Lactate and the Critically ILL Patient icon

Lactate and the Critically ILL Patient

Lactate and the Critically Ill Patient

International Veterinary Emergency and Critical Care Symposium 2006

Søren Boysen, DVM, DACVECC
University of Montreal
Sainte-Hyacinthe, QC, Canada

Hyperlactatemia and lactic acidosis occur commonly in critically ill patients, in clinical disorders such as shock, low cardiac output states, acute liver failure, severe sepsis, cancer, seizure, poisoning and drug therapy. With the advent of hand held lactate analyzers that are readily available, lactate is rapidly becoming a valuable test in the armamentarium of clinicians to help assess the perfusion status and response to therapy of animals presenting in states of shock.


Lactate occurs in two isometric forms, type L and type D. This discussion will focus on the L isomer, as it is the isomer produced by mammalian cells, has the greatest clinical significance, and it is the isomer measured by most analyzers. The D isomer has been reported in cases of short bowel syndrome (secondary to bacterial lactate production and absorption from the GI tract), and accounts for some of the lactate in Ringer's solutions.

Hyperlactatemia is defined as a plasma lactate level above normal regardless of the corresponding acid base status. Although references vary slightly between dogs and cats and between sample sites (artery vs vein), most veterinary literature supports that values > 2.5 mmol/l are high in the non-stressed dog or cat.

Lactic acidosis is defined as hyperlactatemia occurring in the presence of academia (pH < 7.35), usually when lactate levels exceed 5 mmol/l. It is important to remember that hyperlactatemia and lactic acidosis are not synonymous and the implications of each may be different. Lactic acidosis can further be divided into "type A", associated with impaired oxygen delivery, and "type B", occurring in the presence of normal oxygen delivery.

Therefore, hyperlactatemia in the critically ill patient may exist in one of three forms: Moderate hyperlactatemia without acidosis (lactate levels generally < 5 mmol/l), lactic acidosis associated with impaired oxygen delivery (Type A), and lactic acidosis associated with normal oxygen delivery (Type B). One should consider these different factors when evaluating hyperlactatemia as they may represent very different pathophysiologic states, with differing implications for therapy and prognosis.

Normal Lactate Production and Metabolism

All lactate is derived from pyruvate, which in turn, is predominantly derived from glucose via the process of glycolysis. Lactate is therefore a normal end product of daily metabolism (glycolysis) and is continually produced in low concentrations throughout the body. Although all body tissues can produce lactate, under normal conditions skeletal muscle, brain, and erythrocytes (lack mitochondria and use only anaerobic glycolysis) are responsible for the majority of lactate production, and the liver and kidneys are responsible for the majority of its metabolism. The liver accounts for approximately 60-70% of lactate consumption, while the kidneys account for 20-30%. Within the liver and kidneys, lactate is converted back to pyruvate (catalyzed by lactate dehydrogenase), allowing either entry to oxidative metabolism or production of glucose via gluconeogenic pathways (Cori cycle). Lactate is also freely filtered by the glomerulus, but the majority is re-absorbed in the proximal tubules, resulting in less than 2% excretion in urine. This may increase to a limited degree during hyperlactatemia. It becomes evident then, that for hyperlactatemia to occur, the net production of lactate must exceed its net clearance.

Under aerobic conditions (when oxygen is available), the pyruvate, formed in the cytosol during glycolysis, enters the mitochondria and undergoes oxidative decarboxylation (via the Krebs cycle and the electron transport chain) resulting in the production of CO2 and H2O and the generation of 36 moles of ATP from each molecule of glucose metabolized. Only a small quantity is normally converted to lactate.

However, under anaerobic conditions pyruvate can no longer enter the Krebs cycle, and the NADH formed during glycolysis cannot enter the electron transport chain due to the lack of oxygen supply. Therefore, for glycolysis to continue during hypoxia, NADH must be converted back to NAD+, and the pyruvate concentration must be decreased. This is achieved with the conversion of pyruvate to lactate (see figure). During recovery from a state of lactic acidosis or hyperlactatemia, reperfusion and increased oxygen delivery result in the conversion of lactate into pyruvate and entry into the Krebs cycle or gluconeogenic pathways as aerobic metabolism continues. During this process, each molecule of lactate metabolized regenerates a molecule of bicarbonate, replacing that used in the initially buffering of lactic acidosis. This is important to keep in mind, as the administration of bicarbonate or other buffers when the patient is acidotic, could result in "overshoot" alkalosis when the underlying state of hypoperfusion is reversed and lactate is subsequently metabolized.

Figure 1.

The majority of the metabolically derived pyruvate originates from glucose (or glycogen) via glycolysis; a smaller part originates from transamination of alanine. Pyruvate can have several metabolic fates: oxidation via the Krebs cycle for energy production, conversion to lactate with recycling of NAD+, or transformation into glucose via gluconeogenic pathways (via the Cori cycle). Lactate that is produced will ultimately be converted to pyruvate.


Pathophysiology of Type A and B Lactic Acidosis

With the exception of hyperlactatemia occurring immediately after strenuous exercise, an elevation of blood lactate always indicates an abnormal condition, the origin of which has clinical significance. A simple clinical classification system has been developed that distinguishes lactic acidosis related to inadequate tissue perfusion or oxygenation (type A) from other causes (type B). In the critical care setting, tissue hypoperfusion is more common, and correlates well with prognosis. While a thorough history and clinical examination in conjunction with the minimum emergency database can differentiate most forms of Type A and B lactic acidosis, it is possible that some critically ill patients may present with features of both. A classic example is sepsis, which may involve lactic acidosis secondary to tissue hypoperfusion (type A), reduced lactate clearance, reduced pyruvate dehydrogenase activity, and abnormal mitochondrial function.

Type A

Type A lactic acidosis is most commonly associated with decreased perfusion and secondary tissue hypoxia leading to increased anaerobic metabolism and hyperlactatemia. When the hypoperfusion is significant and on going, acidosis occurs when the body's buffering capacities become overwhelmed. In people the correlation between lactate levels and the severity of hypoperfusion has been defined, and although not studied in dogs, clinical experience suggests that a similar correlation exists. When lactate concentrations are 3-5 mmol/l mild hypoperfusion is believed to be present, concentrations of 5-7 mmol/l are associated with moderate hypoperfusion and concentrations > 7 mmol/l are associated with severe hypoperfusion. Other less common causes of type A lactate acidosis include severe hypoxemia (PaO2 < 40 mmHg) and severe anemia (PCV < 15%) in the face of adequate tissue perfusion.

Type B

Lactic acidosis occurring in the setting of normal oxygen delivery may represent reduced tissue uptake or utilization of oxygen (cyanide toxicity, mitochondrial failure), reduced lactate clearance (i.e., hepatic or renal failure) or may be iatrogenic through the administration of certain medications (glucose and fructose infusions, epinephrine, acetaminophen, salicylates, nitroprusside, lactulose, sorbitol, activated charcoal, or dialysis using lactate-containing fluids). Thiamine deficiency has also been associated with hyperlactatemia. Finally, some malignancies such as lymphoma have been associated with increased blood lactate levels in dogs.

It is also possible that hyperlactatemia may occur due a rapid increase in metabolic rate where lactate production exceeds metabolism, and a relative, rather than absolute, tissue hypoxia (e.g., strenuous exercise, trembling and seizures). Hyperlactatemia occurring in this situation is transient, and following the rapid increase in metabolic rate, 80% of the excess lactate is converted back to pyruvate, which is then metabolized to carbon dioxide by aerobic metabolism.

Ringer's lactate solution contains 28mmol/L of lactate as a racemic mixture of the D and L forms. The majority of analyzers' measure only the L lactate isomer and will not detect all of the lactate in Ringer's solutions. In addition, dilution and metabolism of the lactate in Ringer's solutions are believed to minimize blood lactate increases from this source. In people, the administration of fluids containing lactate did not result in a significant change in lactate concentrations in normal subjects and those with hemorrhagic shock when given boluses of 20 ml/kg. However, dogs with lymphoma have been shown to have increased lactate concentrations following infusion of Ringer's lactate, and it might be expected that patients with impaired liver and/or renal function might also have increased levels of lactate following administration with Ringer's lactate.

Blood Sampling and Handling

Plasma lactate values obtained from the cephalic vein, jugular vein, and femoral artery of dogs vary slightly, but not enough to influence general clinical management when a value of < 2.5 mmol/l is used as the cut off for normal. In contrast, uncooperative patients, that display signs of stress and/or struggling, and/or the prolonged occlusion of the vessel can cause mild increases in lactate. Increased muscle activity in a shivering animal can produce moderate increases in lactate values. In addition, because red blood cells continue to utilize glucose and produce lactate after blood has been collected, blood left unseparated at room temperature may result in increased lactate levels. It has therefore been recommended that samples be analyzed within 5 minutes of collection. There are slight differences in lactate levels between plasma, serum and whole blood, but in the author's clinical experience these differences, although present, are not likely to have a major clinical influence on case management. Although plasma or heparinized whole blood is commonly analyzed, there are reports of unheparinized whole blood being evaluated with some hand held analyzers in people. The effects of hematocrit or other interfering substances on lactate values in canine and feline blood have not been fully investigated.


Overall, the severity and duration of type A lactic acidosis correlates with overall oxygen debt, potential organ dysfunction and mortality in the critically ill. In one human study, arterial lactate values of more than 5 mmol/l on admission to the ICU were associated with a mortality rate exceeding 80% at 30 days. Studies in dogs have also shown a correlation between lactate levels and outcome in cases with GDV and in cases presenting to an ICU in general. However, the magnitude of a single lactate value, taken out of context of the disease, may be misleading. Values of over 30 mmol/l have been reported in perfectly healthy sprinters (and racing greyhounds) following strenuous exercise, whereas values of 3.0 mmol/l in people were specific (98%) for predicting death in the emergency department. The high lactate levels produced during strenuous exercise rapidly dissipate, while lower levels which remain elevated for extended periods of time in cases of hypoperfusion, correlate to prolonged hypoxia with accompanying cell destruction and death. In addition, the prognosis of Type A lactic acidosis tends to vary with the underlying cause of hypoperfusion. In people, a serum lactate of 7.3 mmol/l was shown to have a 50% survival with hemorrhagic shock, while a value of 5.0 mmol/l was shown to have a 50% survival with sepsis. This stresses the importance that the history, physical examination and clinical findings must be considered in conjunction with the presence of hyperlactatemia and that sequential lactate values are more reliable at determining outcome, and response to therapy. In the absence of other markers of oxygen debt or cardiovascular instability, hyperlactatemia alone has not been correlated with adverse postoperative outcomes in people.


Although hypoperfusion is the most common cause of lactic acidosis, it is important to consider other causes (type B) and look for supporting evidence of impaired oxygen delivery (tachycardia, pale mucous membranes, weak pulses, prolonged capillary refill time, decreased mentation, hypotension) in patients presenting with hyperlactatemia. For example, it would be inappropriate to institute shock therapy for treatment of hyperlactatemia in the lymphoma patient that is cardiovascularly stable with normal tissue perfusion. However, if concurrent evidence exists to support impaired oxygen delivery, the only effective treatment for type A lactic acidosis is improvement of tissue oxygenation. In these cases, appropriate measures include treatment of shock, restoration of circulating fluid volume, improvement or augmentation of cardiac function, resection of ischemic tissue, and amelioration of sepsis. Aggressive intravenous fluid resuscitation is usually the cornerstone of therapy once underlying cardiopulmonary disease has been ruled out. The hematocrit should be followed and the administration of packed red cells or whole blood should be considered if significant anemia exists. Colloids should be considered if total protein is less than 4.5 mg/dl or albumin levels are less than 2.0 mg/dl. The use of sodium bicarbonate remains controversial, but given the metabolism of lactate is accompanied by a concurrent increase in bicarbonate, it is not usually indicated.

When assessing lactate in regards to the patient's response to therapy,it is important to remember that lactate dynamics vary with the cause of hyperlactatemia, and therefore the expected decline following resuscitative efforts will also vary. For example, the half-live of hyperlactatemia during seizures in people is approx 60 minutes (may be shorter in dogs) with little if any, impairment of lactate metabolism. In contrast, the half-life of hyperlactatemia in patients with shock may be as high as18 hours. The different half-life of hyperlactatemia is likely explained by impaired hepatic extraction of lactate, on going alterations in carbohydrate metabolism (i.e., stress) or the conversion of the liver from an organ that normally consumes lactate to one that produces it in cases of hypoxemia and shock.

Lactate in Body Fluid Cavities

The value of measuring lactate concentration in several different body fluid cavities has been investigated. Body fluid lactate concentrations may increase from diverse processes such as reduced blood flow, hypoxia, inflamed tissues and granulocyte or bacterial metabolism when these cells are present in body fluid cavities.

Abdominal Fluid: Conclusions regarding the value of lactate concentrations in abdominal fluid of small animals are somewhat conflicting. A study by Levin et al found lactate concentrations in abdominal fluid from dogs with septic effusions was increased (>2.5 mmol/l). Another study by Nestor et al found lactate concentrations in abdominal fluid from dogs with neoplastic effusions was also increased (mean 3.81 +/- 1.6 mmol/l). These results suggest that abdominal fluid lactate levels > 2.5 mmol/l may be the result of septic and/or neoplastic processes. Lactate concentrations are believed to be elevated in septic effusions due to bacterial metabolites and neutrophilic glycolysis. One might also expect to see elevated lactate levels secondary to neutrophilic glycolysis in diseases such as acute necrotizing pancreatitis, which can also be associated with highly neutrophilic abdominal effusions. Neoplastic cells on the other hand have been shown to use anaerobic glycolysis for energy, thereby producing increased levels of lactate. To try and increase the accuracy of detecting septic abdominal effusions, Levin et al examined the abdominal fluid to peripheral blood lactate gradient and found that a difference of > 2 mmol/l was 63% sensitive and 100 % specific for the detection of septic effusions in dogs, while an abdominal fluid to peripheral blood lactate gradient > 0.5 mmol/l was 78 % sensitive and 78 % specific at detecting septic abdominal effusions in cats. Unfortunately, the number of cases in this study was small and future studies using a larger population of cases may further dictate the diagnostic significance of lactate concentrations in abdominal effusions of dogs and cats.

Synovial Fluid: The value of lactate concentrations in synovial fluid has been investigated in humans. Data suggests that synovial fluid lactate levels can be valuable in rapidly excluding a diagnosis of septic arthritis with a negative predictive value as high as 98%. Its value in differentiating septic arthritis from other forms of inflammatory arthritis (rheumatoid) is less clearly defined as both septic and nonseptic forms of arthritis have been shown to result in increased synovial fluid lactate concentrations.

Pericardial Effusions: Lactate concentrations were investigated in dogs as a potential diagnostic aid in differentiating pericardial effusions associated with identifiable masses from those believed to be benign (no identifiable mass). Although a statistically significant difference was found between suspected neoplastic pericardial effusions (median 9.1 mmol/L) and pericardial effusions believed to be benign (median 3.7 mmol/L), the authors concluded there was too much overlap between the two groups to make lactate a useful diagnostic aid in differentiating neoplastic from nonneoplastic causes of pericardial effusions.

Pleural Fluid: Lactate levels have also been measured in pleural fluid accumulations in people and similar to results in abdominal fluid, the finding of a low lactate makes a septic process unlikely, while a high level is most often associated with sepsis, although other nonseptic processes (tuberculosis and some forms of cancer) can also cause high pleural lactate concentrations.

^ Cerebral Spinal Fluid: Lactate levels have also been evaluated in the central spinal fluid of people. As lactate crosses the blood-CSF barrier at a very slow rate the concentrations in the plasma and CSF may be different. There are studies that suggest CSF lactate may serve as a predictor of morbidity and mortality when associated with status epilepticus and patients suffering from stroke. In addition, CSF lactic acidosis, which implies brain tissue acidosis, may play a role in the clinical course of severe head injury. Over a 4-day post-trauma period, patients with a poor outcome posttraumatic brain injury had a higher ventricular CSF lactate levels than patients with moderate disabilities or a good outcome. Finally, CSF lactate levels and cell counts have been shown to correlate with the presence of bacterial meningitis, although elevated lactate levels have also been reported in people with viral infections.


Blood lactate is a very useful bedside test in helping to detect the presence of hypoperfusion and has prognostic implications for type A lactic acidosis and its treatment. It may also prove useful in helping to detect or rule out the presence of a septic effusion in various body fluid cavities, and have prognostic implications when measured in fluids such as CSF following trauma. There are only a few published studies in veterinary medicine at this time, and future studies will likely further define its role in the diagnosis and management of dogs and cats presenting to the ICU.


References are available upon request.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Sшren Boysen, DVM, DACVECC
University of Montreal
Sainte-Hyacinthe, Quebec, Canada

What Does Lactate Tell You About Your Patient?

International Veterinary Emergency and Critical Care Symposium 2006

Pamela A. Wilkins, DVM, MS, PhD, DACVIM, DACVECC
University of Pennsylvania School of Veterinary Medicine, New Bolton Center, George D Widener Hospital for Large Animals
Kennett Square, PA, USA

Lactic acidosis is frequently encountered in the intensive care unit. It occurs when there is an imbalance between production and clearance of lactate. Although lactic acidosis is often associated with a high anion gap and is generally defined as a lactate level >5 mmol/L and a serum pH <7.35 in humans, the presence of hypoalbuminemia may mask the anion gap and concomitant alkalosis may raise the pH.1,2 The causes of lactic acidosis are traditionally divided into impaired tissue oxygenation (Type A) and disorders in which tissue oxygenation is maintained (Type B). In critically ill patients, the clinical distinction between Type A and Type B lactic acidosis is often obscure, and patients generally have features of both types.1,2

Causes of Type A Lactic Acidosis

 Decreased Oxygen Delivery


 Volume depletion

 Blood loss

 Cardiogenic shock

 Septic shock

 Severe anemia

 Severe hypoxemia

 Carbon monoxide poisoning

 Increased Oxygen Demand




Causes of Type B Lactic Acidosis

 Inadequate Oxygen Utilization

 Systemic inflammatory response syndrome (SIRS)

 Diabetes mellitus


 Parenteral nutrition

 Thiamine deficiency

 Congenital lactic acidosis

 Mitochondrial myopathies



 D-lactic acidosis

Lactate in SIRS

The most common cause of lactic acidosis in the intensive care setting is the systemic inflammatory response syndrome (SIRS). Traditionally, this has been classified as a cause of Type A lactic acidosis. Because these patients are frequently hemodynamically unstable, it has been assumed that the increase in lactate production is the result of inadequate oxygen delivery. However, findings in experimental animals and septic patients over the past 2 decades have challenged this belief, suggesting that Type B lactic acidosis is a root cause. Increased pyruvate production, decreased pyruvate dehydrogenase activity, regional differences in lactate production, release of lactate from lung parenchyma, and decreased clearance of lactate have all been implicated as possible mechanisms contributing to lactic acidosis in SIRS.1,2

Decreased clearance of lactate has been demonstrated in SIRS. The liver and kidney play important roles in lactate utilization. When blood flow to the liver decreases significantly, the liver not only becomes a lactate producer but also becomes ineffective at clearing extrahepatic lactate. Studies have shown that lactic acidosis develops not only in hemodynamically unstable patients but also in the setting of adequate tissue perfusion and oxygenation. The studies described above account for much of our current knowledge on the mechanisms of increased lactate concentration and the development of lactic acidosis seen in SIRS.1,2

Lactic acidosis is a broad-anion gap metabolic acidosis caused by lactic acid overproduction or underutilization. The quantitative dimensions of these two mechanisms commonly differ by 1 order of magnitude. Overproduction of lactic acid, also termed type A lactic acidosis, occurs when the body must regenerate ATP without oxygen (tissue hypoxia). Circulatory, pulmonary, or hemoglobin transfer disorders are commonly responsible. Overproduction of lactate also occurs with cyanide poisoning or certain malignancies. Underutilization involves removal of lactic acid by oxidation or conversion to glucose. Liver disease, inhibition of gluconeogenesis, pyruvate dehydrogenase (thiamine) deficiency, and uncoupling of oxidative phosphorylation are the most common causes. The kidneys also contribute to lactate removal.1

Several cases of lactic acidosis associated with propylene glycol accidental overdose have been reported in the literature. Propylene glycol is a vehicle for numerous medications and is metabolized in the liver to pyruvate and lactate with some evidence that renal tubular toxicity may also contribute to the acidosis. Numerous other medications and toxic substances have been reported to induce lactic acidosis. Vasoactive substances, such as epinephrine and norepinephrine, have the potential to increase lactate levels and contribute to lactic acidosis. There have been rare reports of pheochromocytoma presenting with severe lactic acidosis.1

Lactate as a Prognostic Indicator

Lactate concentration is often used as a prognostic indicator and may be predictive of a favorable outcome if it normalizes within 48 hours, sometimes referred to as 'lactate clearance'. In humans, higher lactate clearance at 6 hours has been associated with a decreased mortality rate in emergency room patients.3

Lactate concentrations obtained at admission in 225 foals presenting to a NICU were predictive of survival at a cut-off of 5.5 mmol/L and 5.0 mmol/L in another study.4,5 Lactate serves as a carbohydrate substrate and energy source and is transported across the placenta to the fetus resulting in neonatal foals having larger lactate concentrations at birth not associated, necessarily, with disease.


Most recently lactate concentrations in peritoneal fluid and venous blood have been used in the evaluation of horses with colic.6-8 Horses with strangulating intestinal obstruction had greater peritoneal lactate values (8.45 mmol/l) than did those with nonstrangulating obstruction (2.09 mmo/l).6 Stall-side lactate determination is now possible and several hand-held monitors have been evaluated and showed utility.7-9 The hand-held monitors have potential for practical field evaluation in addition to use in intensive care situations.

The routine measurement of lactate concentration, however, should not determine therapeutic interventions. Unfortunately, treatment options remain limited and should be aimed at discontinuation of any offending drugs, treatment of the underlying pathology, and maintenance of organ perfusion. The use of base, most usually sodium bicarbonate, in the treatment of lactic acidosis remains controversial.10 The mainstay of therapy of lactic acidosis remains prevention.


1.  Fall PJ, Szerlip HM. Lactic acidosis: from sour milk to septic shock. J Intensive Care Med. 2005, 20(5):255-71

2.  Luft FC. Lactic acidosis update for critical care clinicians. J Am Soc Nephrol. 2001,12 Suppl 17:S15-9.

3.  Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004; 32(8):1637-42.

4.  Corley KT, Donaldson LL, Furr MO. Arterial lactate concentration, hospital survival, sepsis and SIRS in critically ill neonatal foals. Equine Vet J. 2005, 37(1):53-9.

5.  Wotman K, Palmer JE, Boston RC, Wilkins PA. Lactate concentration in foals presenting to a neonatal intensive care unit: Association with outcome. J Vet Intern Med 2005, 19(3): 409.

6.  Latson KM, Nieto JE, Beldomenico PM et al. Evaluation of peritoneal fluid lactate as a marker of intestinal ischaemia in equine colic. Equine Vet J. 2005, 37(4):342-6.

7.  Saulez MN, Cebra CK, Daily M. Comparative biochemical analyses of venous blood and peritoneal fluid from horses with colic using a portable analyser and an in-house analyser. Vet Rec. 2005, 157(8):217-23.

8.  Schulman ML, Nurton JP, Guthrie AJ. Use of the Accusport semi-automated analyser to determine blood lactate as an aid in the clinical assessment of horses with colic. J S Afr Vet Assoc 2001; 72(1):12-7.

9.  Tennent-Brown B, Boston RC, Wilkins PA. Assessment of a hand-held lactate monitor and the use of serum lactate disappearance as a prognostic indicator in equine emergencies J Vet Emerg Crit Care, 2006, in press.

10. Kraut JA, Kurtz JA. Use of base in the treatment of acute severe organic acidosis by nephrologists and critical care physicians: results of an online survey. ^ Clin Exp Nephrol 2006; 10(2):111-7.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Pamala A. Wilkins, DVM, MS, PhD, DACVIM, DACVECC
University of Pennsylvania School of Veterinary Medicine
New Bolton Center, George D Widener Hospital for Large Animals
Kennett Square, PA, USA

Clinical Use of Lactate: You Be the Judge...

International Veterinary Emergency and Critical Care Symposium 2005

Royal Veterinary College
London, UK

"For much of the 20th century, lactate was largely considered a dead end waste product of glycolysis due to hypoxia ... and a key factor in acidosis induced tissue damage. Since the 1970s a lactate revolution has occurred. At present we are in the midst of a lactate shuttle era; the lactate paradigm has shifted. There is essentially unanimous support for a cell to cell lactate shuttle. The bulk of the evidence suggests that lactate is an important intermediary in numerous metabolic processes, a particularly mobile fuel for aerobic metabolism, and perhaps a mediator of redox state among various compartments both within and between cells. Lactate can no longer be considered the usual suspect for metabolic crimes, but is instead, a central player in cellular, regional and whole body metabolism."

LB Gladden.^ Lactate metabolism: a new paradigm for the third millennium. Journal of Physiology. 2004; 558 (1): 5-30

"Those who fill our professional ranks are habitually conservative. This salutary mental attitude expresses itself peculiarly in our communal relations; namely, when a new idea appears which is more or less subversive to old notions and practices, he who originates the idea must strike sledge hammer blows in order to secure even a momentary attention. This must then be followed by a long, patient, propaganda and advertising until in the grand finale, the public, indifferent at first, is aroused, proceeds to discuss, and finally accepts the iconoclastic proposal as a long accepted fact of its own invention and asks wonderingly, "Why such a bother? What after all is new about this? We knew it long ago!"

Howard A. Kelly, MD.^ Electrosurgery in gynaecology. Annals of Surgery. 1931; 93: 323.

"Paradigms must be sufficiently unprecedented to attract an enduring group of adherents away from competing modes of scientific activity yet sufficiently open-ended to leave all sorts of problems for the redefined group of practitioners to resolve."

Thomas Kuhn. ^ The structure of scientific revolutions. University of Chicago Press. Chicago, IL

I respectfully submit to members of the jury that measuring plasma lactate concentration can be used to detect and monitor hypoperfusion provided that one understands the relevant pathophysiology. Indeed, its clinical value has been recognized for over 40 years. Global hypoperfusion is by far the most common cause of pathological hyperlactataemia in dogs and cats and the magnitude of hypoperfusion-induced hyperlactataemia is far greater than most, if not all, other pathological causes. Lactate rises proportionally to the severity of hypoperfusion in dogs hence the magnitude of hyperlactataemia is proportional to the severity of the insult but not its reversibility. In contrast, failure of lactate clearance is a grave prognostic indicator. In a recent, retrospective pilot study by the author, mortality where eulactataemia was not achieved was 97%. Sceptics offer the criticism that lactate is an insensitive perfusion indicator, yet the very same people do not think twice when using creatinine as an indicator of renal function... Other doubting Thomases criticise its lack of specificity yet have no concerns regarding ordering cholesterol on their biochemistry screens...

I conclude my opening remarks by posing the jury 2 simple questions:

1.  What practical and objective measure of perfusion would you choose for use in your clinic?
The plain and simple fact is: you have no choice.

2.  So does it work?
Ladies and gentlemen: YOU BE THE JUDGE!!!

Cellular energy is generated in the form of high energy phosphate compounds via 3 processes: glycolysis, the citric acid cycle, and the electron transport chain/oxidative phosphorylation. Glycolysis occurs in the cytosol, whereas the citric acid cycle and electron transport chain/oxidative phosphorylation occur in mitochondria. The latter two processes require aerobic conditions, whereas glycolysis does not require oxygen. This allows energy production to occur in conditions of relative or absolute cellular hypoxia. Glycolysis generates much less energy than aerobic metabolism on a molar basis, with only 2 moles of adenosine triphosphate (ATP) produced per mole of glucose converted to lactate. In comparison, 36 moles of ATP are produced when glucose is fully oxidized to carbon dioxide and water. Glycolysis, however, proceeds much faster than aerobic energy production which offsets the lower molar energy yield. Glycolysis also produces pyruvate and consumes nicotinamide adenine dinucleotide (NAD+). Therefore, to enable anaerobic energy production to continue, the cell disposes of excess pyruvate and regenerates NAD+ by converting pyruvate to lactate. The main disadvantage of lactate production is the indirect production of H+ ions and subsequent organic metabolic acidosis. Lactate is then either converted back to pyruvate and oxidized via the citric acid cycle or used for gluconeogenesis in the liver and kidney. Utilization of lactate consumes H+ ions and generates CO2 (which is in equilibrium with bicarbonate) so once tissue hypoxia is reversed, lactic acidosis should be self correcting.

Lactate and lactic acid are not synonymous: lactic acid, CH3CH(OH)COOH, is a strong acid that, at physiological pH, is almost completely ionized to lactate, CH3CH(OH)COO-, and H+. Elevated blood lactate concentration is termed hyperlactataemia, however, this may or may not be associated with acidaemia (a blood pH lower than 7.35) depending upon buffer reserves and concurrent acid/base disturbances. Lactic acidosis is a situation where lactate production exceeds lactate clearance, i.e., a state where lactic acid causes a fall in pH. Lactic acidaemia refers to an acidaemic blood pH and hyperlactataemia. A plasma lactate concentration over 5 mmol/L is usually associated with acidaemia.

Lactate is a charged molecule; nevertheless it equilibrates rapidly across cell membranes using a membrane transport system that carries lactate across the membrane in conjunction with H+ (which incidentally is why organic acidoses do not cause hyperkalaemia). Recent evidence suggests that this lactate excretion from the cell is vitally important in the regulation of intracellular pH. Increased cellular lactate production, therefore results in an elevated interstitial and blood lactate concentration. All tissues can produce lactate, but basal lactate production is highest in skin, red blood cells (which lack mitochondria), brain and muscle. Lactate consumption is highest in the liver and kidney. Because lactate is an important metabolic fuel, the kidney does not excrete lactate until a moderate degree of hyperlactataemia is present. Intraerythrocytic lactate concentration equilibrates with, but lags behind acute changes in plasma lactate concentration so plasma, rather than whole blood lactate concentration should be used in a clinical setting. The reference range for plasma lactate concentration in normal dogs by direct amperometry is less than 2.5 mmol/L.

Clinical use of plasma lactate concentration

If you find yourself in Kelly's "habitually conservative" bunch, then compare your thoughts on lactate as a perfusion and prognostic indicator to your feelings about using creatinine as an indicator of renal function. Everyone seems comfortable with the latter even though they fully realise that creatinine is affected by prerenal, renal and postrenal factors as well as non-creatinine chromogens and does not rise until renal function falls by more than 75%. Lactate rises when the tissues cannot compensate any more by increasing oxygen extraction ratio. Furthermore, we all wax eloquent about how arterial blood pressure only falls when hypovolaemia becomes severe, yet we seem more than happy to monitor it and even use it to guide fluid therapy. If you have used creatinine to monitor renal function or arterial blood pressure to guide fluid therapy then you have tacitly endorsed the use of lactate as a perfusion indicator. Hyperlactataemia, in the first instance, is usually due to hypoperfusion and needs correcting as a matter of urgency. And don't worry about its lack of sensitivity. Hyperlactataemia tells you that tissue hypoperfusion is past critical. If your lactate is not increased, hypoperfusion is unlikely to have reached danger levels.

Hyperlactataemia occurs when lactate production exceeds lactate extraction. Because glycolysis can proceed more rapidly than the oxidation of pyruvate, hyperlactataemia can occur in the absence of tissue hypoxia when glycolysis and lactate production are increased (e.g., alkalosis, glucose infusion, and sepsis without hypoperfusion). Hyperlactataemia also occurs due to relative, rather than absolute, tissue hypoxia when energy requirements exceed the capacity of aerobic metabolism, (e.g., exercise, trembling and seizures). Hyperlactataemia from tissue hypoxia can occur due to hypoperfusion, severe reductions in arterial oxygen content in the absence of hypoperfusion, or rarely due to cellular inability to utilize oxygen.

(clinical evidence of absolute
or relative tissue hypoxia)

(no clinical evidence
of tissue hypoxia)

Shock (systemic hypoperfusion)

B1 (in association with an underlying disease)


Diabetes mellitus


Severe liver disease



Local hypoperfusion


Gastric necrosis and other causes of splanchnic ischemia


Aortic thromboembolism

Thiamine deficiency

Other causes of tissue hypoxia

B2 (due to drugs or toxins)

Severe hypoxemia (PaO2 < 30-40 mmHg)


Severe euvolaemic anaemia (packed cell volume < 15%)


Carbon monoxide toxicity


Increased glycolysis


Excessive muscular activity

Ethylene glycol










Propylene glycol






B3 (due to congenital metabolic defects)


Mitochondrial myopathy







The most common and usually the most severe cause of hyperlactataemia is systemic tissue hypoperfusion. Therefore hyperlactataemia should always prompt an aggressive search for an underlying cause of tissue hypoperfusion. Since the classification scheme for hyperlactataemia was developed many of the causes of hyperlactataemia have been shown to include some component of tissue hypoperfusion.

The majority of studies have used arterial blood samples, despite the fact that clinical evidence supporting the use of arterial samples is largely absent. In normal dogs the differences between arterial, jugular and cephalic samples are minimal. In 60 healthy dogs, statistically significant but clinically irrelevant differences in plasma lactate concentrations were detected among blood samples from the cephalic vein (highest), femoral artery, and jugular vein (lowest). Mean plasma lactate concentration in the first sample obtained, irrespective of sampling site, was lower than in subsequent samples. The reference range for plasma lactate concentrations was 0.3 to 2.5 mmol/L. Clinical experience and data from human medicine suggest that this is also the case in hypoperfused patients.

Blood sampling technique and sample handling can increase plasma lactate concentration. Restraint and prolonged venous occlusion appear to cause only mild increases (2.5-3.5 mmol/L), whereas muscular activity during sampling is more important. In normal dogs, trembling during venipuncture can yield plasma lactate concentrations of 6-7 mmol/L. In cats, plasma lactate concentration is often increased due to muscular activity during restraint. In blood samples with a normal plasma lactate concentration held on ice, or in plasma or serum samples separated from red blood cells kept at room temperature, there is no major elevation of lactate concentration if the sample is analyzed within half an hour. In blood samples kept at room temperature, lactate concentration increases by approximately 0.2 mmol/L after 30 minutes, mainly due to glycolytic activity in red blood cells.

For severe lactic acidosis to occur, increased lactate production must be associated with a reduction in lactate clearance. The major determinant of the relative contribution to lactate production or extraction by different tissues in hypoperfused states appears to be blood flow. In mild to moderate haemorrhage in dogs, blood flow to the gut is greatly reduced whereas blood supply to the liver is preserved. Although intestinal lactate production is increased, the liver is still able to extract and metabolize it. In severe hemorrhagic shock, the liver actually becomes a net producer of lactate. Numerous experimental studies have documented that increases in blood lactate concentration correlate well with oxygen debt and critical levels of oxygen delivery. Clinical experience suggests that mild systemic hypoperfusion is associated with a plasma lactate concentration of 3-5 mmol/L, moderate hypoperfusion with a lactate of 5-7 mmol/L and in severe hypoperfusion, lactate levels exceed 7mmol/L. A retrospective study evaluating plasma lactate concentration in dogs with hemorrhagic shock secondary to anticoagulant rodenticide toxicity showed that lactate concentration was significantly higher as clinical perfusion parameters deteriorated. Lactate concentration, (mean, (range)) in 41 dogs with mild, moderate and severe hypoperfusion groups were 2.4 (1.4-3.4), 3.6 (2.3-5.5) and 7.9 (6.1-10.5) mmol/L respectively (whoops: unpublished data).

Notably, plasma lactate concentrations almost invariably fall following successful fluid resuscitation and can therefore be used to guide fluid therapy. If the plasma lactate concentration fails to normalize following appropriate fluid resuscitation it is likely that there is ongoing systemic hypoperfusion or an occult source of lactate production. Higher lactate concentrations are associated with a poorer outcome in people. In one of the first studies (Weil and Afifi, 1970) as lactate concentration increased from 2.1 to 8.0 mmol/L survival decreased from 90% to 10%. Clinical experience suggests that similar results will be obtained in canine patients. If plasma lactate concentration fails to fall below 10 (or 8 or 6 or 4 or be the judge!) mmol/L following appropriate fluid challenge, the prognosis appears to be poor. In a recent, retrospective pilot study by the author, mortality where eulactataemia was not achieved was 97%. The cause of hyperlactataemia influences the respective cut-off values, for example, survival for a given lactate concentration is better in hemorrhagic versus septic shock. This is analogous to long term prognosis with neurogenic pulmonary oedema. If it is due to a smack on the nose in a puppy then prognosis is pretty good, whereas if it is caused by a seizure secondary to an aggressive brain tumour in an old Labrador then prognosis pretty much sucks.

In a retrospective study of 102 dogs with gastric dilatation volvulus, 69 of 70 (99%) dogs with plasma lactate concentration < 6.0 mmol/L survived, compared with 18 of 31 (58%) dogs with plasma lactate concentration > 6.0 mmol/L. Median plasma lactate concentration in dogs with gastric necrosis (6.6 mmol/L) was significantly higher than concentration in dogs without gastric necrosis (3.3 mmol/L). The positive predictive value of a lactate to predict gastric necrosis was 75%. Another potential application of lactate concentration in veterinary patients may be to predict survival or the likelihood of limb salvage in cases of feline aortic thromboembolism. Serum lactate concentration has also been shown to be predictive of survival in groups of dogs in an intensive care unit, dogs with heartworm caval syndrome, and in horses with acute abdominal crises.

Hyperlactataemia seen in patients with sepsis and septic shock appears to be a much more complicated situation. Certainly when these patients have more severe hypovolaemia, lactate concentration is often increased. However, the hypermetabolic state seen with sepsis may result in increased glycolysis and pyruvate production at a rate faster than it can enter the citric acid cycle. Some of the pyruvate is consequently converted to lactate. In these patients, although lactate is increased, the lactate: pyruvate ratio would be expected to be normal. There is increasing evidence from both experimental studies and clinical studies in people, that the hyperlactataemia seen in volume replete septic patients is related to hypermetabolism. In the author's experience, patients with sepsis that are relatively volume replete have only mild hyperlactataemia and moderate to severe hyperlactataemia is usually associated with concurrent hypovolaemia.

Hyperlactataemia due to increased muscular activity is different from other causes in that resolution is more rapid. Extreme exercise in greyhounds generates lactate concentrations greater than 30 mmol/L, whereas seizures tend to cause elevations in the 6-10 mmol/L range. The degree of hypoxemia seen in most veterinary patients should not cause hyperlactataemia. Severe anaemia, however, may result in mild to moderate hyperlactataemia in the absence of hypoperfusion and anaemic animals will develop hyperlactataemia due to hypovolaemia earlier than animals with normal red blood cell concentrations. Hyperlactataemia in association with underlying disease processes in the absence of hypoperfusion and drug-induced causes remain largely undocumented in veterinary medicine. Lymphoma in dogs is associated with elevated resting lactate levels and a mild increase in hyperlactataemia following glucose challenge. An increased susceptibility to hyperlactataemia following intravenous fluid therapy with lactate-containing crystalloids has also been reported in dogs with lymphoma. Clinical experience suggests that hyperlactataemia in a dog with relatively normal perfusion warrants a cancer hunt.

Lactate quantitation in fluids other than blood may be useful as a predictor of bacterial infection, as an indicator of a successful response to antibiotic therapy, and as a means of assessing the degree of tissue injury and therefore prognosis. Lactate concentration in abdominal fluid in patients with ascites may be useful as a diagnostic adjunct for detecting bacterial peritonitis. Abdominal fluid lactate concentration in dogs and cats with bacterial peritonitis was 8.4 ± 4.2 mmol/L compared to 4.2 ± 2.9 in non-bacterial causes of abdominal effusion. The gradient between venous and abdominal fluid lactate concentration may be a more accurate predictor of bacterial peritonitis than the absolute concentration. Lactate concentration in cerebrospinal fluid has been used in people to detect bacterial meningitis and correlates with the severity of central nervous system damage and prognosis. Similarly, synovial fluid lactate concentration may also be helpful in the diagnosis of bacterial arthritis.

Because hyperlactataemia is usually a manifestation of an underlying disease process, treatment for lactic acidosis comprises intravenous fluid resuscitation and the diagnosis and correction of the specific cause. Aggressive intravenous fluid therapy using crystalloids, colloids, or blood products is usually necessary in the patient with lactic acidosis due to hypovolaemia in the absence of cardiopulmonary disease. Maintaining a packed cell volume of >20% seems wise with respect to the effects of anaemia on arterial oxygen content and hyperlactataemia. The use of intravenous sodium bicarbonate should only be considered in patients with severe haemodynamic compromise and acidosis (pH<7.10) that are refractory to intravenous volume loading and provided that pulmonary ventilation is adequate. Thiamine treatment may also be rational in the treatment of lactic acidosis because it is an essential cofactor in the oxidation of pyruvate.

Anyway I'll sign off with some words from the great Douglas G. Altman and J. Martin Bland, two of the forefathers of modern medical statistics: "Absence of evidence is not evidence of absence." BMJ 1995; 311:485 (19 August)


Additional references are available upon request.

1.  de Papp E, Drobatz KJ, Hughes D. Plasma lactate concentration as a predictor of gastric necrosis and survival among dogs with gastric dilatation-volvulus: 102 cases (1995-1998). Journal of the American Veterinary Medical Association 215 (1):49-52, 1999.

2.  Hughes D, Rozanski ER, Shofer FS, Laster LL, Drobatz KJ. Effect of sampling site, repeated sampling, pH, and PCO2 on plasma lactate concentration in healthy dogs. Am.J.Vet.Res. 60 (4):521-524, 1999.

3.  Hughes D. Lactate measurement: diagnostic, therapeutic, and prognostic implications. In Bonagura J (ed.) Kirk's Current Veterinary Therapy XIII. Philadelphia, WB Saunders, 1999: pp 112-116.

4.  Lagutchik MS, Ogilvie GK, Wingfield WE, Hackett TB. Lactate kinetics in veterinary critical care: a review. Journal of Veterinary Emergency and Critical Care 6 (2):81-95, 1996.

5.  Lagutchik MS, Ogilvie GK, Hackett TB, Wingfield WE. Increased lactate concentrations in ill and injured dogs. Journal of Veterinary Emergency and Critical Care 8 (2):117-127, 1998.

6.  Mizock BA, Falk JL: Lactic acidosis in critical illness. Crit Care Med 20:80, 1993.

7.  Toffaletti JG: Blood lactate: biochemistry, laboratory methods, and clinical interpretation. Critical Reviews in Clinical Laboratory Sciences 28:253, 1991.

8.  Weil MH, Afifi AA: Experimental and clinical studies on lactate and pyruvate as indicators of the severity of acute circulatory failure (shock). Circulation: 41:989, 1970.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Royal Veterinary College
London, UK

Download 75.43 Kb.
leave a comment
Date conversion21.10.2012
Size75.43 Kb.
TypeДокументы, Educational materials
Add document to your blog or website

Be the first user to rate this..
Your rate:
Place this button on your site:

The database is protected by copyright ©exdat 2000-2017
При копировании материала укажите ссылку
send message