The respiratory system is divided into upper and lower respiratory tracts: the upper airways consist of the nose, nasal conchae, sinus and pharynx; the lower respiratory tract includes the larynx, trachea, bronchi and lungs.² Larger airways are lined with stratified epithelial tissue, which have a relatively high cellular turnover rate; these cells protect and clear these large airways. There are also additional specialised features of this tissue including an extensive distribution of mucus/goblet cells and cilia, which facilitate the mucociliary clearance system and aid airway clearance.

Upper Respiratory Tract

The nasal cavities contain an extremely vascular and mucoid environment for warming and humidifying inhaled gases. To maximise exposure to this surface area, the nasal conchae create turbulent gas flow. Cilia at the top of the epithelial cells and mucus provide filtration and cleaning of the inhaled air. Mucus is moved by the cilia lining the conducting airways towards the pharynx at a rate of 1–2 cm per minute. One litre of mucus is produced every day with only a small part not reabsorbed by the body.^3,⁴

The pharynx is a muscular tube that transports food and air to the oesophagus and larynx, respectively. Inferior to the pharynx, the larynx consists mostly of cartilage attached to other cartilage and surrounding structures, and houses the vestibular (false) vocal folds and the true vocal cords (see Figure 13.2).⁵ An important pair of cartilages within the larynx is the pyramid-shaped arytenoids, which act as attachment points for the vocal cords. This area is easily damaged by pressure from endotracheal tubes; the most significant independent risk factor for injury to the arytenoids is the length of intubation time.⁶ The thyroid cartilage (‘Adam’s apple’) and the cricoid cartilage protect the glottis and the entrance to the trachea.⁴ Another cartilage in the larynx is the triangular-shaped elastic epiglottis which protects the lower airways from aspiration of food and fluids into the lungs. The epiglottis usually occludes the inlet to the larynx during swallowing. The primitive cough, swallow and gag reflexes further protect the airway.⁴

FIGURE 13.2 Larynx. (A) Cartilages and ligaments; (B) Neck muscles.⁵

Lower Respiratory Tract

The trachea is a hollow tube approximately 11 cm long and 2.5 cm in diameter, and marks the beginning of the lower respiratory tract. The trachea is supported by 16–20 C-shaped cartilages, and is another area at risk of pressure damage from artificial airways. The trachea divides at the carina into the left and right main bronchi. The bronchial tree has two main stem bronchi that are structurally different. The right bronchus is wider and angles slightly where it divides further into the three lobes of the right lung. The most common site of aspiration of foreign objects is the right bronchus because of its anatomical position. The acutely angled left main bronchus divides further into the two main lobes of the left lung.

The airways within each lung branch out further into secondary (or lobar) bronchi then tertiary (or segmental) bronchi. Further divisions within these conducting airways end with the terminal bronchioles, the smallest airways without alveoli. These conducting airways do not participate in gas exchange but form the anatomical dead space (approximately 150 mL).⁷

Larger airways have a greater proportion of supporting cartilage, ciliated epithelium, goblet and serous cells and hence a mucous layer. As the airways become smaller, cartilage becomes irregularly dispersed, the number of goblet cells and amount of mucus decreases until, at the alveolar level, there is only a single layer of squamous epithelial cells. Alveolar macrophages are present in these epithelial cells, and phagocytose any small particles that may enter the alveolar area. Smooth muscle surrounds and supports the bronchioles, enabling airway diameter change and subsequent changes in airway resistance to gas flow.⁸

Thorax/Lungs

The lungs and heart are protected within the thoracic cage. Expansion of the thorax enables the lungs to fill with air during inspiration when respiration is triggered, and to passively compress to expel air from the lungs during expiration. The diaphragm separates the thorax from the abdomen and actively participates in the ventilation process. The diaphragm is the most important inspiratory muscle, performing approximately 80% of the work of breathing. Inspiration is initiated from the medulla, sending impulses through the phrenic nerve to stimulate the diaphragm to contract and flatten. The phrenic nerve originates in the cervical plexus and involves the third to fifth cervical nerves. It splits into two parts, passing to the left and right side of the heart before it reaches the diaphragm. For this reason, patients can have ventilation difficulties if phrenic nerve damage is due to C3–C5 trauma.^8,⁹

The conducting airways move inspired air towards the respiratory unit, ending in the terminal bronchioles. The respiratory bronchioles, the alveolar ducts and alveolar sacs form the respiratory unit where the diffusion of gas molecules, or gas exchange, occurs. The respiratory unit makes up most of the lung with a volume of 2.5–3 L during rest ⁷ (see Figure 13.3).

FIGURE 13.3 Lower airway branches.⁵

Control of Ventilation

Normal breathing occurs automatically and is a complex function not fully understood. It is coordinated by the respiratory centre, regulated by controllers in the brain, effectors in the muscles and sensors including chemoreceptors and mechanoreceptors. There are also protective reflexes that respond to irritation of the respiratory tract such as coughing and sneezing.

Controller

In the brainstem, the medulla oblongata and the pons regulate automatic ventilation while the cerebral cortex regulates voluntary ventilation (see Figure 13.7). The respiratory rhythmic centre in the medulla can be divided into inspiratory and expiratory centres, with the following functions:⁸

• The inspiratory centre (or dorsal respiratory group) triggers inspiration.

• The expiratory centre (or ventral respiratory group) only functions during forced respiration and active expiration.

• The pneumotaxic and apneustic centre in the pons adjusts the rate and pattern of breathing.

• The cerebral cortex provides conscious voluntary control over the respiratory muscles. This voluntary control cannot be maintained when PCO₂ and hydrogen ion (H⁺) concentration become markedly elevated; an example is the inability to hold your breath for very long.⁸ Emotional and autonomic activities also often affect the pace and depth of breathing.

FIGURE 13.7 Respiratory centres and reflex controls.⁴

Effectors

The diaphragm is the major muscle of inspiration, although the external intercostal muscles are also involved. The accessory muscles of inspiration (scalenes, sternocleidomasteoid muscles and the pectoralis minor of the thorax) are active only during exercise or strenuous breathing. Expiration is a passive act and only the internal intercostal muscles are involved at rest. During exercise, the abdominal muscles also contribute to expiration.⁴ Inspiration is triggered by stimulus from the medulla, causing the diaphragm to contract downwards, and the external intercostal muscles to contract, lifting the thorax up and out. This action lowers pressure within the alveoli (intra-alveolar pressure) relative to atmospheric pressure. Air rushes into the lungs to equalise the pressure gradient. After contraction has ceased, the ribs and diaphragm relax, the pressure gradient reverses, and air is passively expelled from the lungs and return to their resting state due to elastic recoil.

Sensors

A chemoreceptor is a sensor that responds to a change in the chemical composition of the blood; there are two types: central and peripheral. Central chemoreceptors account for 70% of the feedback controlling ventilation, and respond quickly to changes in the pH of cerebral spinal fluid (CSF) (increase of PCO₂ in arterial blood).⁹ If the PCO₂ in arterial blood remains high for a prolonged period, as in chronic obstructive pulmonary disease (COPD), a compensatory change in HCO₃ occurs and the pH in CSF returns to its near normal value.⁷ Under these conditions a patient breathes due to hypoxic drive; that is, low levels of O₂ are detected by peripheral chemoreceptors and this triggers breathing. For this small percentage of the population with COPD, care is required when administering oxygen so that the stimulus to breathe is not compromised, as increases in PO₂ may reduce respiratory drive. Peripheral chemoreceptors respond to low partial pressure of oxygen in arterial blood (PaO₂) and contribute to maintaining ventilation, functioning optimally when oxygen levels fall below 70 mmHg.⁷

Central chemoreceptors located in the medulla respond to changes in hydrogen ion concentration in the CSF that surrounds these receptors. A change in the partial pressure of carbon dioxide in arterial blood (PaCO₂) causes movement of CO₂ across the blood–brain barrier into the CSF and alters the hydrogen ion concentration. This increase in hydrogen ions stimulates ventilation. Central chemoreceptors do not however respond to changes in PaO₂ levels. Opiates also have a negative influence on these chemoreceptors causing less sensitivity to changes in hydrogen ion concentration.⁷ Note also that hyperventilation may reduce the level of PaCO₂ to a level that could cause accidental unconsciousness if the breath is held after hyperventilation. This phenomenon is well known amongst divers and is due to increasing levels of CO₂ as the primary trigger of breathing. If the CO₂ level is too low due to hyperventilation, the breathing reflex is not triggered until the level of oxygen has dropped below what is necessary to maintain consciousness.

Peripheral chemoreceptors are located in the common carotid arteries and in the arch of the aorta. These receptors are sensitive to changes in PaO₂ and are the primary responders to hypoxaemia, stimulating the glossypharyngeal and vagus nerves and providing feedback to the medulla. Peripheral chemoreceptors also detect changes in PaCO₂ and hydrogen ion concentration/pH in arterial blood.⁹ Other receptors include stretch receptors located in the lungs that inhibit inspiration and protect the lungs from over-inflation (Hering–Breuer reflex), and in the muscles and joints (see Figure 13.7).

Pulmonary Volumes and Capacities

In healthy individuals, the lungs are readily distensible or compliant; when exposed to high expanding pressures or in disease states, compliance is increased or decreased. A range of lung volumes and capacities are illustrated in Figure 13.8. Tidal volume (TV) is the volume of air entering the lungs during a single inspiration and is normally equal to the volume leaving the lungs on expiration (around 500 mL). During inspiration, the TV of inspired air is added to the 2400 mL of air already in the lungs. This volume of air that remains in the lungs after a normal expiration is the functional residual capacity (FRC),⁴ which:

• has an important role in keeping small alveoli open and avoiding atelectasis

• can be reduced during anaesthesia or neuromuscular blockade, most likely due to loss of muscle tone ¹²

• if reduced, results in the smallest alveoli closing at the end of the expiration (the ‘closing volume’).

FIGURE 13.8 For lung volume measurements, all values are approximately 25% less in women. ERV, expiratory reserve volume; IC, inspiratory capacity; IRV, inspiratory reserve volume; FRC, functional residual capacity; TLC, total lung capacity; RV, residual volume; VC, vital capacity; VT, tidal volume.¹⁰

The closing volume plus the residual volume is called the ‘closing capacity’. The closure of the smallest airways may occur because dependent areas of the lungs are compressed, although this is not the only mechanism as these airways also close in the weightlessness of space. The closing volume is dependent on patient age; in a young healthy person it is 10% of vital capacity, while for an individual aged 65 years it increases to 40%, approximating total FRC.¹¹

Alveolar Ventilation

Minute volume (MV), often referred to during mechanical ventilation, is TV multiplied by respiratory frequency (e.g. 500 mL × 12 breaths per minute = 6000 mL MV). Importantly, only the first 350 mL of inhaled air in each breath reaches the alveolar exchange surface, with 150 mL remaining in the conducting airways (called the ‘anatomic dead space’). Alveolar ventilation is the amount of inhaled air that reaches the alveoli each minute (e.g. 350 mL × 12 = 4200 mL of alveolar ventilation).⁸

Work of Breathing

In a resting state, energy requirements to breathe is minimal (less than 5% of total O₂ consumption).⁷ However, changes in airway resistance and lung compliance affect the work of breathing (WOB), resulting in increased oxygen consumption (VO₂).¹³ As noted earlier, the lungs are very distensible and expand during inspiration. This expansion is called the elastic or compliance work and refers to the ease by which lungs expand under pressure. Lung compliance is often monitored when patients are mechanically ventilated, and is calculated by dividing the change in lung volume by the change in trans-pulmonary pressure.³ For the lung to expand, it must overcome lung viscosity and chest wall tissue (called ‘tissue resistance work’). Finally, there is airway resistance work – movement of air into the lungs via the airways. The work associated with resistance and compliance is easily overcome in healthy individuals but in pulmonary disease, both resistance and compliance work is increased.^3,¹⁴ During exertion, when increased muscle function heightens metabolic rate, oxygen demand rises to match consumption and avoid anaerobic metabolism, and work of breathing is increased. The term ‘work of breathing’ is often used in those who are critically ill, when basic respiratory processes are challenged and breathing consumes a far greater proportion of total energy.

Principles of Gas Transport and Exchange in Alveoli and Tissues

Oxygen and carbon dioxide is transported in the bloodstream between the alveoli and the tissue cells by the cardiac output. Delivery of oxygen to tissues and transfer of carbon dioxide from the tissues to the capillary occurs by diffusion and is therefore dependent on the pressure gradient between the capillary and the cell. Diffusion involves molecules moving from areas of high concentration to low concentration. Other determinants of the rate of diffusion include the thickness of the alveolar membrane, the amount of surface area of the membrane available for gas transfer and the inherent solubility of the gas. Carbon dioxide diffuses about 20 times more rapidly than oxygen because of the much higher solubility of carbon dioxide in blood.⁷ At the most distal ends of the conducting airways lies an extensive network of approximately 300 million alveoli. The surface area of the lungs if spread out flat is about 90 m² – about 40 times greater than the surface of the skin.⁴ Gas exchange occurs through the exceptionally thin alveolar membranes. Oxygen uptake takes place from the external environment via the lungs through to the blood in the adjacent alveolar capillary networks. Similarly, carbon dioxide diffuses from capillaries to the alveoli and is then expired.

Oxygen Transport

In oxygenated blood transported by the pulmonary capillaries, there is 20 mL of oxygen in each 100 mL of blood. Oxygen is transported in two ways; dissolved in plasma (about 0.3 mL; 1.5%) with the remainder bound to haemoglobin.⁸ The 1.5% of oxygen dissolved in the blood is what constitutes PaO₂ and measured by arterial blood gases.⁴ One gram of haemoglobin carries 1.34 mL oxygen, and the level of saturation within the total circulating haemoglobin can be measured clinically, commonly by pulse oximetry. The amount of oxygen actually bound to haemoglobin compared with the amount of oxygen the haemoglobin can carry is commonly reported as SaO₂. Oxygen is attached to the haemoglobin molecule at four haem sites. As the majority of oxygen transport is via haemoglobin, if all four sites are occupied with oxygen molecules the blood is determined to be ‘fully saturated’ (SaO₂ = 100%).¹⁴

A large reserve of oxygen is available if required, without the need for any increase in respiratory or cardiac workload. Oxygen extraction is the percentage of oxygen extracted and utilised by the tissues. At rest, just 25% of the total oxygen delivered to the tissue is extracted, although this amount does vary throughout the body, with some tissue beds extracting more and others taking less. Normally, the oxygen saturation of venous blood is 60–75%; values below this indicate that more oxygen than normal is being extracted by tissues. This can be due to a reduction in oxygen delivery to the tissues, or to an increase in the tissue consumption of oxygen.^8,⁹

Oxygen delivery (DO₂) and oxygen consumption (VO₂) are important aspects to consider in the management of a critically ill patient. Normal oxygen delivery in a healthy person at rest is approximately 1000 mL/min. Normal oxygen consumption is 200–250 mL/min,⁹ but this can increase significantly during episodes of sepsis, fever, hypercatabolism and shivering.¹⁴ The difference between normal delivery and normal consumption highlights the large degree of oxygen reserve available to the body.

Oxygen–Haemoglobin Dissociation Curve

As blood is transported to the tissues and end-organs, the affinity of haemoglobin and oxygen to combine decreases, relative to the surrounding arterial oxygen tension. This relationship is illustrated by the oxyhaemoglobin dissociation curve (see Figure 13.9). As oxygen is offloaded at the tissue level, carbon dioxide binds more readily with haemoglobin, to be transported back to the lungs for removal.⁴

FIGURE 13.9 Shift of the oxyhaemoglobin dissociation curve (A) to the right and (B) to the left.⁸⁵

In the upper part of the curve (within the lungs), relatively large changes in the PaO₂ cause only small changes in haemoglobin saturation. Therefore, if the PaO₂ drops from 100 to 60 mmHg (14–8 kPa), the saturation of haemoglobin changes only 7% (from a normal 97% to 90%). The lower portion (steep component) of the oxygen–haemoglobin dissociation curve, when PaO₂ is between 60 and 40 mmHg (8–5 kPa) reflects however that as haemoglobin is further de-saturated, larger amounts of oxygen are released for tissue use, ensuring an adequate oxygen supply to peripheral tissues is maintained even when oxygen delivery is reduced.⁴ Oxygen saturation still remains at 70–75%, leaving a significant amount of oxygen in reserve. The relationship between the two axes of this curve assumes normal values for haemoglobin, pH, temperature, PaCO₂ and 2,3-DPG. Changes to any of these values will shift the curve to the right or left and therefore reflect different values for PaO₂ and SaO₂.⁸

Carbon Dioxide Transport

Carbon dioxide is transported by blood in three forms: combined with water as carbonic acid (80–90%), dissolved (5%), or attached to plasma proteins (5–10%), including haemoglobin. The dissolved carbon dioxide constitutes PaCO₂ and is measured by arterial blood gases. The greater solubility of CO₂ when compared with oxygen results in rapid diffusion across the capillary membranes, and therefore the gas can be easily removed for elimination.⁴ Carbon dioxide, a byproduct of cellular respiration, is produced at a rate of 200 mL/min, with only minor differences in normal concentrations in arterial (480 mL/L) and venous (520 mL/L) blood.⁹

Relationship Between Ventilation and Perfusion

Gas exchange is the key function of the lungs, and the unique anatomy of capillaries and alveoli facilitates this process. However, a number of physiological factors mean that the ventilation (V) to perfusion (Q) ratio is not matched in a 1 : 1 relationship. As normal alveolar ventilation is about 4 L/min and pulmonary capillary perfusion is about 5 L/min, the normal ventilation to perfusion ratio (V/Q) is 0.8.⁷ In addition, pressure in the pulmonary circulation is low relative to systemic pressure, and is influenced much more by gravity/hydrostatic pressure. In the upright position, lung apices receive less perfusion compared with the bases.⁷ In the supine position, apical and basal perfusion is almost equal, but the posterior (dependent) portion of the lungs receives greater perfusion than the anterior lung area. Ventilation is also uneven throughout the lung, with the bases receiving more ventilation per unit volume than the apices.⁷

Pressure within the surrounding alveoli also influences blood flow through the pulmonary capillary network. The pressure gradients between the arterial and venous ends of a capillary network normally determine blood flow. However, alveolar pressure can be greater than venous and/or arterial pressure, and therefore influences blood flow and gas exchange.

For a patient in an upright position, in:

• Zone 1 (upper area of the lungs): alveolar pressure is generally greater than both arterial and venous capillary pressure [P_A>P_a>P_v], and blood flow is reduced, leading to alveolar dead space (alveoli ventilated but not adequately perfused).

• Zone 2 (middle portion of the lungs): perfusion and gas exchange is influenced more by pressure differences between arterial and alveolar pressures than by the usual difference between arterial and venous pressures [P_a>P_A>P_v], with a normal V/Q ratio.

• Zone 3 (lung bases): alveolar pressure is lower than both arterial and venous pressures [P_a>P_v>P_A], and ventilation is reduced leading to intrapulmonary shunting (alveoli perfused but not adequately ventilated)⁷ (see Figure 13.10).

FIGURE 13.10 The effects of gravity and alveolar pressure on pulmonary blood flow. Notice the three lung zones.⁸⁶

These physiological relationships are more complex in a critically ill patient when ventilation and/or lung perfusion is further compromised by disease processes and positive pressure ventilation, and the patient is in a supine or semi-recumbent position.⁷

Acid–Base Control: Respiratory Mechanisms

The respiratory system plays a vital role in acid–base balance. Changes in respiratory rate and depth can produce changes in body pH by altering the amount of carbonic acid (H₂CO₃) in the blood. When dissolved, CO₂ forms bicarbonate ion (HCO₃⁻), carbonic acid (H₂CO₃) and carbonate ion (CO₃²⁻); these concentrations affect the acid–base balance. In common with other acids, carbonic acid partially dissociates when in solution, to form CO₂ and water or bicarbonate and hydrogen ion:

The strength of the dissociation is defined by the Henderson–Hasselbach equation that describes the relationship between bicarbonate, CO₂ and pH, and explains why an increase in dissolved CO₂ causes an increase in the acidity of the plasma, while an increase in HCO₃⁻ causes the pH to rise (i.e. acidity falls):

(6.1 = the dissociation constant in plasma).¹¹

Respiratory acidosis is caused by CO₂ retention and increases the denominator in the Henderson–Hasselbach equation resulting in a decreased pH level. This condition occurs when a patient takes small breaths at a low respiratory rate (hypoventilation). In the acute state the body cannot compensate. If the patient develops chronic CO₂ retention over a long period, there will be a renal response to the increase in CO₂. The renal system retains bicarbonate to return the pH to normal (i.e. respiratory acidosis is compensated).

Respiratory alkalosis occurs when a patient hyperventilates with large, frequent breaths; CO₂ decreases in arterial blood and pH rises. If this condition is maintained (e.g. walking at high altitude), the kidney excretes bicarbonate and pH returns to normal (i.e. the respiratory alkalosis is compensated).¹¹

Pathophysiology

Three common pathophysiological concepts that influence respiratory function in critically ill patients are hypoxaemia, inflammation and oedema. The principles for these phenomena are discussed below. Related presenting disease states including respiratory failure, pneumonia, acute lung injury, asthma and chronic obstructive pulmonary disease are described in Chapter 14.

Hypoxaemia

Hypoxaemia describes a decrease in the partial pressure of oxygen in arterial blood (PaO₂) of less than 60 mmHg.⁴ This state leads to less efficient anaerobic metabolism at the tissue and end-organ level, and resulting compromised cellular function. Hypoxia is abnormally low PO₂ in the tissues, and can be due to:

• ‘hypoxic’ hypoxia: low PaO₂ in arterial blood due to pulmonary disease

• ‘circulatory’ hypoxia: reduction of tissue blood flow due to shock or local obstruction

• ‘anaemic’ hypoxia: reduced ability of the blood to carry oxygen due to anaemia or carbon monoxide poisoning

• ‘histotoxic’ hypoxia: a cellular environment that does not support oxygen utilisation due to tissue poisoning (e.g. cyanide poisoning).⁷

A hypoxic patient can show symptoms of fatigue and shortness of breath if the hypoxia has developed gradually. If the patient has severe hypoxia with rapid onset, they will have ashen skin and blue discolouration (cyanosis) of the oral mucosa, lips, and nail beds. Confusion, disorientation and anxiety are other symptoms. In later stages, unconsciousness, coma and death occur.¹⁵

Acute respiratory failure is a common patient presentation in ICU that is characterised by decreased gas exchange with resultant hypoxaemia.¹⁶ Two different mechanisms cause acute respiratory failure: Type I presents with low PO₂ and normal PCO₂; Type II presents with low PO₂ and high PCO₂¹ (see Chapter 14 for further discussion).

In general, impaired gas exchange results from alveolar hypoventilation, ventilation/perfusion mismatching and intrapulmonary shunting, each resulting in hypoxaemia. Hypercapnia may also be present depending on the underlying pathophysiology.¹⁷

Alveolar hypoventilation occurs when the metabolic needs of the body are not met by the amount of oxygen in the alveoli. Hypoxaemia due to alveolar hypoventilation is usually extrapulmonary (e.g. altered metabolism, interruption to neuromuscular control of breathing/ventilation) and associated with hypercapnia.¹⁷

Ventilation/perfusion (V/Q) mismatch results when areas of lung that are perfused are not ventilated (no participation in gas exchange) because alveoli are collapsed or infiltrated with fluid from inflammation or infection (e.g. pulmonary oedema, pneumonia). This results in an overall reduction in blood oxygen levels, which can usually be countered by compensatory mechanisms.¹

Intrapulmonary shunting is an extreme case of V/Q mismatch. Shunting occurs when blood passes alveoli that are not ventilated. There can be significant intrapulmonary shunting, and therefore overwhelming reductions in PaO₂.¹⁸ Carbon dioxide levels may still be normal but depending on the onset and progression of the respiratory pathophysiology, compensatory mechanisms may not be able to maintain homeostasis^1,¹¹ (see Figure 13.11).

FIGURE 13.11 Ventilation perfusion mismatch.¹⁸

Tissue Hypoxia

There are few physiological changes with mild hypoxaemia (when O₂ saturation remains at 90% despite a PaO₂ of 60 mmHg [8 kPa]), with only a slight impairment in mental state. If hypoxaemia deteriorates and the PaO₂ drops to 40–50 mmHg (5.3–6.7 kPa), severe hypoxia of the tissues ensues. Hypoxia at the central nervous system level manifests with headaches and somnolence. Compensatory mechanisms include catecholamine release, and a decrease in renal function results in sodium retention and proteinuria.¹⁹

Different tissues vary in their vulnerability to hypoxia, with the central nervous system and myocardium at most risk. Hypoxia in the cerebral cortex results in a loss of function within 4–6 seconds, loss of conscious in 10–20 seconds and irreversible damage in 3–5 minutes.¹¹ In an environment that lacks oxygen, cells function by anaerobic metabolism and produce much less energy (adenosine triphosphate [ATP]) than with aerobic metabolism (2 versus 38 ATP molecules per glucose molecule), and lactic acid increases. With less available energy, the efficiency of cellular functions such as the Na+/K+ pump, nerve conduction, enzyme activity and transmembrane receptor function diminishes.¹⁹ The overall effect of interruption to these vital cellular activities is a reduction in organ or tissue function, which in turn compromises system and body functions.

Changes to the oxyhaemoglobin dissociation curve also occur in states related to hypoxia. The curve shifts to the right when there is acidosis and/or raised levels of PCO₂ as commonly seen in respiratory failure. Although this change may alter patient oxygen saturation readings, the increased release of oxygen from haemoglobin to the tissues has obvious benefits for tissue oxygenation and cellular metabolism.⁷

Compensatory Mechanisms to Optimise Oxygenation

When PO₂ in the alveolus is reduced, hypoxic pulmonary vasoconstriction occurs, with contraction of smooth muscles in the small arterioles in the hypoxic region, directing blood flow away from the hypoxic area of the lung.⁷ Peripheral chemoreceptors also detect hypoxaemia and initiate compensatory mechanisms to optimise cellular oxygen delivery. Initial responses are increased respiratory rate and depth of breathing, resulting in increased minute ventilation, and raised heart rate with possible vasoconstriction as the body attempts to maintain oxygen delivery and uptake. This overall up-regulation cannot be sustained indefinitely, particularly in a person who is critically ill, and compensatory mechanisms begin to fail with worsening hypoxaemia and cellular and organ dysfunction. Unless the hypoxaemia is reversed and/or respiratory and cardiovascular support is provided, irreversible hypoxia and death will ensue.

Inflammation

Inflammatory processes can occur at a local level (e.g. as a result of inhalation injuries, aspiration or respiratory infections) or are secondary to systemic events (e.g. sepsis, trauma). Damage to the pulmonary endothelium and type I alveolar cells appear to play a key role in the inflammatory processes associated with ALI.²⁰ Once triggered, inflammation results in platelet aggregation and complement release. Platelet aggregation attracts neutrophils, which release inflammatory mediators (e.g. proteolytic enzymes, oxygen free radicals, leukotrienes, prostaglandins, platelet-activating factor [PAF]). Neutrophils also appear to play a key role in the perpetuation of ALI/ARDS.¹ As well as altering pulmonary capillary permeability, resulting in haemorrhage and fluid leak into the pulmonary interstitium and alveoli, mediators released by neutrophils and some macrophages precipitate pulmonary vasoconstriction. Resulting pulmonary hypertension leads to diminished perfusion to some lung areas, with dramatic alterations to both perfusion and ventilation leading to significant V/Q mismatches, and the subsequent signs and symptoms typically seen in patients with pulmonary inflammation/oedema.