Lactate Flashcards
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 carbohydrate energy substrate reservoir
continued energy production when cellular energy requirements exceed the capacity of cellular aerobic respiration
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
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
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
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
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
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
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
ATP use, not lactate production
reduced H+ consumption, not increased lactate production per se
hyperlactatemia without concurrent acidosis
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
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
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
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
“Lactic acidosis”
hyperlactatemia with a concurrent metabolic acidosis
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
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
Type A Hyperlactatemia
Increased Oxygen Demand (5)
Decreased Oxygen Delivery (5)
Exercise Trembling/shivering Muscle tremors Seizure activity Struggling
hypoperfusion
Severe anemia
Severe hypoxemia
Carbon monoxide poisoning
Type B Hyperlactatemia
B1:
B2:
B3:
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
Exercise-related hyperlactatemia ranges from
resolves:
4.5 mmol/L- 30 mmol/L in racing Greyhound
T1/2 30 to 60 min
hypoperfusion grading
cats
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.
Why is lactate a late indicator:
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.
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.
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
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.
little washout
which isomer predominates
L‐lactate and D‐lactate
L‐lactate accounts for >99% of total body lactate
is lactate strong ion per Stewart approach
yes acidifying effect in a manner similar to chloride as per Stewart’s physicochemical approach
every 1 mmol/L (9 mg/dL) increase in lactate, SBE will decrease by ___
1 unit
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)
6.0 mmol/L (54.0 mg/dL) had gastric necrosis
Carbon monoxide binds to hemoglobin with a greater affinity than oxygen - carboxyhemoglobin
shifts the oxyhemoglobin curve
left
Warburg’s effect
lymphoma and hemangiosarcoma may exhibit hyperlactatemia despite apparently normal perfusion
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
MoA DM and > lactate
DKA 2 mech:
Cats DKA which type of lactate
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
Liver is >lactate common?
no but severe hepatic dysfunction or failure, the liver can become a net lactate producer
severe liver disease is rarely associated with hyperlactatemia unless they are acutely challenged by a lactate load or are experiencing concurrent hypoperfusion
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:
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
T4
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
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
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
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
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
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
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
Type b2 drugs
Acetaminophen -
Salicylates -
B-agonists
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
Cyanide/sodium nitroprusside
cause:
MoA inhibits aerobic metabolism by noncompetitively inhibiting:
results in ATP depletion, acidosis, hyperlactatemia, and _____ hyperoxia due to impaired oxygen extraction
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
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 -
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
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
promoting amino acid conversion to pyruvate, inhibiting PDH, potentiating the hyperlactatemic effect of catecholamines and altering carbohydrate metabolism
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:
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
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:
lactate and acetate in the colon
L‐ and D‐hyperlactatemia
only modest increases in plasma L‐ and D‐lactate are observed
Lactate measured in pulmonary arterial or peripheral arterial blood essentially reflects ____
vs venous it that local tissue bed - in normal prefusion not huge difference
the mixture of all venous effluents in the body
ABG better assessment
handheld analyzers may be inaccurate and imprecise at lactate concentrations within and just above the reference range. means..
3 mmol/L measured using a handheld may be artifactually high or a true high value
why are even small rises in lactate significant
only produced after tissue oxygen extraction is maximized, which means it is a late (i.e., insensitive) indicator of tissue hypoperfusion
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 _____
24 to 48 hours, survival is less likely
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
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.
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:
- ill and injured dogs
- dogs with SIRS
- IMHA (Holhan)
- gastric dilation-volvulus (Beer)
- severe soft tissue infections
- heartworm-associated caval syndrome
- babesiosis
- 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
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?
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.
cause of high peritoneal fluid lactate concentrations with septic peritonitis MoA
has not been definitively confirmed
likely due to a combination of production by WBC, RBCs, and bacteria, as well as tissue anaerobiosis
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
(lac initial - lact time2)/lact initial
WHy may supplimenting thiamine help?
Thiamine pyrophosphate is a coenzyme associated with pyruvate dehydrogenase, thiamine supplementation may have theoretical benefits and can be considered as an adjunctive treatment
