The Use of Hyperoxic Management During CPB Should be Avoided

Medical oxygen is considered a drug, which is essential for cardiopulmonary bypass (CPB) and is administered in a wide range of FiO2?protocols (0.21-1.0) prior to the start of bypass, during bypass and even during separation from bypass. Prior to Cardiopulmonary Bypass, the protocols to initiate the procedure are generally based on the manufacturers IFU, patient demographics (weight, disease state, etc), clinical experience or just clinician comfort. Setting gas flows into the membrane compartment to start bypass can be just as varied; with some having no gas flow until bypass is initiated, some setting gas flows to calculated top flows of 1:1 before the pump is turned on and some setting gas flows at ≤ 1.0 LPM prior to going on bypass. Regardless of method used, the clinical objective for all bypass cases should be to avoid going on bypass with cold hyperoxic and acidic primes. This is because when using hyperoxic and hypothermic primes to initiate bypass, they create ideal conditions for gas coming out of solution and creating gaseous microemboli (GME), as the cold?hyperoxic fluid enters a normothermic blood stream with an accelerated velocity through an arterial cannula. These microbubbles at the start of bypass may in part be due to Bernoulli’s effect in the presence of laminar flow, or they may be created in the vortices of turbulent flow or cavitation as the prime leaves the arterial cannula tip and enters the native blood stream. Under the latter conditions, the creation of GME at the cannulation site can persist for as long as 2 to 10 min after CPB has been initiated.

Before discussing the issues around hyperoxia, we first must find a common definition of what hyperoxia is and at what partial pressure of arterial oxygen (PaO2) can we say hyperoxemia is present. The definition of hyperoxia is relatively clear and is considered to occur when our blood, tissues and organs are exposed to a higher than normal partial pressure of oxygen (PO2) or an excess supply of oxygen. Since the normal PaO2?(normoxia) when breathing room air is considered to be between 80 mmHg and 100 mmHg (with saturations > 98%) we have to agree that PaO2’s > 100 mmHg would be considered hyperoxic. Normoxic PaO2’s are able to support homeostasis and normal acid base balance in a normothermic (37°C) adult patient.

During both in vivo and ex vivo investigations into the effects of hyperoxia management versus normoxia management during CPB, many investigators have tended to set normoxia ranges anywhere between 75 mmHg to 150 mmHg, while at the same time having varied opinions about what is considered a state of hyperoxia in their individual investigations (eg. > 200 mmHg, > 300 mmHg, > 350 mmHg or > 400 mmHg). Theoretically they are all correct, but hyperoxia is perhaps best described during CPB as a PaO2?> 185 mmHg in most acyanotic individuals. However, in cyanotic pediatric patients, the normal values for PO2?are actually considered to be between 50 and 80 mmHg due to the nature of the hypoxic physiology they live with everyday. Hyperoxia in these patients is considered to be present when PaO2’s are greater than 100-150 mmHg.

Under hyperoxic conditions during CPB, large amounts of ROS free radicals are produced. With intracellular and extracellular biological systems, the effect of ROS elevation disrupts the balance between oxidants and antioxidants, which subsequently results in damage to cells and tissues. Endothelial cells exposed to hyperoxia for a period of 30 minutes will produce free radicals via the mitochondrial electron transport system… and reperfusion injury is associated with bursts of superoxide anions.?

Oxygen is also considered to be a vasoactive drug, and hyperoxia has been found to be associated with increasing pulmonary artery wedge pressures, mean arterial pressures, systemic vascular resistance, reduced stroke volumes,?increased left ventricular end diastolic pressures and reductions in coronary artery blood flow. Cyanotic patients are perhaps the most susceptible to the adverse effects of hyperoxia, or what some would consider normal PaO2’s at the start of CPB.

It would seem intuitive to most that if our lungs breathe room air (0.21 O2) and our blood has a normal PaO2?of ≈ 100 mmHg, the same thing would occur if we set our gas blenders to room air while we ventilated the membrane during priming with asanguineous fluids. Unfortunately, it most cases it does not, and the lowest PO2?some will be able to attain during priming in the extracorporeal circuit with a blender at an FiO2?of 0.21, is somewhere between 147 and 153 mmHg.

When it comes to using a gas blender to adjust the FiO2?for effective patient management, there are several methods to?monitor the adequacy of oxygenation, such as; blood gas analysis with arterial saturations > 98%, acid base balance?with lactates < 4.0 mmol/L, venous saturations > 70% and oxygen delivery > 262 ml/minute/m2?during CPB for better renal perfusion and reductions in the incidence of post-operative acute kidney injury. The necessity to use hyperoxia for routine CPB cases to increase arterial hemoglobin saturations to 100% is rare and may have no useful clinical benefits. However, the use of hyperoxia prior to deep hypothermic circulatory arrest (DHCA) has been demonstrated to provide better cerebral protection due to tissue super-saturations and the presence of excessive dissolved O2?in the blood prior to circulatory arrest. But what are the consequences to hyperoxic management during cardiopulmonary bypass?

Cyanosis in neonate and pediatric cardiac abnormalities is often associated with chronic hypoxia, malnutrition and growth failure. There is a considerable amount of evidence that hyperoxia is detrimental in those patients with cyanotic heart disease and has been shown to induce myocardial?injury and postoperative dysfunction in these patients. Postoperative cardiac dysfunction is a major cause of morbidity and mortality in cyanotic heart disease patients, despite successful surgical correction. Some examples of cyanotic heart disease or disorders are;

Coarctation or interruption of the?aorta

Ebstein’s?anomaly

Hypoplastic left heart?syndrome

Tetralogy of?Fallot

Total anomalous pulmonary venous?return

Transposition of the great?arteries

Truncus?arteriosus

Eisenmenger?syndrome

Critical Pulmonary and Aortic?stenosis

Morita stated that when cardiac surgery is performed on cyanotic infants, CPB is usually initiated with hyperoxic?primes without consideration of possible cytotoxic effects of hyperoxemia on the hypoxic myocardium. Modi et al?investigated 29 pediatric patients (20 cyanotic, 9 acyanotic) undergoing hyperoxic CPB and found that early reoxygenation of cyanotic pediatric hearts was associated with significant early stage myocardial injury. Oxidative stress is a major part of the cellular mechanism resulting in myocardial damage, and reoxygenation injury with hyperoxemia is associated with the production of ROS by the formation of oxygen-derived free radicals such as superoxide and peroxide, leading to cell membrane degradation from lipid peroxidation.

It was demonstrated that both inflammatory and stress responses triggered by CPB in cyanotic patients are similar with both hyperoxic and normoxic bypass management. However, oxygen mediated injury does occur in the presence of hyperoxia with cyanotic patients at the start of CPB, resulting in myocardial, cerebral, and hepatic injury. It appears to be well reported?that controlled normoxic reoxygenation in cyanotic patients at the start of CPB, significantly reduces reoxygenation injury from oxidative stress and myocardial cell injury.

Ghorbel and coworkers confirmed that hyperoxia at the start of CPB in cyanotic patients is associated with significant gene expression changes, which were not seen when the reoxygenation was controlled. These genes altered by hyperoxic CPB were down regulated genes involved in intracellular signaling, metabolic process, and transport… suggesting that hyperoxic bypass can have deleterious effects on the myocardium. In a review of normoxic and hyperoxic CPB in pediatric cyanotic patients, Mokhtari et al??found significant evidence to support the avoidance of hyperoxia and encouraged the use of controlled reoxygenation in this patient population. The abundance of?evidence to support the incidence of reoxygenation injury in cardiac patients with cyanotic heart disease clearly indicates that the use of hyperoxia should be avoided, and normoxic controlled use of oxygen management during CPB in this patient population may reduce myocardial injury and improve patient outcomes after cardiac surgery. When reviewing the material associated with hypoxic myocardial cells and reoxygenation injury caused by cytotoxic substances such as nitric oxide, peroxynitrite and ROS oxygen free radicals, we have to consider the potential for myocardial injury through the introduction of hyperoxic blood through the use of standard blood cardioplegia or blood microplegia. It is well known that reperfusion injury can occur when hyperoxic blood encounters ischemic, hypoxic myocardial tissues as the cross clamp is removed. But this same potential for reperfusion injury can occur after prolonged periods of arrest between cardioplegia delivery times, when hyperoxic blood cardioplegia is delivered directly to the hypoxic myocardium with the cross clamp still on the aorta. It is during this time that coronary reperfusion with hyperoxic blood can produce myocardial damage through lipid peroxidation and ROS injury.

The occurrence of myocardial oxidant injury from oxygen free radicals and inflammatory mediators (IL-6, IL-8 and TNFa)?are also associated with hyperoxic management of bypass in acyanotic patients. Kagawa et al examined 22 acyanotic pediatric patients using normoxic (PaO2?100-150 mmHg) and hyperoxic management (PaO2?200-300 mmHg) of bypass. The authors found that normoxemic management of bypass in acyanotic children can minimize oxidant injury and reduce inflammatory cytokines, leading to the minimization of SIRS.

In a randomized study of 48 patients undergoing CPB, Belboul and co-workers showed a significant increase in morbidity when using hyperoxic PO2’s (190-300 mmHg), compared to normoxemic PO2’s (80-112 mmHg) on bypass. In comparison to the normoxemic group, those managed with high PO2’s had a significantly increased period of postoperative ventilator support, increased bleeding and increased blood product usage. This same hyperoxic group had a significant increase in arrhythmias, myocardial infarctions and respiratory insufficiency. Liver enzymes and creatinine levels were also found to be significantly lower in the group managed with normoxemia. Ihnken and co-workers found that the reintroduction of hyperoxic blood (PO2?of 400 mmHg) into hypoxic piglet hearts produced highly cytotoxic substances such as nitric oxide, peroxynitrite and oxygen free radicals. Their conclusions were that reoxygenation of hypoxic hearts with hyperoxic blood (PO2’s > 150 mmHg) causes oxidant related damage to the myocardium that is characterized by lipid peroxidation.

The use of hyperoxia during CPB serves no clinically useful purpose during routine bypass in cyanotic and acyanotic patients, and the potential for causing myocardial reoxygenation injury is real, especially during the initiation of CPB in the cyanotic pediatric population and during blood cardioplegia delivery, which far outweighs any theoretical benefits of reducing microbubble activity. Another popular theoretical approach to the use of hyperoxia is with the Oxygen Pressure Field Theory (OPFT). This was a concept that was theorized back in the early 1900's, long before the hazards of hyperoxia during Cardiopulmonary Bypass were known and has no direct clinical evidence of patient benefits or reduced patient harm. Randomly increasing the FiO2?to 100% by a clinician during Extracorporeal Circulation?because of suspected microbubble activity, personal opinions or a 100 year old Theory may adversely affect patient outcomes due to dramatic increases in oxidative stress.

Simply put ... opinions are for everyone, theories are for in vitro and in vivo research and evidence based science is for clinical applications.

Therefore, due to an abundance of evidence about the hazards of using hyperoxia during CPB, hyperoxic management of patients during routine CPB should be avoided, and clinicians should practice the use of normoxic management (PaO2 <185 mmHg) of patients using the present Point of Care clinical and laboratory technologies that are so common place in modern day cardiac operating rooms.

Gerard J Myers RT, CCP Emeritus - Cardiac Surgery Perfusion Books - LivaNova Italy, 2015