The treatment of critically ill patients is dominated by the notion that promoting the supply of oxygen to the vital organs is a necessary and life-sustaining measure. Oxygen is provided in a much liberal and unregulated fashion, while the tendency for oxygen to degrade and decompose organic (carbon-based) matter is either overlooked or underestimated. In contrast to the notion that oxygen protects cells from injury in the critically ill patient, the accumulated evidence over the past 15 years suggests that oxygen is responsible for the cell injury that accompanies critical illness. Oxygen’s ability to act as a lethal toxin has monumental implications for the way we treat critically ill patients.
The Oxidation Reaction:
In general terms an oxidation reaction is a chemical reaction between oxygen and another chemical species. Because oxygen removes electrons from other atoms and molecules, oxidation is also described as the loss of electrons by an atom or molecule. The chemical species that removes the electrons is called an oxidizing agent or oxidant.
The companion process (i.e., the gain of electrons by an atom or molecule) is called a reduction reaction, and the chemical species that donates the electrons is called a reducing agent. Because oxidation of one atom or molecule must be accompanied by reduction of another atom or molecule, the overall reaction is often called a redox reaction.
When an organic molecule (a molecule with a carbon skeleton) reacts with oxygen, electrons are removed from carbon atoms in the molecule. This disrupts one or more covalent bonds, and as each bond ruptures, energy is released in the form of heat and light (and sometimes sound). The organic molecule then breaks into smaller fragments.
When oxidation is complete, the parent molecule is broken down into the smallest molecules capable of independent existence. Because organic matter is composed mainly of carbon and hydrogen, the end-products of oxidation are simple combinations of oxygen with carbon and hydrogen: carbon dioxide and water.
Oxygen is a weak oxidizing agent, but some of its metabolites are potent oxidants capable of producing widespread and lethal cell injury. The mechanism whereby oxygen metabolism can produce more powerful oxidants than the parent molecule is related to the atomic structure of the oxygen molecule.
The Oxygen Molecule:
Oxygen in its natural state is a diatomic molecule. The orbital diagram to the right of the O2 symbol shows how the outer electrons of the oxygen molecule are arranged. The circles in the diagram represent orbitals. (An orbital is an energy field that can be occupied by electrons. It is distinct from an orbit, which is a path that represents a specific point in space and time.)
An atom or molecule that has one or more unpaired electrons in its outer orbitals is called a free radical. (The term free indicates that the atom or molecule is capable of independent existence—it is free-living.).
Free radicals tend to be highly reactive chemical species by virtue of their unpaired electrons. However, not all free radicals are highly reactive. This is the case with oxygen, which is not a highly reactive molecule despite having two unpaired electrons.
The reason for oxygen’s sluggish reactivity is the directional spin of its two unpaired electrons. No two electrons can occupy the same orbital if they have the same directional spin. Thus, an electron pair cannot be added to oxygen because one orbital would have two electrons with the same directional spin, which is a quantum impossibility. This spin restriction limits oxygen to single electron additions, and this not only increases the number of reactions needed to reduce molecular oxygen to water, but it also produces more highly reactive intermediates.
The Metabolic Pathway:
Oxygen is metabolized at the very end of the electron transport chain, where the electrons and protons that have completed the transport process are left to accumulate. The complete reduction of molecular oxygen to water requires the addition of four electrons and four protons.
The first reaction adds one electron to oxygen, and produces the superoxide radical.
O2 = e- –> O2
The superoxide radical has one unpaired electron, and thus is less of a free radical than oxygen. Superoxide is neither a highly reactive radical nor a potent oxidant. Nevertheless, it has been implicated in conditions associated with widespread tissue damage, such as the reperfusion injury that follows a period of ischemia. The toxicity of superoxide may be caused by the large daily production, which is estimated at 1 billion molecules per cell, or 1.75 kg (4lb) for a 70-kg adult.
The addition of one electron to superoxide creates hydrogen peroxide, a strong oxidizing agent (and the source of acid rain in the atmosphere).
O2 + e- + 2H+ –> H2O2
Hydrogen peroxide is very mobile, and crosses cell membranes easily. It is a powerful cytotoxin and is well known for its ability to damage endothelial cells. It is not a free radical, but it may have to generate a free radical (a hydroxyl radical) to express its toxicity.
Hydrogen peroxide is loosely held together by a weak oxygen-oxygen bond. This bond ruptures easily, producing two hydroxyl radicals, each with one unpaired electron.
An electron is donated to one of the hydroxyl radicals, creating one hydroxyl ion (OH-) and one hydroxyl radical (•OH). The electron is donated by iron in its reduced form, Fe(II), which serves as a catalyst for the reaction. Iron is involved in many free radical reactions, and is considered a powerful pro-oxidant.
The iron-catalyzed dissociation of hydrogen peroxide proceeds as follows:
H2O2 + FE(II) –> OH- + .OH + FE(III)
The hydroxyl radical is the ace of free radicals. It is one of the most reactive molecules in biochemistry and often reacts with another chemical species within five molecular diameters from its point of origin. This high degree of reactivity limits the mobility of the hydroxyl radical, and this may serve as a protective device to limit the toxicity of the hydroxyl radical. However, the hydroxyl radical is always dangerous because it can oxidize any molecule in the human body.
The metabolism of oxygen in neutrophils has an additional pathway that uses a myeloperoxidase enzyme to chlorinate hydrogen peroxide, creating hypochlorous acid (hypochlorite).
H2O2 + 2Cl- –> 2HOCL
When neutrophils are activated, the conversion of oxygen to superoxide increases twenty fold. This is called the respiratory burst, which is an unfortunate term because the increased O2 consumption has nothing to do with energy metabolism. When the increased metabolic traffic reaches hydrogen peroxide, about 40% is diverted to hypochlorite production and the remainder forms hydroxyl radicals. Hypochlorite is the active ingredient in household bleach. It is a powerful germicidal agent and requires only milliseconds to produce lethal damage in bacteria.
The final reaction in oxygen metabolism adds an electron to the hydroxyl radical and produces two molecules of water.
OH + OH- + e- + 2H+ –> 2H2O
Therefore, the metabolism of one molecule of oxygen requires four chemical reactions, each involving the addition of a single electron. This process, then, requires four reducing equivalents (electrons and protons).
Under normal conditions, about 98% of the oxygen metabolism is completed, and less than 2% of the metabolites escape into the cytoplasm. This is a tribute to cytochrome oxidase, which carries on the reactions in a deep recess that effectively blocks any radical escape. This degree of suppression is necessary because of the ability of free radicals to start chain reactions.
The superoxide radical is mobile but not toxic, whereas the hydroxyl radical is toxic but not mobile. Combining the advantages of each oxidant yields a scheme that has the mobile oxidant serving as a transport vehicle that can reach distant places. Once at the desired location, this metabolite could then generate hydroxyl radicals to produce local damage. This scheme is intuitively satisfying, regardless of its validity.
Free Radical Reactions:
The damaging effects of oxidation are largely the result of free radical reactions. This describes the two basic types of free radical reactions: those involving free radicals and non-radicals and those involving two free radicals.
Radical and Non-Radical:
When a free radical reacts with a non-radical, the non-radical loses an electron and is transformed into a free radical. Therefore, the union of a radical and a non-radical begets another radical (thus illustrating the survival value of the free radical). Because free-radicals are often highly reactive in nature. This type of radical-regenerating reaction tends to become repetitive, creating a series of self-sustaining reactions known collectively as a chain reaction. The tendency to produce chain reactions is one of the most characteristic features of free radical reactions. A fire is one example of a chain reaction involving free radicals, and fires illustrate a very important feature of chain reactions: the tendency to produce widespread damage. A chain reaction that is capable of producing widespread organ damage.
The rancidity that develops in decaying food is the result of oxidative changes in polyunsaturated fatty acids. This same process, called lipid peroxidation, is also responsible for the oxidative damage of membrane lipids. The lipophilic interior of cell membranes is rich in polyunsaturated fatty acids (e.g., arachidonic acid) and the characteristic low melting point of these fatty acids may be responsible for the fluidity of cell membranes. Oxidation increases the melting point of membrane fatty acids and reduces membrane fluidity. The membranes eventually lose their selective permeability and become leaky, predisposing cells to osmotic disruption.
The peroxidation of membrane lipids proceeds; The reaction sequence is initiated by a strong oxidant such as the hydroxyl radical, which removes an entire hydrogen atom (proton and electron) from one of the carbon atoms in a polyunsaturated fatty acid. This creates a carbon-centered radical (C•), which is then transformed into an oxygen-centered peroxy radical (COO•) that can remove a hydrogen atom from an adjacent fatty acid and initiate a new series of reactions. The final propagation reaction creates a self-sustaining chain reaction that will continue until the substrate (i.e., fatty acid) is exhausted, or until something interferes with the propagation reaction. (The latter mechanism is the basis for the antioxidant action of vitamin E).
Free radical reactions have been implicated in the pathogenesis of more than 100 diseases, but it is not clear whether oxidant injury is a cause or a consequence of disease. However, a chain reaction is an independent process (i.e., independent of the initiating process), and if it causes tissue injury it becomes an independent pathologic process (a primary illness).
Though it is believed that such a deadly oxidation reaction happens inside the human body but there is also evidence that an anti oxidation reaction is also happening that counter the effects of oxidation reaction. The components that support the anti oxidation (Reduction reaction) are either enzymatic anti-oxidant or non-enzymatic anti-oxidants.
However the risk and severity of oxidation-induced tissue injury are determined by the balance between oxidant and antioxidant activities. When oxidant activity exceeds the neutralizing capacity of the antioxidants, the excess or unopposed oxidant activity can promote tissue injury, leading to several other complications resulting to death in later stage, if not managed properly.