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Cellular pathophysiology. Part 2: responses following hypoxia

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Sharon Edwards, MSc, RN, DipN, PGCEA.

Senior Lecturer, Department of Nursing and Midwifery, University of Hertfordshire

During hypoxic injury blood flow falls below a certain critical level that is required to maintain cell viability. The interrupted supply of oxygenated blood to cells results in anaerobic metabolism and loss of adenosine triphosphate (ATP), and cellular membrane disruption (see Figure 1).


The nurse’s role following injury or hypoxia to cells is related to maintaining a normal haemodynamic state, prevent excessive cellular/organ damage and loss of circulating volume. This involves the administration of oxygen, fluids and adequate nutrition. Pharmacological interventions may be available as treatment options for the future.

Cellular changes

Cellular changes can be caused by any of the types of injury listed in Table 1 in the first paper in this series (Edwards, 2003), including hypovolaemia/ hypotension, pressure sores, heart failure, myocardial infarction, shock and pulmonary embolism. All these states can, if left to progress, interfere with tissue perfusion, oxygen transport and the synthesis of ATP, leading to a reduction in the availability of energy, nutrients and ultimately hypoxia, causing serious cell damage.

Cellular energy production

Nutrients, such as glucose and fatty acids, as well as oxygen, enter the cell across the cell membrane. Hypoxic injury results in an inadequate flow of nutrients and oxygen to the cell. If tissue perfusion continues to be insufficient, hypoxia occurs and the cell resorts to anaerobic metabolic pathways for energy production. This produces several changes in cell function: mitochondrial activity is diminished due to a lack of oxygen for glycolysis and the electron transport chain; cellular ATP stores are rapidly used up (Gosling, 1999). The end product is lactic acid and nitric oxide, which can rapidly build up in high concentrations in the cell and blood, lowering the pH.

The formation of lactic acid

Consequently, the results of anaerobic metabolism are the production of lactic acid and a reduction in the energy available for cell work. Lactic acidosis reduces myocardial contractility, arteriolar responsiveness to further adrenaline and noradrenaline release, potentiating vasomotor collapse and stimulating the intravascular clotting mechanism.

However, acidaemia has the beneficial effect of shifting the oxyhaemoglobin dissociation curve to the right, thereby facilitating the release of oxygen from haemoglobin (Marieb, 2001). Eventually, a large number of cytotoxic, vasodilator, vasoactive and other substances are released from the cell into the circulation, resulting in progressive vasodilatation, myocardial depression, increased capillary permeability and, eventually, intravascular coagulation (Huddleston, 1992).

The formation of free radicals/nitric oxide

Free radicals can be formed in a number of ways, but their damaging presence usually results from an absence of oxygen, which in normal physiology is the final resting place for electron flow via the mitochondrial electron transport chain. When oxygen is missing or diminished, electrons build up on carriers. The carriers are unable to pass on the electrons to the next level (Zuccarelli, 2000).

The most well-known molecule associated with the formation of free radicals is nitric oxide. Under normal circumstances this is a potent vasodilator and a regulator of blood flow (Marieb, 2001). Nitric oxide can accumulate in high concentrations, and can react with other free radicals thereby setting up two mechanisms of cell death: oxidative injury and energy depletion (Edelstein et al, 1997). The end result of these mechanisms include those listed in Box 1 (Zuccarelli, 2000).

The mitochrondria can lose their membrane potential in high concentrations of nitric oxide and halt ATP production all together. This process can lead to endothelial damage, further stimulating the inflammatory response (Huddleston, 1992).

Cellular membrane disruption

As oxygen levels fall in the cell, there is a rapid shift from aerobic to anaerobic metabolism. Anaerobic glycolysis leads to the accumulation of lactic acid, and a reduction in ATP for cellular work. Without intervention oxygen deprivation will be accompanied by cellular membrane disruption, leading to electrolyte disturbance.

Without sufficient supplies of ATP the plasma membrane of the cell can no longer maintain normal ionic gradients across the cell membranes and the sodium potassium pump can no longer function. This changes the ionic concentration of potassium and sodium. Potassium leaks into the extracellular space and sodium followed by water will move into the cell, causing cellular oedema and an increased intracellular osmotic pressure (Edwards, 2001). The cell may eventually burst.

The high intracellular potassium and low intracellular sodium and calcium concentration are maintained by active transport systems. Thus, one of the most rapid effects of hypoxia, and a shortage of ATP, is perturbation of the normal ionic gradients across the cell membrane, with a rapid efflux of potassium from the cell, and movement of sodium and calcium into the cell (Gosling, 1999).

Increased sodium in the interior of cells result in water also entering the cell, driven by osmotic forces causing cellular swelling and distortion, which may interfere with organelle function (Buckman et al, 1992). The cytoplasmic membrane of cells becomes increasingly permeable to larger molecular weight proteins, not simply due to direct cellular injury but also due to the systemic intracellular energy debt.

This may affect the conduction of electrical impulses within the cells, which require an intact cell membrane and functioning ionic channels. The contraction of muscle results from the passage of electrical impulses down specialised pathways, which require the movement of sodium and potassium ions in and out of the cell to produce an action potential. These may limit movement and contraction of muscle and tissues affected. These changes are reversible if the oxygen is restored, allowing cells to contract normally.

Physiological progression

If left unchecked, intracellular acidaemia becomes extreme, cellular dysfunction becomes intemperate. This leads to intracellular lysosome membrane disruption and intracellular calcium and may finally lead to irreversible cell damage and death.

The role of lysosomes

An important cell structure containing enzymes, which break down cell waste, the lysosomal membrane becomes fragile when the cell is injured or deprived of oxygen (Marieb, 2001). Lysosomal membrane instability is made worse by the lack of ATP and the cell starts to use its own structural phospholipids as a nutrient source. Eventually the lysosomal membrane becomes more permeable and may rupture. This allows the release of lysosomal enzymes, resulting in self-digestion of the cell. The use of steroids is thought to help stabilise the lysosomal membrane and prevent lysosmal enzyme damage to the cell (Guthrie, 1982).

The role of calcium

The influx of calcium into the cell has a different cause than the initial membrane permeability change involving sodium and potassium. The mechanisms by which the calcium content of cells is regulated are dysfunctional because of a lack of ATP (Gosling and Alpar, 1999). There is ample evidence to identify excess intracellular calcium as the true neurotoxic ion following hypoxia.

The importance of calcium cannot be underestimated. It is critical in maintaining membrane potentials and in promoting the release of neurotransmitters at the synapse (Zuccarelli, 2000). Its paramount role requires calcium to be readily available to the cell stored in cellular organelles; its toxicity requires it to be sequestered and buffered when released, its passage controlled by a large variety of voltage-gated and ligand-gated channels (Tymianski and Tator, 1996). The alteration in channel permeability results in depolarisation of the cell membrane, resulting in reversal of sodium/ calcium pumps and calcium is pumped in.

Intracellular calcium is an important signalling system responsible for activation of phospholipases and proteases, and its derangement results in membrane disruption and remodelling (Zuccarelli, 2000). As a result, calcium accumulates in the mitochondria, causing structural derangement of the organelles, and may be the hallmark of irreversible cellular injury and, eventually, death (Buckman et al, 1992).

Implications for practice

The nursing interventions that relate to the physiological processes that occur following an injury or hypoxia are related to maintaining a normal haemodynamic state, preventing excessive cellular/ organ damage and loss of circulating volume.

Oxygen supply and demand/prevention of respiratory failure

An imbalance between oxygen supply and tissue demands is fundamental to the nature of the insult. Oxygen supply and demand is maintained in balance as long as supplies of oxygen are available and carbon dioxide is eliminated through ventilation, perfusion, diffusion and cell metabolism. Any alteration of any part of these processes cause impaired gas exchange.

Oxygen supply and demand deficits may relate to pulmonary trauma, causing damage to the chest wall and pulmonary contusions. However, deficits in oxygen supply may exist when the lungs are not directly injured, as any insult may give rise to an increase in demand over supply, due to the neuroendocrine response, leading to cellular hypoxia, production of lactic acid and the lowering of blood pH. In an acid environment chemoreceptors are stimulated, and consequently this increases respiratory rate in an attempt to eliminate the excess acid. This can exhaust the patient, leading to increased demands for oxygen. When these processes become overwhelmed, the victim is at risk of pulmonary complications, leading to a supply-demand deficit that gives rise to an oxygen debt.

The nurse is responsible for administrating humidified oxygen, the continuous frequent monitoring of respiratory rate, depth and pattern of breathing and any signs of change. There are detailed arterial blood gas tests that can be done to determine acid base balance, but these are not always available in all clinical situations.

Prevention of a low circulating volume

The release of mediators effects the microvasculature, organs, and the regional circulation causing vasodilatation, permeability changes, and coagulation. The vasodilatation in certain areas increases blood flow, the movement of fluid from the circulation due to permeability changes, which causes tissue oedema in the area, and contributes to the disruption of the normal circulation (Edwards, 2001). The coagulation may cause blockage of the vasculature as a result of microvascular thrombi, which causes further tissue damage.

The consequence of selective vasoconstriction and dilatation is a maldistribution of circulating volume and may lead to organ dysfunction (Huddleston, 1992). The movement of fluid and vasodilatation impede cell movement, function and result in a relative rather than true hypovolaemia (Edwards, 1998). Therefore, the nurse’s role is to administer prescribed fluid regimens for the immediate restoration of an effective circulating blood volume. This may require the use of blood, blood products, a balanced salt and/or water solution, colloid solution or a combination of all (Edwards, 1998).

The administration of adequate nutrition

With the stimulation of the neuroendocrine system there is a substantial increase in metabolic rate, oxygen consumption, and the production of carbon dioxide and heat. This amplification of energy production is accomplished at the expense of lean body mass. A patient with profound injuries will have hypermetabolism due to stress, and use mixed fuel sources.

Energy requirements are amplified to supply nutrients and oxygen to active tissues and organs involved in the defence against the results of injury. Inflammation, immune function and tissue repair all require an increase in nutritional substrates to support their function (Lehmann, 1993). All potential sources of glucose are mobilised as sources of fuel. Amino acids and glycerol are converted into glucose via gluconeogenesis, and glycogen stores are converted via glycogenolysis. The result is a hyperglycaemia.

The release of catecholamines causes decreased deposition of fat stores (lipogenesis), and increased breakdown of fat (lipolysis). The liver degrades fatty acids for use as fuel, and fat deposits may accumulate in the liver, leading to signs and symptoms of liver failure, including hyperbilirubinaemia, elevated levels of liver enzymes, and hepatic encephalopathy (Cheevers, 1999). Zinc distributed via the liver becomes deficient, which is associated with impaired wound healing (Tan, 1997).

As protein continues to be broken down and used for energy serum, levels of proteins reduce (Chee-vers, 1999). Circulating proteins are responsible for maintaining stability of the colloidal oncotic pressure of the vascular bed. A decreased level of these proteins, such as albumin, result in decreased colloidal oncotic pressure, and hypoalbuminaemia, causing pooling of fluid in the interstitial space, characterised by oedema. Protein loss is accompanied by potassium, magnesium and phosphate loss (Tan, 1997).

The use of all energy sources following an insult causes an exhaustion of energy stores and sources, and deprives cells of nutrients, reducing their function. There is an increase in cellular metabolism, oxygen consumption, cardiac work and carbon dioxide production. The myocardium becomes depressed, leading to dysfunction.

Clearly protein depletion and starvation contribute to morbidity and mortality following an insult. Therefore it is imperative to initiate feeding regimens early (Edwards, 2000). The timing and the route of nutritional support can favourably influence the metabolic response to injury.

Prevention of shock is discussed in Box 2.

Pharmacological interventions

Treatments for conditions such as heart failure, trauma and so on, generally focus on haemodynamic abnormalities, and interventions that maintain circulating volume, administration of oxygen to meet supply and demand, and the prevention of shock. This type of nursing is demanding and intense. There has recently been a steady increase in research looking at the release of mediators following cell injury, the effects of which can continue for months or years after the initial event (Edward, 2002).

It is now being proposed that it is the cellular, chemical involvement and the complex activation of neurohormones released within minutes of the initial injury that are the true culprits in death and disability associated with certain conditions. Immediate pharmacological intervention aimed at deterring the onset or progress of cell death could define the future of emergency care (Zimmerman et al, 1993). There are continued efforts to discover new drugs that could prove essential as our understanding of the epidemiology of disease develops.


The cellular elements and the chemical mediators which are released within minutes of an injury/ hypoxia do not act alone. The interconnections between cellular elements, their secretions, the immune system, and the nervous system are highly regulated and serve to benefit human body functions. When there is traumatic or hypoxic injury to cells, the interconnections between these systems becomes evident. They act together to choke the tissue, depriving it of control over its micro-circulation and necessary oxygen, rendering membrane potentials useless to maintain organ function.

The nurse’s role in caring for the patient with a hypoxic or cellular injury is mainly focused on maintaining haemodynamic abnormalities such as circulating volume, nutrition and oxygen levels, together with observing for signs of shock and deterioration. It is now thought that the progressive worsening of some conditions results from neurohormonal changes, which occur as the body tries to compensate for haemodynamic abnormalities. Therefore, when treating victims with any physiological insult there is a possibility of further injury and even death from events totally unrelated to the initial injury.

There is hope for effective pharmacological intervention at the initial stages, before further injury begins. The fact that the mediators of injury are already resident in normal physiology means that their activity can be modified or pathways promoted that can lead to regeneration. This is the direction of much current essential clinical research and could revolutionise the future of nursing care.



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