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What is the optimal oxygen management strategy during cardiopulmonary bypass (CPB)? Normoxemia is the normal oxygen tension in arterial blood (PaO2), defined as 75–100 mmHg at room air . Thus, hypoxemia is defined as a PaO2 less than 75 mmHg, and hyperoxemia as a PaO2 greater than 100 mmHg at room air. It is well known that during CPB, flow is reduced, and tissues contain lower arterial oxygen tension than normal physiological levels. Conventionally, oxygen management on cardiopulmonary bypass has been approached cautiously, with supernormal PaO2 levels being the norm. This has been accomplished by maintaining higher FiO2 concentrations throughout CPB. Historically, it was thought that the “extra” oxygen provided improved oxygen delivery and a margin of safety during perioperative cardiac procedures . Current research, however, is questioning this strategy, and perfusionists vary widely in what they believe is the optimal PaO2 range for their practice.
This review aims to examine the effects of hyperoxic oxygen management on cardiopulmonary bypass in forming reactive oxygen species (ROS) and its potential role in reperfusion injury to the myocardium. Furthermore, it will explore the effects of practicing hypoxemia versus normoxia on neurological and pulmonary functions, and other organs. Also, it will reveal what recent studies have shown to be best. Lastly, a short survey was conducted to collect data from perfusionists in the US to determine what arterial pO2 protocols are being used and how they relate to the most current research regarding hyperoxia on cardiopulmonary bypass.
How it works
Cardiac ischemic injury can be an acute or progressing disease state caused by restricting blood supply to the myocardium . The myocardium extracts approximately 75% of the oxygen present in the blood flow of the coronaries, with an upper limit of 95% depending on demand. Physiologically, supply is increased by alterations in coronary blood flow, with most O2 consumption attributed to the left ventricle. The left ventricle’s determinants of oxygen demand depend on various factors, including pressure-volume work, heart rate, temperature, wall stress, inotropic state, basal metabolism, and other homeostatic mechanisms. A disproportionate decrease in O2 supply can cause ischemia.
Ischemia may also occur due to increase in O2 demand disproportionate to supply. For reperfusion injury to occur, the presence of ischemia is required. During cardiac surgery, Ischemia can occur before cardiopulmonary bypass has been initiated, at the initiation of CPB, during CPB but before cardioplegia (CPG) has been given, during CPG delivery, during the release of the cross-clamp, and during attempts to reanimate the heart. Ischemia during these times is a significant source of post-cardioplegia injury and increases the risk for reperfusion injury. Acute coronary syndrome leading to ischemic injury can worsen by hypotension, arrhythmias, cardiogenic shock, or coronary artery spasms. Before surgery, it is most likely seen in patients with coronary artery disease (CAD) when the collateral flow is compromised.
Ischemic injury can occur during the seemingly protected period of arrest despite the delivery of cardioplegia. This happens when there is maldistribution of cardioplegia to areas of the heart distal to stenotic coronary arteries or inadequate retrogradely delivered to the right side of the heart. Similarly, intermittent or interrupted CPG can lead to inadequate protection and ischemia. Finally, during the release of the cross clamp, when the heart is beginning to beat on its own again, kinked grafts, tight anastomoses, air emboli, and dysrhythmias contribute to the development of ischemic injuries; this allows the tissue to become susceptible to reoxygenation damage. Should any of the above occur, the risk of reperfusion injury increases as the clamp is removed and blood flow and, thus, oxygen supply is restored.
The primary goal of coronary artery bypass grafting is to revascularize areas of the heart that have been without normal coronary flow. However, abrupt reperfusion can extend ischemic injury. While the exact cause of reperfusion injury has not been elucidated, several factors have been studied and found to be compounding components. These include the severity and duration of previous ischemia, radical oxygen generation, sodium and calcium influx, loss of normal calcium homeostasis, inflammation via neutrophil-derived products, and mitochondrial dysfunction via the opening of the mitochondrial permeability transition pore (mPTP). It is debated whether hyperoxic blood gas management can cause some or all of these mechanisms during CPB.
In the normal metabolism of oxygen in the body, reactive oxygen species (ROS) are formed. Oxygen, as it exists in nature, is as dioxygen molecules or O2. Each oxygen atom has two unpaired electrons in its atomic orbital. Following the Octet Rule, unpaired electrons cause the bit to be unstable. To become stable, species containing one or more unpaired electrons will undergo oxidation-reduction reactions to populate their outer atomic shell. In the presence of hydrogen ions, oxygen is reduced via the transfer of electrons to form water. However, a small percentage is incompletely reduced, and superoxide radicals (-O2) are produced. Superoxide is the basis for most of the remaining reactive oxygen species. Physiologically, small amounts of ROS production have a positive purpose in maintaining homeostasis, including cell signaling and the immune defense mechanisms of neutrophils and phagocytes . However, large concentrations of ROS have been shown to cause ROS-induced injury via the peroxidation of lipid membranes and membranous organelles. One study was unable to link hyperoxia to lipid peroxidation, however.
According to Hadjinikolaou et al., hyperoxia did not contribute to lipid peroxidation in coronary artery operations . They measured whole plasma hydroperoxide concentrations (WPHC) in venous blood samples pre- and post-CPB and found that high PO2 (340 mmHg versus 10 mmHg) did not influence WPHC after 1-hour post-CPB. Hydroperoxide concentrations returned to normal after 6 hours. They concluded that post-CPB lipid peroxidation could not be explained by hyperoxia, and thus ischemic-based reperfusion injury, neutrophil activation, and inflammation are likely the primary pathogenic mechanisms. However, Ihnken et al. and Inoue et al. conducted similar experiments. They found that malondialdehyde levels, a byproduct of lipid peroxidation, were higher in patient groups exposed to supranormal arterial blood oxygenation.
ROS originate from various sources, including activated neutrophils, mitochondria, cardiomyocytes, and vascular endothelium. During CPB, the complement cascade is activated, which leads to neutrophil activation and adhesion to the vascular endothelium. Once adhered to the endothelium, neutrophils release cytotoxic products that stimulate the production of -O2 by NADP oxidase in the neutrophil membrane.
The free radical hypothesis of reperfusion injury suggests that ROS accumulation during reoxygenation induces oxidative cell damage and increases inflammatory cytokine expression in cells. Fujii et al. hypothesized that hypoxemic management during CPB caused more significant inflammatory responses than normoxic management . They conducted an experiment in which rats were separated into three groups: control without CPB (labeled group “SHAM”), hypoxemic (PaO2 > 400 mmHg) with CPB, and normoxic (PaO2: 100–150 mmHg) with CPB. They measured the serum levels of cytokines such as tumor necrosis factor- (TNF-), interleukin (IL)-6, and IL-10, as well as biochemical markers such as lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase. The lung’s wet-to-dry (W/D) weight ratio was measured as an index of lung edema. Superoxide generation was measured via dihydroethidium (DHE) staining of lung and liver tissues sampled 120 minutes after bypass initiation. Blood was tested before CPB, 60 minutes after CPB initiation, and 120 minutes after CPB initiation.
During CPB in each group, the flow was maintained at 70 mL/kg/min, and PaCO2 was held at 35–45 mmHg. According to their results, at the end of CPB, the hyperoxia CPB group showed markedly increased pro-inflammatory cytokine levels versus the normoxia CPB and control groups, with a maximum TNF value of 1237 ± 62 pg/mL and IL-6 of 1695 ± 73 pg/mL. Conversely, the normoxic CPB group showed increased anti-inflammatory cytokine levels compared with the control, with a maximum value of IL-10 of 1003 ± 36 pg/mL. Biochemical marker levels also significantly increased in all categories in the hyperoxia CPB group compared to the other groups. Compared to the control group, both CPB groups showed increased W/D ratios; however, the hyperoxia CPB group indicated higher pulmonary edema than the normoxia CPB group. Similarly, DHE staining of the lung and liver tissue samples showed more significant superoxide production in the hyperoxic CPB group. They concluded that higher arterial oxygen tension aggravates the systemic inflammatory response induced by the production of cytokines and superoxide in the CPB rat model.
The largest oxygen consumers in the cardiomyocyte are the mitochondria, which make ATP through oxidative phosphorylation. The mitochondrial permeability transition pore (mPTP) has been associated with reperfusion injury, specifically cardiac cell apoptosis, and necrosis . The mPTP is a membrane voltage and Ca2+-dependent high-conductance channel in the inner mitochondrial membrane. Physiologically, it remains closed and acts as a switch controlling cardiomyocyte viability. In reaction to increased levels of reactive oxygen species, calcium, and inorganic phosphate within normal pH ranges, the mPTP opens, leading to organelle swelling and the destruction of ATP generation. Intracellular levels of magnesium and ADP, along with acidosis, counteract their opening in the presence of ROS and Ca2+ during ischemia. However, during the initial moments of reperfusion, the overabundance of ROS and Ca2+ overwhelms the cell, causing the mPTP to open. If just enough ATP is present in the myocyte, apoptosis may be triggered, but necrosis follows if there is not enough ATP.
McGuiness et al. conducted a multicenter, randomized, controlled study regarding avoiding hypoxemia versus the standard of care during cardiopulmonary bypass . They followed the incidence and severity of acute kidney injury (AKI) and cardiac surgery-associated multiorgan dysfunction (CSA-MOD) biomarkers, the duration of mechanical ventilation, and the length of hospital stay to assess the effect of hypertension on CPB. A total of 298 patients were randomized into two groups: 148 patients received the usual standard of care, in which PaO2 was maintained between 130 and 230 mmHg (mean, 178 mmHg) during CPB, and 150 patients received interventional care, in which PaO2 was held at normoxic levels of 75 to 90 mmHg. There were no significant differences between the groups in blood flow management or the oxygen delivery index. According to their results, there was no significant difference in the incidence of acute kidney injury, nor was there a difference in the duration of mechanical ventilation or the length of hospital stay. They concluded that avoiding hyperoxia, defined as PaO2 less than 230 mmHg, produced no significant difference between the standard-of-care groups. However, they acknowledged that the study was limited in that the difference in PaO2 between the two groups was moderate (80 mmHg), and more significant amounts of hyperoxia were present.
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