occur _______ of macrocirculatory hemodynamic variables

supporting the concept that circulatory shunting at the capillary level may lead to local, heterogenous tissue hypoxia and hyperlactatemia despite apparently adequate oxygen delivery

A

maldistributive shock and is suspected to be an

NO production, activated leukocytes =
1.  microcirculatory heterogeneity
2. microvascular thrombosis 
3. microcirculatory shunting 
contributes to the concurrent hyperlactatemia and increased SvO2 seen in sepsis

independently of macrocirculatory hemodynamic

28
Q

Altered cellular respiration

also known as

can lead to hyperlactatemia by a number of different pathways including:

What has been implicated as a cause of aerobic hyperlactatemia particularly in the presence of severe inflammation, sepsis, or oxidative stress:

Mitochondrial respiration can fail bc:

Alkalosis stimulates

glucose, increased

A

cytopathic hypoxia

mitochondrial dysfunction
upregulation of glycolysis
impaired gluconeogenesis

Mitochondrial dysfunction

direct cytochrome inhibition(like CN)
impaired mitochondrial regeneration
loss of electrochemical gradient between the mitochondrial matrix and intermembrane space resulting

dysfunction of the PDH

glycolytic enzyme phosphofructokinase, subsequently increasing pyruvate and therefore lactate

29
Q

catecholamines:
MoA:

Na+‐K+‐ATPase pumps:

upregulation of skeletal muscle Na+‐K+‐ATPase associated glycolysis as a clinically significant source of lactate:

Hyperlactatemia has even been documented in healthy university students following a university exam

Catecholamine‐induced hyperlactatemia likely explains the hyperlactatemia seen with pheochromocytoma

A

increased cAMP via β2‐adrenergic stimulation
=enhanced glycogenolysis, glycolysis, lipolysis, and stimulation of Na+‐K+‐ATPase pumps

associated with lactate‐producing glycolytic pathways that are not coupled to mitochondrial respiration

septic shock
hemorrhagic shock
exercise‐related hyperlactatemia

30
Q

Type b2 drugs
Acetaminophen -

Salicylates -

B-agonists

A

impairing mitochondrial respiration
hepatic dysfunction
causing methemoglobinemia

decrease the availability of CoA
inhibit succinate dehydrogenase

inhibiting cAMP breakdown enhancing β‐receptor
=enhanced glycogenolysis, glycolysis, lipolysis, and and by directly stimulating the Na+‐K+‐ATPase pumps

31
Q

Cyanide/sodium nitroprusside
cause:

MoA inhibits aerobic metabolism by noncompetitively inhibiting:

results in ATP depletion, acidosis, hyperlactatemia, and _____ hyperoxia due to impaired oxygen extraction

A

secondary to smoke inhalation, ingestion of toxins including stone fruit pits, cassava roots, bitter almonds and bamboo shoots
infusions of sodium nitroprusside

ferric iron in cytochrome c oxidase (complex IV), the final step in the electron transport chain

venous hyperoxia

32
Q

sodium nitroprusside is metabolized into 1 molecule of nitric oxide and 5 molecules of _____

Serial lactate measurements can be of value when monitoring for the development of cyanide toxicity …
why is VBG and ABG unreliable -

A

cyanide, iatrogenic cyanide toxicity occasionally occurs

inhibits ferric iron in cytochrome c oxidase (complex IV), the final step in the electron transport chain

hyperoxia due to impaired oxygen extraction

33
Q

Glucocorticoids
MoA:
Glucocorticoids elicit hyperlactatemia by promoting

Both anti‐inflammatory (1 mg/kg/day) and immunosuppressive (4 mg/kg/day) doses of prednisone resulted in statistically significant and clinically relevant increases in lactate concentrations in healthy Beagles

A

promoting amino acid conversion to pyruvate, inhibiting PDH, potentiating the hyperlactatemic effect of catecholamines and altering carbohydrate metabolism

34
Q

Alcohols (ethanol, methanol, propylene glycol, ethylene glycol)

Ethanol metabolism shifts the NAD+/NADH ratio in favor of lactate production meaning more:

clinical relevance of ethanol induced hyperlactatemia remains controversial

Methanol is found in paint remover, windshield washing fluid, antifreeze, and some illicit alcohols
MoA:

Ethylene glycol
highly palatable organic solvent found in common antifreeze, is metabolized into the toxic metabolites:

A

NADH needing to be reduced?

ADH - alcohol dehydrogenase converts methanol into formaldehyde
converted into formate, causing metabolic acidosis and inhibiting the electron transport chain, promoting hyperlactatemic

glycolic acid
oxalate
glyoxylic acid

increased NADH/NAD+ ratio develops and pyruvate metabolism is inhibited - promoting lactate formation

35
Q

Lactulose
a synthetic, nondigestible disaccharide that is broken down into:

If excessive quantities of lactulose are administered, or if the lactulose is retained in the colon, lactate can potentially be absorbed by the colonic mucosa, resulting in systemic:

A

lactate and acetate in the colon

L‐ and D‐hyperlactatemia
only modest increases in plasma L‐ and D‐lactate are observed

36
Q

Lactate measured in pulmonary arterial or peripheral arterial blood essentially reflects ____

vs venous it that local tissue bed - in normal prefusion not huge difference

A

the mixture of all venous effluents in the body

ABG better assessment

37
Q

handheld analyzers may be inaccurate and imprecise at lactate concentrations within and just above the reference range. means..

A

3 mmol/L measured using a handheld may be artifactually high or a true high value

38
Q

why are even small rises in lactate significant

A

only produced after tissue oxygen extraction is maximized, which means it is a late (i.e., insensitive) indicator of tissue hypoperfusion

39
Q

prognostic utility of lactate:
If the process causing hyperlactatemia has a high mortality, then lactate is more likely to be prognostically useful (e.g., sepsis) but less helpful if the cause is easily correctable (e.g., simple hemorrhage)

decrease in lactate concentration with treatment is a much more reliable prognostic indicator. In general, with severe disease processes, if plasma lactate concentration does not fall back to normal within _____

A

24 to 48 hours, survival is less likely

40
Q

addition of treatment targeted toward lactate clearance to the Surviving Sepsis campaign resuscitation bundle reduced mortality risk ____in people with severe sepsis.

mortality was 60% in patients with severe sepsis that demonstrated <10% decrease in [LAC] within the first 6 hours of treatment compared to 19% in those with ≥10% decrease in [LAC] over the same time period

A

twofold

28, 150 patients with severe sepsis, normotensive patients presenting with [LAC] >4 mmol/L were as likely to die (29.0%) as patients presenting with hypotension but with [LAC] <4 mmol/L (29.3%)

A low lactate concentration is a better predictor of survival than a high lactate is of death.

41
Q

Some degree of prognostic utility has been reported for :

The APPLE (acute patient physiologic and laboratory evaluation) for dogs and cats found lactate to be one of the:

A
  1. ill and injured dogs
  2. dogs with SIRS
  3. IMHA (Holhan)
  4. gastric dilation-volvulus (Beer)
  5. severe soft tissue infections
  6. heartworm-associated caval syndrome
  7. babesiosis
  8. abdominal evisceration
    9 cats (limited ) HCH, and septic peritonitis

most significant variables associated with mortality and included lactate in both the full and fast scoring systems for both species

42
Q

Abdominal fluid from some severe cases of septic peritonitis may have a low:
high:

Can this be used as sole method for diagnosis of septic peritonitis?

A

low glucose (<50 mg/dl; 2.8 mmol/L
PO2
pH (<7.0)

and high PCO2 and lactate

No, studies of septic peritonitis published to date had such low numbers of patients that these diagnostic guidelines should not be used as a sole method for diagnosis of septic peritonitis.

43
Q

cause of high peritoneal fluid lactate concentrations with septic peritonitis MoA

A

has not been definitively confirmed

likely due to a combination of production by WBC, RBCs, and bacteria, as well as tissue anaerobiosis

44
Q

lactate clearance can be used as a therapeutic endpoint to guide goal-directed fluid therapy
Lac clearance = % change

approximate guideline, plasma lactate concentration should decrease by half every 1 to 2 hours for hypoperfusion causes

A

(lac initial - lact time2)/lact initial

45
Q

WHy may supplimenting thiamine help?

A

Thiamine pyrophosphate is a coenzyme associated with pyruvate dehydrogenase, thiamine supplementation may have theoretical benefits and can be considered as an adjunctive treatment