Amar M. Bhatt, MD Ravi S. Tripathi, MD
BASICS
DESCRIPTION
• Anaerobic metabolism is the body’s mechanism of continually responding to stress and sustaining life-preserving measures during malperfusion, until favorable conditions are resumed.
• The human body’s major source of energy comes from the consumption of glucose via aerobic methods:
– Aerobic metabolism: Occurs when there is an adequate delivery of oxygen. The O2 molecule functions as an electron acceptor to produce a maximal amount of energy in the form of ATP (adenosine triphosphate).
– Anaerobic metabolism: Occurs during times of malperfusion and oxygen supply–demand mismatch. The body generates ATP via a rapid, oxygen-free variation of glycolysis with lactate as a byproduct (the Pasteur Effect).
PHYSIOLOGY PRINCIPLES
• ATP is a nucleotide that provides chemical energy for all cells in the body; it is produced via carbohydrate (primarily) and non-carbohydrate metabolism.
• Aerobic metabolism (oxygen-dependent) occurs via metabolism of glucose within the cytoplasm and mitochondria; each molecule of glucose is capable of producing 36 ATP.
– Glycolysis: Glucose is a 6-carbon structure that is first broken down into pyruvate, a 3-carbon structure. This process takes place in the cytoplasm and results in the net production of 2 ATP.
– Citric acid cycle (Krebs’ cycle): Using the pyruvate molecules and available oxygen, the citric acid cycle generates 2 additional ATP per original glucose molecule via an 8-step process and 18 different enzymes. In addition, this also generates NADH, FADH2, and other byproducts (e.g., GTP) that can be converted to ATP.
– Oxidative phosphorylation: NADH and FADH2 are metabolized in the mitochondria to create an additional 24 molecules of ATP per original glucose molecule. This occurs via oxidative phosphorylation (the electron transport chain), driven by a proton gradient.
• Gluconeogenesis: In the absence of readily available supplies of glucose, the body is able to use non-carbohydrates (e.g., lactate, glycerol, and certain amino acids or fatty acids) to generate glucose. Gluconeogenesis takes places via enzymes found in the cytoplasm and mitochondria of hepatic cells; liver dysfunction or failure can, thus, result in hypoglycemia and require supplemental dextrose solutions.
• Glycogenolysis: The body can also convert complex carbohydrates, such as glycogen, to glucose. This pathway occurs in the liver and muscle; it also requires a functioning liver.
• Anaerobic metabolism (oxygen-independent) occurs when the demand for oxygen is greater than its supply. For each glucose molecule, only 2 ATP are produced.
– In states where oxygen is reduced/absent, pyruvate is metabolized to lactate via lactate dehydrogenase as an end-product of anaerobic metabolism (pyruvate lactate dehydrogenase)
– Physiologic states (exercise): The anaerobic threshold is a theoretical point during dynamic exercise when muscle tissue switches over to anaerobic metabolism as an additional energy source.
– Pathologic states: Stress, hypoxia, or hypotension/shock
• Central nervous system: The CNS consumes large amounts of energy to maintain normal electrical function and cellular metabolism.
– Because it cannot store ATP, it requires a constant supply of both glucose and oxygen (∼3–3.5 mLO2/100 g/min).
– Anaerobic metabolism can result in a 95% decrease in energy production per available dependent on the aerobic metabolism of fats, carbohydrates, and amino acids. Under ischemic or hypoxic conditions, the energy liberated by lactate production or anaerobic metabolism (as compared to aerobic metabolism) is not sufficient for myocardial function and ventricular contraction.
• Pulmonary: Lactic acidosis stimulates peripheral and central chemoreceptors to augment the medullary respiratory center. This leads to a compensatory increase in oxygen intake and excretion of carbon dioxide. As with any change in acid–base homeostasis, the ventilatory response to acidosis is driven primarily by central chemoreceptors; whereas peripheral chemoreceptors are primarily affected by hypoxemia.
• Hemoglobin: Acidosis decreases the affinity of hemoglobin for oxygen; it improves oxygen uploading/delivery to acidotic tissue. This is expressed as a right shift in the oxygen–
hemoglobin dissociation curve.
ANATOMY
Erythrocytes do not possess mitochondria.
DISEASE/PATHOPHYSIOLOGY
• Lactate accumulation occurs during anaerobic metabolism and results in an anion gap metabolic acidosis.
– An anion gap is a term used to describe "unmeasured anions” (e.g., lactate, ethanol, uremia, certain toxins, ketones) during states of metabolic acidosis.
– Hypoperfusion (e.g., cardiogenic shock following cardiac surgery or myocardial ischemic
– In an attempt to maintain a normal acid–base environment, cells utilize protein transporters and enzymes via an active process to maintain a homeostatic concentration of carbon dioxide, bicarbonate, and protons.
PERIOPERATIVE RELEVANCE
• Hyperlactatemia can result from:
– Increased lactate production (Type A): Due to anaerobic metabolism
– Decreased lactate clearance (Type B): Due to liver disease, hypermetabolic states, and inhibition of pyruvate dehydrogenase
• Anaerobic metabolism is not an uncommon physiologic derangement seen in the perioperative arena; it can result when there is a mismatch of oxygen delivery and demand:
– Hypoxia/hypoxemia: Esophageal or mainstem intubation, hypoxic mixture, hypoventilation, V/Q mismatch, shunt perfused. For example, a normal or high blood pressure may be a vasoconstrictive response to a low cardiac output state.
• Septic shock: Hyperlactatemia is typically present in patients with sepsis or septic shock and the etiology is multifactorial (3).
– Hypovolemia: Septic shock is associated with fluid-responsive physiology. Thus, an elevated lactate level could indicate a “dry” patient.
– Hypoperfusion: Sepsis is also accompanied by a hypermetabolic state with enhanced glycolysis. Patients with “normal” filling pressures (e.g., central venous pressure) and cardiac indices (e.g., cardiac index) may not have adequate oxygen delivery.
– Cytopathic hypoxia: Despite adequate volume status and perfusion, tissue dysfunction at
the cellular level may persist in sepsis and represents impaired cellular function.
– Lactate is a well-established prognostic indicator in sepsis and septic shock. Obtaining serial serum lactate levels aids in identifying tissue hypoperfusion in patients who are not hypotensive but are at risk for septic shock; an elevated lactate (>4 mmol/L or 36 mg/dL) likely indicates inadequate oxygen delivery. Early goal-directed therapy should be considered in patients with sepsis and/or an elevated lactate level.
– As part of the Surviving Sepsis Guidelines, a resuscitation bundle for patients with sepsis includes, but it is not limited to:
A minimal initial crystalloid bolus of 20 mL/kg or equivalent
Vasopressor therapy to maintain a mean arterial pressure >65 mm Hg Obtaining blood cultures and administering appropriate antibiotic therapy
Maintaining adequate central venous pressure and central venous oxygen saturation EQUATIONS
• Glucose + 2 ADP + 2 Pi → 2 Lactate + 2 ATP + 2 H2O
• Pyruvate + NADH + H+ ←→Lactate + NAD+
REFERENCES
1. Cassavaugh J, Lounsbury KM. Hypoxia mediated biological control. J Cellular Biochem.
2010;112(3):735–744.
2. Javidi L. Pathophysiology of lactic acidosis and its clinical importance after cardiac surgery. Iran J Cardiac Surg. 2008;2:18–24.
3. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock. Crit Care Med.
2008;36:1394–1396.
ADDITIONAL READING
• Chaitman BR. Exercise stress testing. In: Bonow RO, Mann DL, Zipes DP, et al, eds.
Braunwald’s heart disease—a textbook of cardiovascular medicine, 9th ed. Philadelphia, PA:
Saunders/Elsevier, 2011, chap. 14.
• Levy B. Lactate and shock state: The metabolic view. Curr Opin Crit Care. 2006;12(4):315–
• Surviving Sepsis Campaign. www.survivingsepsis.org321.
See Also (Topic, Algorithm, Electronic Media Element)
• Base excess
• Metabolic acidosis
• Septic shock
• Cardiopulmonary bypass (CPB)
CLINICAL PEARLS
• Lactate production can serve as a marker of anaerobic metabolism and tissue hypoxia.
• When there is concern for adequate oxygen delivery, lactate and base deficit measurements can serve as markers of adequate tissue perfusion.
ANAPHYLAXIS
Lori Gilbert, MD
BASICS
DESCRIPTION
• An acute, life-threatening reaction with an onset of minutes to hours. It is usually, but not always, the result of an immunologic mechanism that involves IgE-mast cell or basophil mediator release; such mediators can include histamine, leukotrienes, and prostaglandins.
• The newest definition of anaphylaxis encompasses 1 of 3 scenarios:
– Acute onset (minutes to hours) of skin and mucosal manifestations, as well as respiratory compromise, hypotension, or shock
– Signs as above, after exposure to a likely antigen, in addition to GI symptoms – Hypotension after exposure to a known antigen
EPIDEMIOLOGY Prevalence
• During anesthesia: Ranges from 1:4,000 to 1:25,000 anesthetics
• Hospital inpatients in the US: 1:3,000; in Europe, the incidence is reported to be much lower.
• In the US, it is estimated that between 1.25% and 16% of the general population is at risk for possibly experiencing an episode of anaphylaxis.
Prevalence
• Lifetime prevalence from all triggers: 0.05–2%
• Food triggers: 90% of anaphylaxis cases are caused by milk, soy, eggs, wheat, peanuts, tree nuts, fish, and shellfish.
Morbidity
• Food allergies account for 30,000 ER visits a year; it is more common among children than adults.
• Latex anaphylaxis is responsible for >200 cases/year.
Mortality
• In the US: ∼2 in 100,000 anaphylaxis cases
• In the UK: 0.65–2% of anaphylaxis cases
• Risk factors age 10–35 years old: Active asthma, peanut allergy, and delayed administration of epinephrine
• Risk factors age 55–85 years old: Cardiovascular or respiratory illness, use of antibiotics or anesthetic agents.
ETIOLOGY/RISK FACTORS