e4 Key words hypertension, hypertensive encephalopathy, nicardip ine, isradipine, labetalol, nitroprusside, kidney disease Abstract Acute severe hypertension is a potential medical emer gency that nee[.]
e4 Abstract: Acute severe hypertension is a potential medical emergency that needs to be addressed immediately This chapter outlines the approach to such patients in the pediatric intensive care unit After a brief evaluation of the possible etiology, antihypertensive treatment should be initiated This is mostly done with intravenous agents, of which a number of options exist, albeit many not well studied in children The intensivist needs a heightened awareness for factors that predispose children to severe hypertensive events as well as an understanding of the clinical symptoms that may reflect end-organ damage from critically high blood pressure Key words: hypertension, hypertensive encephalopathy, nicardipine, isradipine, labetalol, nitroprusside, kidney disease SECTION VIII Pediatric Critical Care: Metabolic and Endocrine 79. Cellular Respiration, 960 80. Biology of the Stress Response, 971 81. Inborn Errors of Metabolism, 976 82. Progress Towards Precision Medicine in Critical Illness, 991 83. Molecular Foundations of Cellular Injury, 996 84. Endocrine Emergencies, 1003 85. Diabetic Ketoacidosis, 1016 959 79 Cellular Respiration SCOTT L WEISS, CLIFFORD S DEUTSCHMAN, AND LANCE B BECKER “In every one of us there is a living process of combustion going on very similar to that of a candle, and I must try to make that plain to you For it is not merely true in a poetical sense.” —Michael Faraday, A Course of Six Lectures on the Chemical History of a Candle (1861) • In 1920, Haldane was credited with the observation that hypoxemia not only stops the (respiration) machine but wrecks the (respiration) machinery as well.1 Indeed, the priorities of pediatric advanced life support and cardiopulmonary resuscitation are to restore oxygen and substrate delivery to tissues and cells Critical care extends these basic principles of restoration of oxygen and substrate delivery to also support oxygen utilization and cellular respiration with the goal to reestablish and maintain bioenergetic homeostasis Alterations in cellular respiration can contribute to a bioenergetic imbalance that results in cell and, ultimately, organ dysfunction.2 Oxygen availability and utilization are vital for cells to efficiently convert the chemical energy of nutrient molecules into useful energy in the form of adenosine triphosphate (ATP).3 This process involves a highly regulated network of enzymatic reactions, largely coordinated in the mitochondria, which normally closely align energy demand with energy production In critical illness, this delicate homeostatic balance may be disrupted and has been identified as a possible final common pathway for organ failure and death.4,5 For example, with improved biological understanding, the 960 • Cellular respiration is largely coordinated in the mitochondria and normally aligns energy demand with energy production In critical illness, disruption of cellular bioenergetic homeostasis may be a final common pathway for organ dysfunction and death Cellular respiration consists of three related series of biochemical reactions: (1) glycolysis of carbohydrates, b-oxidation of fatty acids, and catabolism of amino acids to produce acetyl- coenzyme A (acetyl-CoA); (2) metabolism of acetyl-CoA in the Krebs cycle to produce electron-rich nicotinamide dinucleotide (NADH) and flavin adenine dinucleotide (FADH2); and (3) shuttling of electrons from NADH and FADH2 along the electron transport system to oxygen in order to synthesize adenosine triphosphate (ATP) in the mitochondria Shock is an imbalance between oxygen (and substrate) delivery and oxygen (and substrate) utilization such that cellular metabolic demands are not met If oxygen delivery is not rapidly • • • PEARLS restored or appropriate oxygen utilization is not restored, ATP turnover will decrease, and an altered state of bioenergetic homeostasis can trigger cell injury and organ dysfunction Persistent mitochondrial dysfunction may contribute to a clinical state of cytopathic hypoxia in which cellular respiration remains abnormal even despite restoration of oxygen delivery Bedside measures of cellular respiration remain challenging The two most commonly used measures, lactate and venous oxygen saturation, provide important information about global oxygen utilization and have proved to be useful to guide acute resuscitation, but they have important limitations More direct measures of cellular respiration may be available in the near future A therapeutic approach that better aligns oxygen (and substrate) utilization with oxygen (and substrate) delivery may help to restore bioenergetic homeostasis and improve cellular—and thus organ—function Several existing and novel therapies may help to improve mitochondrial function in particular concept of septic shock has evolved from a state solely defined by cardiovascular dysfunction to now include cellular metabolic abnormalities Consequently, a working knowledge of cellular respiration is a key tenet of critical care medicine This chapter reviews (1) major pathways of cellular respiration with a focus on the mitochondria; (2) the role of impaired cellular respiration in critical illness, particularly in shock and multipleorgan dysfunction syndrome (MODS); (3) clinical assessment of oxygen utilization and mitochondrial function; and (4) potential therapeutic strategies to improve mitochondrial respiration and restore bioenergetic homeostasis Pathways of Cellular Respiration Plants harness the sun’s energy to split water into hydrogen and oxygen (Fig 79.1) The hydrogen is then attached to carbon to create glucose and starch, while the oxygen is released into the atmosphere Animals, including humans, eat plants to acquire carbohydrates (as well as other animals to obtain protein and fat), CHAPTER 79 Cellular Respiration 961 Sunlight energy enters ecosystem C6H12O6 Photosynthesis (in chloroplasts) CO2 Glucose Carbon dioxide O2 H2O Oxygen Water + + Cellular respiration ATP Drives cellular work Heat energy exits ecosystem • Fig 79.1 Cyclical process through which plants help animals to convert the sun’s energy into usable cellular energy in the form of adenosine triphosphate ultimately removing the hydrogen and combining it with oxygen to regenerate water Through this cyclical process, humans convert energy in the form of photons from the sun to usable cellular energy in the form of ATP through a process called oxidative phosphorylation.6 As will be discussed, an interconnected and alternative pathway of anaerobic respiration also exists within the cytoplasm However, in the absence of oxygen, it is not sufficient to sustain human life.7 Apart from erythrocytes, all human cells possess mitochondria These organelles account for nearly all total body oxygen consumption and are responsible for more than 90% of ATP production.8 Although mitochondria participate in many cellular processes other than ATP production, this chapter focuses on their role as the bioenergetic powerhouse of the cell An alternative end production of oxygen consumption is the formation of reactive oxygen species (ROS), which is also discussed Mitochondrial involvement in cell signaling, heat production, calcium regulation, hormone synthesis, cell death pathways, and genomic/epigenomic expression are reviewed elsewhere.8,9 A typical human adult male consumes approximately 380 L of oxygen per day, with well-conditioned athletes achieving rates up to 10 times higher.10 Oxygen serves as the final electron receptor at the terminal complex of the mitochondrial electron transport system (ETS) Through a series of oxidation-reduction (redox) reactions, electrons are transferred through the ETS to oxygen, pumping protons from the mitochondrial matrix to the intermembrane space, producing a proton motive force that is coupled to ATP production by ATP synthase (ETS complex V) Mitchell first described this chemiosmotic principle—the coupling of biological electron transfer to ATP synthesis—in the 1960s.11 It is now recognized that 3 1021 protons per second are transferred across all of the inner mitochondrial membranes in an adult male producing ATP at a rate of 1020 molecules per second This is equivalent to a turnover rate of 65 kg of ATP per day, with even higher rates during periods of activity.10 The phosphorylation of adenosine diphosphate (ADP) to form ATP through aerobic and, to a lesser extent, anaerobic processes 962 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine Cytoplasm Mitochondria Amino acids De am ina tio (6C) Glycolysis (3C) Glucose Pyruvate I II III Nutrient catabolism Krebs cycle Electron transport/ oxidative phosphorylation Energy-rich electron carrier formation (NADH, FADH2) n/o Acetyl-CoA formation xid ATP ati PDH (6C) Citrate on (2C) Acetyl-CoA NADH CO2 NADH FADH on i t a xid NADH (4C) Oxaloacetate o β- ATP synthesis NAD+ I (:) II FADH2 FAD+ ATP (:) III ATP (:) IV Fatty acids O2 H2O • Fig 79.2 Metabolic fates of pyruvate, the end product of glycolysis (Modified from Baynes JW, Dominiczak MH Medical Biochemistry New York: Elsevier; 2009.) provides the currency for cells to perform a wide range of energyconsuming activities, such as the active pumping of solutes against a concentration gradient across a membrane barrier The first law of thermodynamics states that the total amount of energy in a system remains constant during a chemical reaction The second law of thermodynamics states that, even though total energy does not change, the net amount of usable or free energy (termed Gibbs free energy and designated by the letter G) is always decreased— that is, a negative DG.5 Chemical reactions are characterized either as those that produce energy (exergonic or DG ,0) or those that consume energy (endergonic or DG 0) In living organisms, the highly complex, ordered state of homeostasis would naturally degrade to a less complex disordered state (i.e., toward a negative overall DG) without continual cellular maintenance By coupling energy-consuming endergonic processes to the hydrolysis of ATP to yield ADP and inorganic phosphate—an energetically favorable exergonic reaction—cells are able to drive forward critical chemical reactions that would otherwise not be possible Complete oxidation of nutrient fuels is accompanied by a large release of free energy that is used to produce ATP In general, cellular respiration consists of three related series of biochemical reactions: • Chemical reactions resulting in the formation of two-carbon acetyl-coenzyme A (acetyl-CoA) through glycolysis of carbohydrates, b-oxidation of fatty acids, and catabolism of amino acids • Metabolism of acetyl-CoA to carbon dioxide in the Krebs cycle with generation of the electron-rich reducing equivalents nicotinamide dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) • Shuttling of electrons from the reducing equivalents in NADH and FADH2 along the mitochondrial ETS, leading to ATP synthesis and ultimately reducing oxygen to water Although the initial catabolic steps vary among the different fuels (e.g., carbohydrates, fats, and amino acids), all nutrient molecules eventually converge to a common mitochondrial pathway (Fig 79.2) Glycolysis (Anaerobic Respiration) Glucose is the principal metabolic substrate for glycolysis and the primary fuel for many organ systems, including the central nervous system Glucose is transported into cells via glucose transporter (GLUT) receptors and down osmotic gradients Once in the cell, glucose enters the glycolytic pathway and is rapidly phosphorylated by the enzyme hexokinase to glucose-6phosphate Consequently, cellular glucose concentrations are low, allowing for a substantial favorable osmotic gradient for glucose to enter cells.12 Ten enzymatic reactions within the cell cytoplasm define the metabolic pathway of anaerobic respiration, termed glycolysis The free energy extracted from glucose through glycolysis is used to synthesize two net molecules of ATP, two molecules of NADH, and two molecules of pyruvate Under aerobic conditions (i.e., when oxygen is available), pyruvate is shuttled into the mitochondrial matrix where it is metabolized by pyruvate dehydrogenase (PDH) to acetyl-CoA and carbon dioxide (CO2), and NAD1 is converted to NADH Thus, PDH is a key enzyme that links cytoplasmic glycolysis to mitochondrial respiration Inhibition of PDH activity occurs with elevated NADH/NAD1, ATP/ ADP, and acetyl-CoA/CoA ratios indicating an energy-replete state, helping to maintain bioenergetic homeostasis Alternatively, under anaerobic conditions, pyruvate is reduced by NADH to lactate by lactate dehydrogenase (LDH) in order to regenerate the NAD1 needed to continue glycolysis During periods of hypoxemia, anaerobic respiration through glycolysis can be increased for a limited time to generate ATP in the absence of oxygen However, glycolysis alone results in a net generation of ... chemical energy of nutrient molecules into useful energy in the form of adenosine triphosphate (ATP).3 This process involves a highly regulated network of enzymatic reactions, largely coordinated in... mitochondria, which normally closely align energy demand with energy production In critical illness, this delicate homeostatic balance may be disrupted and has been identified as a possible final common... organ dysfunction Persistent mitochondrial dysfunction may contribute to a clinical state of cytopathic hypoxia in which cellular respiration remains abnormal even despite restoration of oxygen delivery