968 SECTION VII I Pediatric Critical Care Metabolic and Endocrine monitoring on 120 children with fluid refractory septic shock, children who had intermittent Scvo2 monitoring performed at 1, 3, and 6[.]
968 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine monitoring on 120 children with fluid refractory septic shock, children who had intermittent Scvo2 monitoring performed at 1, 3, and hours had significantly lower in-hospital mortality (33% vs 55%, P 02) and a reduction in the number dysfunctional organs (2 vs 3, P , 001).73 An important limitation of Scvo2 is the need for central venous access, making this laboratory value difficult to obtain in many children who may not otherwise require such an invasive procedure In addition, continuous Scvo2 measurements require a specialized catheter that may not be available in all centers Several studies have also failed to show an advantage of using Scvo2 over other markers, including lactate, in predicting in-hospital mortality.74,75 Three large randomized trials also recently failed to show that routine Scvo2 monitoring improved outcomes during resuscitation of adults with septic shock.69–71 Consequently, although both low (,70%) and high (.80%) Scvo2 may provide general insight into the global state of Do2-Vo2 mismatch, this measure, much like lactate, cannot detect tissue-specific changes in bioenergetic homeostasis Microdialysis Microdialysis allows for the measurement of energy-related metabolites within the interstitial space of a regional tissue bed This is most commonly performed using a thin, flexible catheter with a semipermeable membrane inserted into skeletal muscle A solution of a known solute concentration is slowly pumped into the catheter, and soluble small molecules—such as glucose, lactate, pyruvate, and glycerol—equilibrate across the membrane The fluid is then collected and analyzed as a regional measurement of cellular metabolic activity Because blood and Do2 are diverted away from skeletal muscle to critical organs (brain, heart, and kidneys) in shock, changes in muscle cellular respiration may be a sensitive indicator of inadequate systemic perfusion Indeed, animal and human studies in sepsis and hemorrhage have demonstrated an association between microdialysis lactate/pyruvate ratios and outcome.76,77 Further studies are needed to validate the utility of microdialysis as a clinically useful measure of cellular respiration Near-Infrared Spectroscopy Near-infrared spectroscopy (NIRS) enables continuous, noninvasive bedside monitoring of regional tissue oxygenation and mitochondrial complex IV redox state As with pulse oximetry, NIRS is based on the principle that the oxygen-carrying pigments hemoglobin and myoglobin and cytochrome a,a3 have well-defined absorption spectra that are influenced by oxygen binding NIRS technology thus uses a modification of the Beer-Lambert law, which describes the relationship between absorption of light and the concentration of deoxygenated hemoglobin (Hb), oxygenated hemoglobin, and intracellular chromophores (cytochrome a,a3) Clinical utilization of NIRS to date has generally focused on monitoring tissue-specific oxy- and deoxyhemoglobin concentrations, most commonly in brain, kidney, and skeletal muscle.78–80 Available NIRS monitors are mathematically weighted toward venous blood, thus largely reflecting deoxygenated Hb levels, and display a number (referred to as regional So2 or rSo2) that varies with local Do2 and extraction A decrease in NIRS rSo2 has been correlated with a fall in local tissue perfusion in animal models of shock, decreased cardiac output in infants following cardiac surgery, and predicted fluid responsiveness in dehydrated children.78–80 However, large variations in “normal” rSo2 levels, the lack of defined “critical threshold” for rSo2, and the inability of rSo2 to differentiate between changes in Do2 or Vo have limited the universal acceptance of NIRS monitoring In addition to hemoglobin, NIRS can assess the cytochrome a,a3 redox state of complex IV in the mitochondrial ETS.81 Cytochrome a,a3 is the terminal component along the ETS that reduces oxygen to water, and it remains in a reduced state during hypoxemia The absorption spectrum of cytochrome a,a3 in its reduced state shows a weak peak at 700 nm, whereas the oxygenated form does not Therefore, monitoring changes in the cytochrome a,a3 redox state can provide a measure of the adequacy of oxidative metabolism.82 To date, however, NIRS assessment of mitochondrial redox state, while promising, has been limited to research settings Optical Spectroscopy Similar to NIRS, optical spectroscopy uses absorption of light by tissues to assess concentration of various analytes of interest Advances in optical spectroscopy have made it possible to measure the oxygenation state of myoglobin independently from that of hemoglobin.83 Myoglobin is an intracellular protein found in skeletal and cardiac muscle cells that is involved in the transport of oxygen from the cytoplasm to the mitochondria Quantification of myoglobin saturation (percentage of total myoglobin bound with oxygen) provides a direct measure of intracellular oxygen availability Arakaki et al at the University of Washington recently demonstrated a progressive decrease in noninvasive muscle oxygenation measurements with increasing severity of shock in trauma patients.84 Optical spectroscopy has the potential to separately identify the oxygenation state in anatomically and physiologically distinct tissue regions, including the vascular (hemoglobin), cellular (myoglobin), and mitochondrial (cytochromes) levels However, clinical application of such data to guide therapy is not yet clear Tissue Oxygen Tension Tissue oxygen tension (tpo2) measures the partial pressure of oxygen within the interstitial space Traditional probes use Clark electrodes, but newer techniques are now available that can more accurately measure tpo2 without themselves consuming oxygen A decrease in Do2 would be expected to lower tpo2, whereas a decrease in Vo2 would raise tpo2 (so long as Do2 levels were not concurrently diminished).85 In sepsis models, several studies have demonstrated that skeletal muscle and mucosal tpo2 are unchanged or increased, suggesting a fall in Vo2 either concurrent with or greater than the decrease in Do2.86,87 In human studies, brain tpo2 monitoring has been demonstrated to improve outcomes following traumatic brain injury.88 A more recently developed technique to measure mitochondrial oxygen tension (mitopo2) may provide a new opportunity to assess mitochondrial function in vivo by noninvasively monitoring the oxygen-dependent change in lifetime of protoporphyrin IX upon photoexcitation with a pulse of light.89 More studies are needed to determine the benefits of tpo2 (and mitopo2) monitoring in pediatric critical illness Magnetic Resonance Spectroscopy Magnetic resonance spectroscopy (MRS) uses radiolabeled molecules to noninvasively measure in vivo tissue metabolite concentrations MRS has been used clinically for more than two decades in neurologic CHAPTER 79 Cellular Respiration disorders to measure blood vessel distribution and architecture, blood flow velocity, regional perfusion and blood volume, blood and tissue oxygenation, lactate production and intracellular pH, Krebs cycle activity, and mitochondrial oxidative phosphorylation in the brain For bioenergetic studies, phosphorus-31 MRS is primarily used to detect changes in phosphocreatine, ATP and inorganic phosphate, and certain compounds related to membrane synthesis and degradation.90 Because phosphocreatine is the primary ATP buffer in muscle, depletion in this molecule leads to a drop in ATP levels.90 Proton MRS can also be used to measure four markers related to oxygen metabolism: the peak of N-acetyl-aspartate (NAA), an amino acid present in neurons that reflects the status of neuronal tissue; creatine, found in glia and neurons, which serves as a point of reference because its level is believed to be stable; choline, a constitutive component of cell membranes that reflects glial proliferation or membrane breakdown; and lactate, a marker of anaerobic metabolism and therefore of ischemia Elevated lactate and decreased NAA are associated with worse neurologic outcome in neonates with asphyxial injury.91,92 Although MRS is useful for diagnosis and prognosis, it is not currently practical as a method to guide minute-tominute patient management Blood Mitochondrial DNA Under conditions of hypoxemia, ischemia, inflammation, and oxidative stress, mitochondrial damage can lead to fragmentation of mtDNA and release into the circulation Therefore, it has been proposed that blood levels (both cellular and free plasma concentrations) of mtDNA may be a biomarker of mitochondrial dysfunction and overall severity of illness.50,93 Increased levels of blood mtDNA have been reported in sepsis, trauma, and brain injury.51,94,95 Circulating mtDNA may also serve as DAMP, propagating inflammation and contributing to distant organ injury, as noted previously.52 Mitochondrial- and Bioenergetic-Targeted Therapy in Critical Illness With increasing recognition of the central role of altered cellular respiration—and mitochondrial dysfunction in particular—in the pathogenesis of organ failure in critical illness, there has been emerging interest in the potential for metabolic- and mitochondrialtargeted therapeutic strategies to improve patient outcomes A therapeutic strategy that partners an upregulation or downregulation of oxygen utilization to better match Do2 may restore bioenergetic homeostasis and improve cellular—and thus organ—function Several existing and novel agents have demonstrated potential to optimize cellular respiration and improve mitochondrial function, though questions of clinical utility remain largely unanswered at this time.96 Antioxidants As discussed earlier, ROS and RNS play essential roles in cell signaling As such, their activity is normally tightly regulated by a network of intracellular antioxidants In sepsis, cardiac arrest, and other severe illnesses, the production of ROS and RNS increases sharply (largely due to alterations of the mitochondrial ETS), leading to a wide array of local cellular damage and systemic inflammation Several exogenous antioxidant supplements have been studied in animal models and humans with critical illness, including vitamin A, vitamin E, vitamin C, coenzyme A, selenium, melatonin, and N-acetylcysteine Although antioxidant supplementation can 969 successfully reduce oxidative stress, clinical trials thus far have failed to convincingly demonstrate an outcome benefit.97 A strategy that better targets antioxidants to the mitochondria has shown some promise in preclinical studies and may be better suited for use in critically ill patients.98,99 Similarly, a series of small synthetic, positively charged peptides less than 10 amino acids in length, termed Szeto-Schiller (SS) peptides, can freely penetrate cell and mitochondrial membranes and have been shown to be effective in some ischemia-reperfusion oxidative stress models.100 Several early-phase human trials of mitochondrial-targeted antioxidants and SS peptides are ongoing Glycemic Control Hyperglycemia and insulin resistance are common findings in critically ill patients The inability of cells to use glucose to generate pyruvate can lead to downstream limitations of oxidative phosphorylation and results in mobilization of fat and protein stores Since the 1990s, there has been substantial interest in the use of exogenous insulin to restore normoglycemia in adult and pediatric critical illness Despite widespread enthusiasm following an adult trial of insulin to achieve tight glycemic control (80–110 mg/dL) that reduced ICU mortality from 8% to 4.6%,101 subsequent studies have failed to replicate the overall benefit, including three randomized pediatric trials.102,103 Interestingly, insulin has been shown to stimulate mitochondrial ATP production in human skeletal muscle ex vivo,104 and maintenance of normoglycemia with insulin preserves hepatic mitochondrial structure and function in adult critical illness.105 Thus, the potential for targeted insulin therapy and glycemic control to improve cellular bioenergetic homeostasis remains unclear (see also Chapter 84) Substrate Provision Several studies suggest that, despite decreased activity of complex I of the mitochondrial ETS, complex II is relatively preserved in sepsis Complex II transfers electrons from FADH2 produced from the oxidation of succinate to coenzyme Q Consequently, supplementation of succinate may help to restore overall ETS activity and ATP production, as has been suggested in animal models of sepsis.106 However, different insults may be prone to distinct pathophysiology and thus variable therapies For example, in a porcine model of pediatric traumatic brain injury, mitochondrial ETS complex II exhibited the most profound decrease in activity.107 Alternative fuels for cellular respiration, including carnitine supplementation, have shown promising results in animal models,108 but direct evidence for benefit in humans has not yet been demonstrated Similarly, supplementation with coenzyme Q, cytochrome c, and caffeine improves mitochondrial function in vitro and in animal models.39,41,109,110 Thiamine supplementation has also been proposed as part of a metabolic resuscitation strategy Thiamine (vitamin B1) is an essential cofactor for PDH, and acute thiamine deficiency in critical illness may cause an acquired form of PDH deficiency Several studies have tested the therapeutic benefits of thiamine in critically ill adults with septic shock, some with encouraging results that are awaiting confirmation in larger trials.111,112 Mitochondrial Biogenesis and Mitophagy All cells that undergo oxidative phosphorylation have robust quality control mechanisms to ensure a full complement of healthy mitochondria Cells optimize the overall mitochondrial number, distribution, and function through a network of interrelated 970 S E C T I O N V I I I Pediatric Critical Care: Metabolic and Endocrine processes of biogenesis, fission, fusion, and mitophagy.52 Mitochondrial biogenesis is the process of synthesizing new functional mitochondria and can be induced by oxidative stress and inflammation.9 Data from both animal studies and septic patients have shown that mitochondrial biogenesis is associated with recovery of organ function and survival Haden et al showed that mitochondrial biogenesis is evident over to days following a nonlethal exposure to Staphylococcus aureus in a rodent model, with a subsequent recovery of oxidative phosphorylation.113 The same group further showed that sepsis survival could be improved in rodents treated with daily exposure to a low dose of carbon monoxide (CO), which stimulates mitochondrial biogenesis.114 A recent phase I trial in adults with acute respiratory distress syndrome demonstrated safety and tolerability of low-dose inhaled CO.115 Similarly, removal of dysfunctional mitochondria—termed mitophagy—has also been shown to be protective in sepsis For example, in both liver and kidney of hyperglycemic critically ill rabbits, biochemical markers indicating insufficient mitophagy were more pronounced in nonsurviving animals.116 Interestingly, after and days of illness, mitophagy was better preserved in animals treated with insulin to preserve normoglycemia, which correlated with improved mitochondrial function and less organ damage.116 Pharmacologic agents that induce mitochondrial biogenesis, such as pioglitazone,117 resveratrol,118 and recombinant human TFAM (transcription factor A, mitochondrial; rhTFAM)119 and that simulate mitophagy, such as rapamycin,116 are currently being explored as potential therapeutic strategies to recover mitochondrial function and restore bioenergetic homeostasis in critical illness Membrane Stabilizers Ultrastructural evidence of mitochondrial injury in critical illness includes damage to the inner mitochondrial membrane and organelle swelling These features are associated with loss of the electrochemical gradient that drives ATP production through oxidative phosphorylation Although the mechanisms underlying these physiologic changes remain incompletely understood, opening of the MPTP is believed to be involved A number of compounds that inhibit pore opening, including cyclosporine A and melatonin, are being investigated as another approach to restore mitochondrial function through membrane stabilization.107,109 Hibernation Another potential strategy to restore bioenergetic homeostasis that could be pursued in the presence of impaired cellular respiration is to suppress metabolic energy expenditure In many hibernating mammals, a purposive metabolic downregulation is a crucial response that facilitates tolerance to a lack of energetic substrates during harsh environmental conditions and promotes survival.120,121 The hibernating state prevents a cellular bioenergetic crisis by reducing demand for ATP when substrate or oxygen supply is low and decreases mitochondrial oxidative stress Although humans not hibernate and have only a limited tolerance to diminished oxygen or substrate delivery to vital organs, the impairment in cytochrome oxidase activity observed during sepsis mimics that of true hibernation, suggesting that, at least early on, such impairment may be an adaptive response to an inflammatory insult.43 Following myocardial ischemia, myocardial hibernation has been well described, with subsequent functional recovery if adequate perfusion is promptly restored Attempts to reduce metabolic demand through induced moderate hypothermia after neonatal hypoxic-ischemic injury, cardiac arrest, traumatic brain injury, and hyperammonemic metabolic crises have demonstrated variable success Ongoing challenges to induced hypothermia include unclear optimal timing, depth, and duration of this therapy Mitochondrial Transplantation Transplantation of autologous healthy mitochondria (e.g., from skeletal muscle) has been shown to act both extracellularly and intracellularly to enhance tissue Vo2, improve bioenergetic homeostasis, and increase ATP synthesis in cells and tissues after ischemia-reperfusion injury Studies have shown that exogenous mitochondria can be incorporated into cardiac cells ex vivo, with many eventually fusing with the endogenous mitochondria network.122 In five children with congenital heart disease requiring extracorporeal membrane oxygenation (ECMO) after myocardial ischemia, direct epicardial injection of isolated autologous mitochondria was followed by improved myocardial function within 24 to 48 hours and ECMO decannulation within a median of days.123 The therapeutic potential for mitochondrial transplantation, although preliminary, is promising Conclusions Although the restoration of tissue perfusion and oxygen/substrate delivery remains a primary goal in critical illness, alterations in cellular respiration contribute to a bioenergetic imbalance that result in cell and, ultimately, organ dysfunction As discussed, impaired Do2 can decrease the ability of cells to produce ATP However, metabolic alterations that affect overall bioenergetic homeostasis may develop, and even persist, irrespective of the state of Do2 Indeed, it may well be the case that utilization of oxygen—or some other metabolic substrate—is of even greater importance to cell survival, organ function, and patient outcomes than normalization of Do2 Although shock is classically defined as an imbalance between oxygen (and substrate) delivery and demand, it is ultimately the state of cellular respiration rather than circulatory dysfunction that determines outcome from critical illness Key References Brealey D, Brand M, Hargreaves I, et al Association between mitochondrial dysfunction and severity and outcome of septic shock Lancet 2002;360:219-223 Fink MP Bench-to-bedside review: cytopathic hypoxia Crit Care 2002;6:491-499 Galley HF Bench-to-bedside review: targeting antioxidants to mitochondria in sepsis Crit Care 2010;14:230 Jones AE, Shapiro NI, Trzeciak S, et al Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial JAMA 2010;303:739-746 Levy RJ Mitochondrial dysfunction, bioenergetic impairment, and metabolic down-regulation in sepsis Shock 2007;28:24-28 Singer M The role of mitochondrial dysfunction in sepsis-induced multi-organ failure Virulence 2014;5:66-72 Viscomi C, Bottani E, Zeviani M Emerging concepts in the therapy of mitochondrial disease Biochim Biophys Acta 2015;1847:544-557 The full reference list for this chapter is available at ExpertConsult.com e1 References Thannickal VJ Oxygen in the evolution of complex life and the price we pay Am J Respir Cell Mol Biol 2009;40:507-510 Singer M Mitochondrial function in sepsis: acute phase versus multiple organ failure Crit Care Med 2007;35(suppl 9):S441-S448 Fink MP Cytopathic hypoxia Is oxygen use impaired in sepsis as a result of an acquired intrinsic derangement in 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