Lactic acidosis

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Lactic acidosis refers to the process leading to the production of lactate by anaerobic metabolism. It increases hydrogen ion concentration tending to the state of acidemia or low pH. The result can be detected with high levels of lactate and low levels of bicarbonate. This is usually considered the result of illness but also results from strenuous exercise. The effect on pH is moderated by the presence of respiratory compensation.

Contents

Lactic acidosis is usually the result of tissue hypoxia which is not the same as arterial hypoxia. Adequate circulation of blood and perfusion of metabolizing tissue to meet demand is necessary to prevent tissue hypoxia. Lactic acidosis can also be the result of illnesses, medications, poisonings or inborn errors of metabolism that interfere directly with oxygen utilization by cells. [1]

The symptoms are generally attributable to the underlying cause, but may include nausea, vomiting, shortness of breath, and generalised weakness.

The diagnosis is made on biochemical analysis of blood (often initially on arterial blood gas samples), and once confirmed, generally prompts an investigation to establish the underlying cause to treat the acidosis. In some situations, hemofiltration (purification of the blood) is temporarily required. In rare chronic forms of lactic acidosis caused by mitochondrial disease, a specific diet or dichloroacetate may be used. The prognosis of lactic acidosis depends largely on the underlying cause; in some situations (such as severe infections), it indicates an increased risk of death.

Classification

The Cohen–Woods classification categorizes causes of lactic acidosis as: [2]

Signs and symptoms

Lactic acidosis is commonly found in people who are unwell, such as those with severe heart and/or lung disease, a severe infection with sepsis, the systemic inflammatory response syndrome due to another cause, severe physical trauma, or severe depletion of body fluids. [3] Symptoms in humans include all those of typical metabolic acidosis (nausea, vomiting, generalized muscle weakness, and laboured and deep breathing). [4]

Causes

The several different causes of lactic acidosis include:[ citation needed ]

Pathophysiology

Glucose metabolism begins with glycolysis, in which the molecule is broken down into pyruvate in ten enzymatic steps. A significant proportion of pyruvate is converted into lactate (the blood lactate-to-pyruvate ratio is normally 10:1). The human metabolism produces about 20 mmol/kg of lactic acid every 24 hours. This happens predominantly in tissues (especially muscle) that have high levels of the "A" isoform of the enzyme lactate dehydrogenase (LDHA), which predominantly converts pyruvate into lactate. The lactate is carried by the bloodstream to other tissues where it is converted back to pyruvate by the "B" isoform of LDH (LDHB). Firstly there is gluconeogenesis in the liver (as well as the kidney and some other tissues), where lactate is converted into pyruvate and then into glucose; this is known as the Cori cycle. In addition, pyruvate generated from lactate can be oxidized to acetyl-CoA, which can enter the citric acid cycle to enable ATP production by oxidative phosphorylation. [3]

Elevations in lactate are either a consequence of increased production or of decreased metabolism. With regards to metabolism, this predominantly takes place in the liver (70%), which explains that lactate levels may be elevated in the setting of liver disease. [3]

In "type A" lactic acidosis, the production of lactate is attributable to insufficient oxygen for aerobic metabolism. If there is no oxygen available for the parts of the glucose metabolism that require oxygen (citric acid cycle and oxidative phosphorylation), excess pyruvate will be converted in excess lactate. In "type B" lactic acidosis the lactate accumulates because there is a mismatch between glycolysis activity and the remainder of glucose metabolism. Examples are situations where the sympathetic nervous system is highly active (e.g. severe asthma). [3] There is controversy as to whether elevated lactate in acute illness can be attributed to tissue hypoxia; there is limited empirical support for this theoretical notion. [15]

Diagnosis

Acid-base disturbances such as lactic acidosis are typically first assessed using arterial blood gas tests. Testing of venous blood is also available as an alternative as they are effectively interchangeable. [3] Normally resulting lactate concentrations are in the range indicated below: [16]

mg/dLmM
Venous blood4.5–19.80.5–2.2
Arterial blood4.5–14.40.5–1.6

Lactic acidosis is classically defined as an elevated lactate together with pH < 7.35 and bicarbonate below 20 mmol/L, but this is not required as lactic acidosis may exist together with other acid-base abnormalities that may affect these two parameters. [3]

Treatment

If elevated lactate is present in acute illness, supporting the oxygen supply and blood flow are key initial steps. [3] Some vasopressors (drugs that augment the blood pressure) are less effective when lactate levels are high, and some agents that stimulate the beta-2 adrenergic receptor can elevate the lactate further. [3]

Direct removal of lactate from the body (e.g. with hemofiltration or dialysis) is difficult, with limited evidence for benefit; it may not be possible to keep up with the lactate production. [3]

Limited evidence supports the use of sodium bicarbonate solutions to improve the pH (which is associated with increased carbon dioxide generation and may reduce the calcium levels). [3] [17]

Lactic acidosis caused by inherited mitochondrial disorders (type B3) may be treated with a ketogenic diet and possibly with dichloroacetate (DCA), [18] although this may be complicated by peripheral neuropathy and has a weak evidence base. [19]

Prognosis

Mild and transient elevations in lactate have limited impact on mortality, whereas sustained and severe lactate elevations are associated with a high mortality. [3]

The mortality of lactic acidosis in people taking metformin was previously reported to be 50%, but in more recent reports this was closer to 25%. [20]

Other animals

Reptiles

Reptiles, which rely primarily on anaerobic energy metabolism (glycolysis) for intense movements, can be particularly susceptible to lactic acidosis. In particular, during the capture of large crocodiles, the animals' use of their glycolytic muscles often alters the blood's pH to a point where they are unable to respond to stimuli or move. [21] Cases are recorded in which particularly large crocodiles which put up extreme resistance to capture later died of the resulting pH imbalance. [22]

Certain turtle species have been found to be capable of tolerating high levels of lactic acid without experiencing the effects of lactic acidosis. Painted turtles hibernate buried in mud or underwater and do not resurface for the entire winter. As a result, they rely on lactic acid fermentation to provide the majority of their energy needs. [23] Adaptations in particular in the turtle's blood composition and shell allow it to tolerate high levels of lactic acid accumulation. In the anoxic conditions where fermentation is dominant, calcium levels in the blood plasma increase. [23] This calcium serves as a buffer, reacting with the excess lactate to form the precipitate calcium lactate. This precipitate is suggested to be reabsorbed by the shell and skeleton, thereby removing it from the bloodstream; studies examining turtles that have been subjected to prolonged anoxic conditions have up to 45% of their lactate stored within their skeletal structure. [23]

Ruminants

In ruminant livestock, the cause of clinically serious lactic acidosis is different from the causes described above.

In domesticated ruminants, lactic acidosis may occur as a consequence of ingesting large amounts of grain, especially when the rumen population is poorly adapted to deal with grain. [24] [25] [26] Activity of various rumen organisms results in accumulation of various volatile fatty acids (normally, mostly acetic, propionic, and butyric acids), which are partially dissociated. [27] Although some lactate is normally produced in the rumen, it is normally metabolized by such organisms as Megasphaera elsdenii and, to a lesser extent, Selenomonas ruminantium and some other organisms. With high grain consumption, the concentration of dissociated organic acids can become quite high, resulting in rumen pH dropping below 6. Within this lower pH range, Lactobacillus spp. (producing lactate and hydrogen ions) are favored, and M. elsdenii and S. ruminantium are inhibited, tending to result in a considerable rise of lactate and hydrogen ion concentrations in the rumen fluid. [28] The pKa of lactic acid is low, about 3.9, versus, for example, 4.8 for acetic acid; this contributes to the considerable drop in rumen pH which can occur. [27]

Because of the high solute concentration of the rumen fluid under such conditions, considerable water is translocated from the blood to the rumen along the osmotic potential gradient, resulting in dehydration which cannot be relieved by drinking, and which can ultimately lead to hypovolemic shock. [24] As more lactate accumulates and rumen pH drops, the ruminal concentration of undissociated lactic acid increases. Undissociated lactic acid can cross the rumen wall to the blood, [29] where it dissociates, lowering blood pH. Both L and D isomers of lactic acid are produced in the rumen; [24] these isomers are metabolized by different metabolic pathways, and activity of the principal enzyme involved in metabolism of the D isomer declines greatly with lower pH, tending to result in an increased ratio of D:L isomers as acidosis progresses. [28]

Measures for preventing lactic acidosis in ruminants include avoidance of excessive amounts of grain in the diet, and gradual introduction of grain over a period of several days, to develop a rumen population capable of safely dealing with a relatively high grain intake. [24] [25] [26] Administration of lasalocid or monensin in feed can reduce risk of lactic acidosis in ruminants, [30] inhibiting most of the lactate-producing bacterial species without inhibiting the major lactate fermenters. [31] Also, using a higher feeding frequency to provide the daily grain ration can allow higher grain intake without reducing the pH of the rumen fluid. [32]

Treatment of lactic acidosis in ruminants may involve intravenous administration of dilute sodium bicarbonate, oral administration of magnesium hydroxide, and/or repeated removal of rumen fluids and replacement with water (followed by reinoculation with rumen organisms, if necessary). [24] [25] [26]

Related Research Articles

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Ketosis</span> Using body fats as fuel instead of carbohydrates

Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability. In physiological ketosis, ketones in the blood are elevated above baseline levels, but the body's acid–base homeostasis is maintained. This contrasts with ketoacidosis, an uncontrolled production of ketones that occurs in pathologic states and causes a metabolic acidosis, which is a medical emergency. Ketoacidosis is most commonly the result of complete insulin deficiency in type 1 diabetes or late-stage type 2 diabetes. Ketone levels can be measured in blood, urine or breath and are generally between 0.5 and 3.0 millimolar (mM) in physiological ketosis, while ketoacidosis may cause blood concentrations greater than 10 mM.

<span class="mw-page-title-main">Adenosine monophosphate deaminase deficiency type 1</span> Metabolic disorder leading to muscle dysfunction

Adenosine monophosphate deaminase deficiency type 1 or AMPD1, is a human metabolic disorder in which the body consistently lacks the enzyme AMP deaminase, in sufficient quantities. This may result in exercise intolerance, muscle pain and muscle cramping. The disease was formerly known as myoadenylate deaminase deficiency (MADD).

<span class="mw-page-title-main">Lactic acid</span> Organic acid

Lactic acid is an organic acid. It has the molecular formula C3H6O3. It is white in the solid state and it is miscible with water. When in the dissolved state, it forms a colorless solution. Production includes both artificial synthesis as well as natural sources. Lactic acid is an alpha-hydroxy acid (AHA) due to the presence of a hydroxyl group adjacent to the carboxyl group. It is used as a synthetic intermediate in many organic synthesis industries and in various biochemical industries. The conjugate base of lactic acid is called lactate (or the lactate anion). The name of the derived acyl group is lactoyl.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Fructose bisphosphatase deficiency</span> Medical condition

In fructose bisphosphatase deficiency, there is not enough fructose bisphosphatase for gluconeogenesis to occur correctly. Glycolysis will still work, as it does not use this enzyme.

<span class="mw-page-title-main">Tumor hypoxia</span> Situation where tumor cells have been deprived of oxygen

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironments in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumor vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

Acidosis is a biological process producing hydrogen ions and increasing their concentration in blood or body fluids. pH is the negative log of hydrogen ion concentration and so it is decreased by a process of acidosis.

<span class="mw-page-title-main">Leigh syndrome</span> Metabolic disease

Leigh syndrome is an inherited neurometabolic disorder that affects the central nervous system. It is named after Archibald Denis Leigh, a British neuropsychiatrist who first described the condition in 1951. Normal levels of thiamine, thiamine monophosphate, and thiamine diphosphate are commonly found, but there is a reduced or absent level of thiamine triphosphate. This is thought to be caused by a blockage in the enzyme thiamine-diphosphate kinase, and therefore treatment in some patients would be to take thiamine triphosphate daily. While the majority of patients typically exhibit symptoms between the ages of 3 and 12 months, instances of adult onset have also been documented.

<span class="mw-page-title-main">Cori cycle</span> Series of interconnected biochemical reactions

The Cori cycle, named after its discoverers, Carl Ferdinand Cori and Gerty Cori, is a metabolic pathway in which lactate, produced by anaerobic glycolysis in muscles, is transported to the liver and converted to glucose, which then returns to the muscles and is cyclically metabolized back to lactate.

In oncology, the Warburg effect is the observation that most cancer use aerobic glycolysis for energy generation rather than the mechanisms used by non-cancerous cells. This observation was first published by Otto Heinrich Warburg, who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme". The existence of the Warburg effect has fuelled popular misconceptions that cancer can be treated by dietary reductions in sugar and carbohydrate.

<span class="mw-page-title-main">Pyruvate carboxylase</span> Enzyme

Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme of the ligase class that catalyzes the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).

<span class="mw-page-title-main">Mitochondrial myopathy</span> Muscle disorders caused by mitochondrial dysfunction

Mitochondrial myopathies are types of myopathies associated with mitochondrial disease. Adenosine triphosphate (ATP), the chemical used to provide energy for the cell, cannot be produced sufficiently by oxidative phosphorylation when the mitochondrion is either damaged or missing necessary enzymes or transport proteins. With ATP production deficient in mitochondria, there is an over-reliance on anaerobic glycolysis which leads to lactic acidosis either at rest or exercise-induced.

Dichloroacetic acid (DCA), sometimes called bichloroacetic acid (BCA), is the organic compound with formula CHCl2CO2H. It is an analogue of acetic acid, in which 2 of the 3 hydrogen atoms of the methyl group have been replaced by chlorine atoms. Like the other chloroacetic acids, it has various practical applications. The salts and esters of dichloroacetic acid are called dichloroacetates.

Pyruvate dehydrogenase deficiency is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. PDCD is a genetic disease resulting from mutations in one of the components of the pyruvate dehydrogenase complex (PDC). The PDC is a multi-enzyme complex that plays a vital role as a key regulatory step in the central pathways of energy metabolism in the mitochondria. The disorder shows heterogeneous characteristics in both clinical presentation and biochemical abnormality.

Pyruvate carboxylase deficiency is an inherited disorder that causes lactic acid to accumulate in the blood. High levels of these substances can damage the body's organs and tissues, particularly in the nervous system. Pyruvate carboxylase deficiency is a rare condition, with an estimated incidence of 1 in 250,000 births worldwide. Type A of the disease appears to be much more common in some Algonkian Indian tribes in eastern Canada, while the type B disease is more present in European populations.

<span class="mw-page-title-main">Lactate dehydrogenase</span> Class of enzymes

Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvate to lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from one molecule to another.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

Inborn errors of carbohydrate metabolism are inborn error of metabolism that affect the catabolism and anabolism of carbohydrates.

<span class="mw-page-title-main">High anion gap metabolic acidosis</span> Medical condition

High anion gap metabolic acidosis is a form of metabolic acidosis characterized by a high anion gap. Metabolic acidosis occurs when the body produces too much acid, or when the kidneys are not removing enough acid from the body. Several types of metabolic acidosis occur, grouped by their influence on the anion gap.

Pseudohypoxia refers to a condition that mimics hypoxia, by having sufficient oxygen yet impaired mitochondrial respiration due to a deficiency of necessary co-enzymes, such as NAD+ and TPP. The increased cytosolic ratio of free NADH/NAD+ in cells (more NADH than NAD+) can be caused by diabetic hyperglycemia and by excessive alcohol consumption. Low levels of TPP results from thiamine deficiency.

References

  1. ↑ Kraut, Jeffrey A.; Madias, Nicolaos E. (2014-12-11). Ingelfinger, Julie R. (ed.). "Lactic Acidosis". New England Journal of Medicine. 371 (24): 2309–2319. doi:10.1056/NEJMra1309483. ISSN   0028-4793.
  2. ↑ Woods, Hubert Frank; Cohen, Robert (1976). Clinical and biochemical aspects of lactic acidosis. Oxford: Blackwell Scientific. ISBN   0-632-09460-5.[ page needed ]
  3. 1 2 3 4 5 6 7 8 9 10 11 12 Kraut, Jeffrey A.; Madias, Nicolaos E. (11 December 2014). "Lactic Acidosis". New England Journal of Medicine. 371 (24): 2309–2319. doi:10.1056/NEJMra1309483. PMID   25494270.
  4. ↑ MedlinePlus Encyclopedia : Lactic acidosis
  5. ↑ Baertling, F; Rodenburg, R. J; Schaper, J; Smeitink, J. A; Koopman, W. J. H; Mayatepek, E; Morava, E; Distelmaier, F (2013). "A guide to diagnosis and treatment of Leigh syndrome". Journal of Neurology, Neurosurgery & Psychiatry. 85 (3): 257–65. doi:10.1136/jnnp-2012-304426. PMID   23772060. S2CID   45323262.
  6. ↑ Santini, A; Ronchi, D; Garbellini, M; Piga, D; Protti, A (July 2017). "Linezolid-induced lactic acidosis: the thin line between bacterial and mitochondrial ribosomes". Expert Opinion on Drug Safety. 16 (7): 833–843. doi:10.1080/14740338.2017.1335305. PMID   28538105. S2CID   23123288.
  7. ↑ Shah, AD; Wood, DM; Dargan, PI (January 2011). "Understanding lactic acidosis in paracetamol (acetaminophen) poisoning". British Journal of Clinical Pharmacology. 71 (1): 20–8. doi:10.1111/j.1365-2125.2010.03765.x. PMC   3018022 . PMID   21143497.
  8. ↑ DeFronzo, R; Fleming, GA; Chen, K; Bicsak, TA (February 2016). "Metformin-associated lactic acidosis: Current perspectives on causes and risk". Metabolism: Clinical and Experimental. 65 (2): 20–9. doi: 10.1016/j.metabol.2015.10.014 . PMID   26773926.
  9. ↑ Fimognari, F. L.; Pastorelli, R.; Incalzi, R. A. (2006). "Phenformin-Induced Lactic Acidosis in an Older Diabetic Patient: A recurrent drama (phenformin and lactic acidosis)". Diabetes Care. 29 (4): 950–1. doi: 10.2337/diacare.29.04.06.dc06-0012 . PMID   16567854.
  10. ↑ Son, Hee-Won; Park, Se-Hun; Cho, Hyun-Oh; Shin, Yong-Joon; Son, Jang-Ho (2016). "Epinephrine-induced lactic acidosis in orthognathic surgery: a report of two cases". Journal of the Korean Association of Oral and Maxillofacial Surgeons. 42 (5): 295–300. doi:10.5125/jkaoms.2016.42.5.295. ISSN   2234-7550. PMC   5104873 . PMID   27847739.
  11. ↑ "Triumeq (Abacavir, Dolutegravir, and Lamivudine Film-coated Tablets) Drug Information: Description, User Reviews, Drug Side Effects, Interactions – Prescribing Information at RxList". RxList. Retrieved 2016-03-25.
  12. ↑ "Truvada Advanced Patient Information". Drugs.com.
  13. ↑ McKenzie, Robin; Fried, Michael W.; Sallie, Richard; Conjeevaram, Hari; Di Bisceglie, Adrian M.; Park, Yoon; Savarese, Barbara; Kleiner, David; Tsokos, Maria; Luciano, Carlos; Pruett, Timothy; Stotka, Jennifer L.; Straus, Stephen E.; Hoofnagle, Jay H. (1995). "Hepatic Failure and Lactic Acidosis Due to Fialuridine (FIAU), an Investigational Nucleoside Analogue for Chronic Hepatitis B". New England Journal of Medicine. 333 (17): 1099–105. doi: 10.1056/NEJM199510263331702 . PMID   7565947.
  14. ↑ Darmon, Michael; Malak, Sandra; Guichard, Isabelle; Schlemmer, Benoit (July–September 2008). "Acute tumor lysis syndrome: a comprehensive review". Revista Brasileira de Terapia Intensiva. 20 (3): 278–285. doi: 10.1590/S0103-507X2008000300011 . ISSN   0103-507X. PMID   25307096.
  15. ↑ Garcia-Alvarez, Mercedes; Marik, Paul; Bellomo, Rinaldo (April 2014). "Stress hyperlactataemia: present understanding and controversy". The Lancet Diabetes & Endocrinology. 2 (4): 339–347. doi:10.1016/S2213-8587(13)70154-2. PMID   24703052.
  16. ↑ Goldman, Lee; Schafer, Andrew (May 11, 2015). Goldman-Cecil Medicine (25 ed.). Elsevier. ISBN   978-1455750177.
  17. ↑ Boyd, JH; Walley, KR (Aug 2008). "Is there a role for sodium bicarbonate in treating lactic acidosis from shock?". Current Opinion in Critical Care. 14 (4): 379–83. doi:10.1097/MCC.0b013e3283069d5c. PMID   18614899. S2CID   22613993.
  18. ↑ Stacpoole, PW; Kurtz, TL; Han, Z; Langaee, T (2008). "Role of dichloroacetate in the treatment of genetic mitochondrial diseases". Advanced Drug Delivery Reviews. 60 (13–14): 1478–87. doi:10.1016/j.addr.2008.02.014. PMC   3746325 . PMID   18647626.
  19. ↑ Pfeffer, G; Majamaa, K; Turnbull, DM; Thorburn, D; Chinnery, PF (2012). Chinnery, Patrick F (ed.). "Treatment for mitochondrial disorders". The Cochrane Database of Systematic Reviews. 4 (4): CD004426. doi:10.1002/14651858.CD004426.pub3. PMC   7201312 . PMID   22513923.
  20. ↑ Kajbaf, F; Lalau, JD (November 2014). "Mortality rate in so-called "metformin-associated lactic acidosis": a review of the data since the 1960s". Pharmacoepidemiology and Drug Safety. 23 (11): 1123–7. doi:10.1002/pds.3689. PMID   25079826. S2CID   24262456.
  21. ↑ Seymour R. S.; Webb G. J. W.; Bennett A. F.; Bradford D. F. (1987). "Chapter 26. Effect of capture on the physiology of Crocodylus porosus" (PDF). In Webb, G. J. W.; Manolis, S. C.; Whitehead, P. J. (eds.). Wildlife Management: Crocodiles and Alligators. Sydney: Surrey Beatty. pp. 253–257.
  22. ↑ Archived 2009-05-02 at the Wayback Machine . Accessed 31 January 2009.
  23. 1 2 3 Jackson, Donald C. (2002). "Hibernating without oxygen: physiological adaptations of the painted turtle". The Journal of Physiology. 543 (3): 731–737. doi:10.1113/jphysiol.2002.024729. PMC   2290531 . PMID   12231634.
  24. 1 2 3 4 5 Kimberling, C. V. 1988. Jensen and Swift's diseases of sheep. 3rd Ed. Lea & Fibiger, Philadelphia. 394 pp.
  25. 1 2 3 Pugh, D. G. 2002. Sheep and goat medicine. Saunders. 468 pp.
  26. 1 2 3 Kahn, C. M. (ed.) 2005. Merck veterinary manual. 9th Ed. Merck & Co., Inc., Whitehouse Station.
  27. 1 2 Van Soest, P. J. 1994. Nutritional ecology of the ruminant. 2nd Ed. Cornell Univ. Press, Ithaca. 476 pp.
  28. 1 2 Nocek J. E. (1997). "Bovine acidosis: implications on laminitis". J. Dairy Sci. 80 (5): 1005–1028. doi: 10.3168/jds.S0022-0302(97)76026-0 . PMID   9178142.
  29. ↑ Owens, FN; Secrist, DS; Hill, WJ; Gill, DR (1998). "Acidosis in cattle: a review". Journal of Animal Science. 76 (1): 275–86. doi:10.2527/1998.761275x. PMID   9464909.[ permanent dead link ]
  30. ↑ Nagaraja, TG; Avery, TB; Bartley, EE; Galitzer, SJ; Dayton, AD (1981). "Prevention of lactic acidosis in cattle by lasalocid or monensin". Journal of Animal Science. 53 (1): 206–16. doi:10.2527/jas1981.531206x. PMID   7319937.
  31. ↑ Dennis, SM; Nagaraja, TG; Bartley, EE (1981). "Effects of lasalocid or monensin on lactate-producing or -using rumen bacteria". Journal of Animal Science. 52 (2): 418–26. doi: 10.2527/jas1981.522418x . PMID   7275867.
  32. ↑ Kaufmann W (1976). "Influence of the composition of the ration and the feeding frequency on ph-regulation in the rumen and on feed in-take in ruminants". Livestock Prod. Sci. 3 (2): 103–114. doi:10.1016/0301-6226(76)90028-2.
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