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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Respiratory failure is defined as a failure in gas exchange due to an impaired respiratory system--either pump or lung failure, or both. The hallmark of respiratory failure is impairment in arterial blood gases. This review describes the mechanisms leading to respiratory failure, the indices that can be used to better describe gas exchange abnormalities and the physiologic and clinical consequences of these abnormalities. The possible causes of respiratory failure are then briefly mentioned and a quick reference to the clinical evaluation of such patients is made. Finally treatment options are briefly outlined for both acute and chronic respiratory failure.
Histologic and ultrastructural analysis of the injured lung has been integral to current concepts of pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). (a) A low-power light micrograph of a lung biopsy specimen collected two days after the onset of ALI/ARDS secondary to gram-negative sepsis demonstrates key features of diffuse alveolar damage, including hyaline membranes, inflammation, intra-alveolar red cells and neutrophils, and thickening of the alveolar-capillary membrane. (b) A higher-power view of a different field illustrates a dense hyaline membrane and diffuse alveolar inflammation. Polymorphonuclear leukocytes are imbedded in the proteinaceous hyaline membrane structure. The blue arrow points to the edge of an adjacent alveolus, which contains myeloid leukocytes. (c) An electron micrograph from a classic analysis of ALI/ARDS showing injury to the capillary endothelium and the alveolar epithelium. Abbreviations: A, alveolar space; BM, exposed basement membrane, where the epithelium has been denuded; C, capillary; EC, erythrocyte; EN, blebbing of the capillary endothelium; LC, leukocyte (neutrophil) within the capillary lumen. The histologic sections in panels a and b are used courtesy of Dr. K. Jones, University of California, San Francisco. Reprinted with permission from the American Thoracic Society.
Respiratory failure occurs due mainly either to lung failure resulting in hypoxaemia or pump failure resulting in alveolar hypoventilation and hypercapnia. Hypercapnic respiratory failure may be the result of mechanical defects, central nervous system depression, imbalance of energy demands and supplies and/or adaptation of central controllers. Hypercapnic respiratory failure may occur either acutely, insidiously or acutely upon chronic carbon dioxide retention. In all these conditions, pathophysiologically, the common denominator is reduced alveolar ventilation for a given carbon dioxide production. Acute hypercapnic respiratory failure is usually caused by defects in the central nervous system, impairment of neuromuscular transmission, mechanical defect of the ribcage and fatigue of the respiratory muscles. The pathophysiological mechanisms responsible for chronic carbon dioxide retention are not yet clear. The most attractive hypothesis for this disorder is the theory of "natural wisdom". Patients facing a load have two options, either to push hard in order to maintain normal arterial carbon dioxide and oxygen tensions at the cost of eventually becoming fatigued and exhausted or to breathe at a lower minute ventilation, avoiding dyspnoea, fatigue and exhaustion but at the expense of reduced alveolar ventilation. Based on most recent work, the favoured hypothesis is that a threshold inspiratory load may exist, which, when exceeded, results in injury to the muscles and, consequently, an adaptive response is elicited to prevent and/or reduce this damage. This consists of cytokine production, which, in turn, modulates the respiratory controllers, either directly through the blood or probably the small afferents or via the hypothalamic-pituitary-adrenal axis. Modulation of the pattern of breathing, however, ultimately results in alveolar hypoventilation and carbon dioxide retention.
Respiratory failure occurs due mainly either to lung failure resulting in hypoxaemia or pump failure resulting in alveolar hypoventilation and hypercapnia. Hypercapnic respiratory failure may be the result of mechanical defects, central nervous system depression, imbalance of energy demands and supplies and/or adaptation of central controllers.
Hypercapnic respiratory failure may occur either acutely, insidiously or acutely upon chronic carbon dioxide retention. In all these conditions, pathophysiologically, the common denominator is reduced alveolar ventilation for a given carbon dioxide production.
Acute hypercapnic respiratory failure is usually caused by defects in the central nervous system, impairment of neuromuscular transmission, mechanical defect of the ribcage and fatigue of the respiratory muscles.
The pathophysiological mechanisms responsible for chronic carbon dioxide retention are not yet clear. The most attractive hypothesis for this disorder is the theory of “natural wisdom”. Patients facing a load have two options, either to push hard in order to maintain normal arterial carbon dioxide and oxygen tensions at the cost of eventually becoming fatigued and exhausted or to breathe at a lower minute ventilation, avoiding dyspnoea, fatigue and exhaustion but at the expense of reduced alveolar ventilation. Based on most recent work, the favoured hypothesis is that a threshold inspiratory load may exist, which, when exceeded, results in injury to the muscles and, consequently, an adaptive response is elicited to prevent and/or reduce this damage. This consists of cytokine production, which, in turn, modulates the respiratory controllers, either directly through the blood or probably the small afferents or via the hypothalamic-pituitary-adrenal axis. Modulation of the pattern of breathing, however, ultimately results in alveolar hypoventilation and carbon dioxide retention.
β‐Endorphinscytokineshypercapniapump failurerespiratory muscles fatigue This study was supported by the Thorax Foundation, Athens, Greece.
Respiratory failure is a condition in which the respiratory system fails in one or both of its gas exchange functions, i.e. oxygenation of and/or elimination of carbon dioxide from mixed venous blood. It is conventionally defined by an arterial oxygen tension (Pa,O2) of <8.0 kPa (60 mmHg), an arterial carbon dioxide tension (Pa,CO2) of >6.0 kPa (45 mmHg) or both. Therefore, the diagnosis of respiratory failure is a laboratory one, but the important point to emphasise is that these cut-off values are not rigid; they simply serve as a general guide in combination with the history and clinical assessment of the patient.
The respiratory system can be said to consist of two parts: the lung, i.e. the gas-exchanging organ, and the pump that ventilates the lungs 1. The pump consists of the chest wall, including the respiratory muscles, the respiratory controllers in the central nervous system (CNS) and the pathways that connect the central controllers with the respiratory muscles (spinal and peripheral nerves). Failure of each part of the system leads to a distinct entity (fig. 1⇓). In general, failure of the lung caused by a variety of lung diseases (e.g. pneumonia, emphysema and interstitial lung disease) leads to hypoxaemia with normocapnia or hypocapnia (hypoxaemic or type I respiratory failure). Failure of the pump (e.g. drug overdose) results in alveolar hypoventilation and hypercapnia (hypercapnic or type II respiratory failure). Although there is coexistent hypoxaemia, the hallmark of ventilatory failure is the increase in Pa,CO2. Undoubtedly, both types of respiratory failure may coexist in the same patient, as, for example, in patients with chronic obstructive pulmonary disease (COPD) and carbon dioxide retention, or in those with severe pulmonary oedema or asthmatic crisis, who first develop hypoxaemia and, as the disease persists or progresses, hypercapnia appears.
Fig. 1.— Download figureOpen in new tabDownload powerpoint Fig. 1.— Types of respiratory failure. The respiratory system can be considered as consisting of two parts: 1) the lung; and 2) the pump. The various types of respiratory failure are presented in a gas tension diagram (fig. 2⇓), which illustrates the various pathways. The solid line represents a respiratory exchange ratio of 0.8. The parallel dotted line shows the corresponding Pa,O2 and Pa,CO2 with an alveolar to arterial oxygen difference (DA‐aO2) of ∼0.67 kPa (5 mmHg), as occurs in normal lung. When a normal subject hyperventilates, alveolar oxygen (PA,O2) and carbon dioxide (PA,CO2) tension and Pa,O2 and Pa,CO2 move down the slope in the direction indicated by the letter H, with rises in PA,O2 and Pa,O2 and falls in PA,CO2 and Pa,CO2. When hypoventilation occurs, in the normal subject, due to drug overdose for example, PA,O2 and Pa,O2 and PA,CO2 and Pa,CO2 move up the slope in the direction shown by the letter D, with falls in PA,O2 and Pa,O2 and rises in PA,CO2 and Pa,CO2. It can be seen that, in the normal lung, when hypercapnia occurs (as in the case of alveolar hypoventilation due to CNS depression), Pa,O2 cannot fall to very low levels. For example, when PA,CO2 increases from 5.3 (40 mmHg) to ∼10.6 kPa (80 mmHg), PA,O2 decreases from ∼13.3 (100 mmHg) to ∼8.0 kPa (60 mmHg). Assuming a DA‐aO2 of 0.67–1.3 kPa (5–10 mmHg), the Pa,O2 is ∼5.3–6.7 kPa (40–50 mmHg). Thus, when the lung is normal, a severe degree of alveolar hypoventilation, resulting in marked carbon dioxide retention, is not associated with excessive hypoxaemia. In lung diseases, however, due to increased DA‐aO2, the same conditions lead to arterial hypoxaemia. Arrow Α, in figure 2⇓, shows a large DA‐aO2 (the horizontal distance between arrow Α and alveolar line D‐H), which is commonly observed in patients with pneumonia, atelectasis or acute respiratory distress syndrome (ARDS). Hyperventilation in these patients leads to very low Pa,CO2. Line Β depicts the pathway of patients with interstitial lung disease or pure emphysema. Line C depicts a mixed state in a patient with lung disease (hypoxaemia) and inadequate alveolar ventilation (V'A). In severe cases (tip of arrow), hypoxaemia is dominant despite hypercapnia and the situation is certainly more dangerous than in pure hypoventilation at an equal Pa,CO2. Patients usually reach line C starting from line Α or B. Patients with COPD or end-stage interstitial lung disease who have remained along the B arrow for a long time move to arrow C as a result of alveolar hypoventilation. Similarly, patients with a gas-exchange abnormality, as shown by arrow Α (acute asthma attack or pulmonary oedema), may move towards arrow B or C as the central controllers or respiratory muscles, or both, become unable to maintain adequate ventilation.
Hypoxaemic (type I) respiratory failure
Four pathophysiological mechanisms account for the hypoxaemia seen in a wide variety of diseases: 1) ventilation/perfusion inequality, 2) increased shunt, 3) diffusion impairment, and 4) alveolar hypoventilation 2. Ventilation/perfusion mismatching is the most common mechanism and develops when there is decreased ventilation to normally perfused regions or when there are lung regions with a greater reduction in ventilation than in perfusion. With shunt, either intrapulmonary or intracardiac deoxygenated mixed venous blood bypasses ventilated alveoli, resulting in “venous admixture”. Diseases that increase the diffusion pathway for oxygen from the alveolar space to the pulmonary capillaries, decrease capillary surface area or shorten the transit time of the blood through the pulmonary capillaries prevent complete equilibration of alveolar oxygen with pulmonary capillary blood.
In the absence of underlying pulmonary disease, hypoxaemia accompanying hypoventilation is characterised by normal DA‐aO2. In contrast, disorders in which any of the other three mechanisms are operative are characterised by broadening of the alveolar/arterial gradient resulting in severe hypoxemia.
Although changes in V'A can change Pa,CO2 considerably, this is not so for Pa,O2. Increases in V'A modestly increase Pa,O2. Owing to the sigmoidal shape of the oxyhaemoglobin dissociation curve, any effect of increasing ventilation on oxygen saturation is minimal above Pa,O2 of 7.3–8.0 kPa (55–60 mmHg). Hypoxaemia resulting from ventilation/perfusion inequality or diffusion abnormalities can easily be corrected by supplementing inspired oxygen, whereas even very high concentrations of inspired oxygen cannot correct hypoxaemia induced by increased pure shunt.
Hypercapnic (type II) respiratory failure
The respiratory equation
The volume of carbon dioxide eliminated per minute (which in a steady state is equal to that produced by the body (V'CO2)) is dependent on the concentration of carbon dioxide in alveolar gas and οn V'A. This is obvious, since the conducting airways do not exchange gas. Thus V'CO2=V'A×alveolar CO2 concentrationor alveolar CO2 concentration=V'CO2/V'A. Alveolar CO2 concentration is the concentration of CO2 in the alveolar gas. Gas concentration is converted to gas pressure (Pgas) by the equation: Pgas (mmHg)=(%concentration×(barometric pressure-water vapour))/100. At sea level, barometric pressure is 670 and water vapour pressure at 37°C is 47 mmHg. It follows that Pgas (mmHg)=%concentration×713/100.
By using factor k (0.863), the constant of proportionality, the “respiratory equation” is obtained, which relates V'A to Pa,CO2: Embedded Image Since V'A=V'E−V'ds, where V'E is minute ventilation and V'ds dead space ventilation, this relation may be expressed as: Embedded Image where VT is tidal volume and fR respiratory frequency.
Equation 2 states that the Pa,CO2 rises if V'CO2 increases (e.g. hyperthermia) at constant V'A, or when, at a constant V'CO2, V'A decreases by virtue of: 1) a rise in V'ds/VT (by increasing V'ds, decreasing VT or both), 2) a decrease in V'E, and 3) both an increase in V'ds/VT and a decrease in V'E 3, 4.
In daily clinical practice, as a patient becomes hypercapnic, more than one factor generally contributes to the rise in Pa,CO2.
CARBON DIOXIDE PRODUCTION
For a young adult, V'CO2 is ∼200 mL·min−1 (or 110 mL·m2 in males and 96 mL·m2 in females). V'CO2 increases during hyperthermia by ∼14% for each degree Celsius rise in temperature, particularly during muscular activity. During inspiratory resistive breathing, the respiratory muscles, in this respect, may show a V'CO2 of 700–800 mL·min−1 5. In the same manner, shivering or an increase in muscle tone, as occurs in tetanus, leads to excessive V'CO2, with an up to three-fold increase, whereas muscular exercise may increase V'CO2>10‐fold. Under normal conditions, an increase in V'CO2 is detected early by the CNS and is then easily compensated for by increasing V'E to maintain a normal Pa,CO2. However, if a patient's ventilatory capacity is impaired, an increase in V'CO2 greatly stresses the ventilatory system and leads to an increase in Pa,CO2.
ALVEOLAR VENTILATION
Equations 1 and 2 imply that, at constant V'CO2 and a given V'ds, V'A changes when VT or fR are varied either at constant or reduced total ventilation. This means that there are four possibilities: 1) unchanged total ventilation with decreased fR, 2) unchanged total ventilation with increased fR, 3) decreased total ventilation with decreased fR, or 4) decreased VT.
Under conditions of unchanged total ventilation and decreased fR, for V'E to remain unchanged, VT must increase. This decreases V'ds/VT, thereby increasing V'A and decreasing Pa,CO2.
Under conditions of unchanged total ventilation and increased fR, for V'E to remain unchanged, VT must decrease. Such a change, however, increases the V'ds/VT ratio and, therefore, V'A decreases and Pa,CO2 increases. In the clinical setting, rapid, shallow breathing may well explain carbon dioxide retention in patients with COPD.
Under conditions of decreased total ventilation and decreased fR, the reduction in fR alone, without affecting V'ds/VT, leads to a certain decrease in V'A by virtue of a reduction in V'E.
Under conditions of decreased total ventilation and decreased VT, there is a reduction in V'E caused by reducing the VT (without reducing fR), which results in an increase in V'ds/VT, and, consequently, in a rise in Pa,CO2. Thus, the drop in V'A is expected to be more pronounced than in the aforementioned cases.
Pathophysiology of ventilatory pump failure
There are three major causes of pump failure leading to hypercapnia 6. 1) The output of the respiratory centres controlling the muscles may be inadequate (anaesthesia, drug overdose and diseases of the medulla), resulting in a central respiratory drive that is insufficient for the demand, or the respiratory centres may reflexively modify their output in order to prevent respiratory muscle injury and avoid or postpone fatigue. 2) There may be a mechanical defect in the chest wall, as is the case in flail chest, diseases of the nerves (Guillain-Barré syndrome) and anterior horn cells (poliomyelitis), or diseases of the respiratory muscles (myopathies). Severe hyperinflation, with flat diaphragm and reduced mechanical action of the inspiratory muscles, as in acute asthmatic attack, is one of the most common causes of impaired mechanical performance of the inspiratory muscles. 3) When working under excessive inspiratory load, the inspiratory muscles may become fatigued, i.e. they become unable to continue to generate an adequate pleural pressure despite an appropriate central respiratory drive and an intact chest wall.
It is obvious that, when there is insufficient activation from the CNS, either temporally (e.g. anaesthesia and overdose) or permanently (e.g. diseases of the medulla), respiratory efforts are inadequate and hypoventilation ensues.
Motor output emanating from the CNS needs to be transferred to the respiratory muscles, a process requiring anatomical and functional adequacy of the spinal cord, peripheral nerves and neuromuscular junction. Any disorder along this pathway results in insufficient inflation of the ribcage inadequate to generate subatmospheric pressure, which is essential for the air to flow into the lungs. Mechanical defects of the chest wall (flail chest, kyphoscoliosis and hyperinflation) are entities that predispose to alveolar hypoventilation since they impose additional work on the inspiratory muscles, which have to displace the noncompliant chest wall and lungs.
Since hyperinflation, commonly occurring in diseases characterised by airways obstruction and loss of elastic recoil of the lungs, has multiple adverse effects on inspiratory muscle function, it deserves to be discussed separately.
For humans to breathe spontaneously, the inspiratory muscles must generate sufficient force to overcome the elastic and resistive load of the respiratory system. Furthermore, the inspiratory muscles should be able to sustain the above mentioned load over time and adjust V'E in such a way that there is adequate gas exchange. Fatigue is the inability of the respiratory muscles to continue to generate sufficient pressure to maintain V'A 6. Fatigue should be distinguished from weakness, which is a fixed reduction in force generation not reversible by rest, although muscle weakness may predispose to muscle fatigue.
Fatigue occurs when the energy supply to the respiratory muscles does not meet the demands. Factors predisposing to respiratory muscle fatigue are those that increase inspiratory muscle energy demands and/or decrease energy supplies 7. Energy demands are determined by the work of breathing and the strength and efficiency of the inspiratory muscles (fig. 3⇓)
Fig. 3.— Download figureOpen in new tabDownload powerpoint Fig. 3.— Respiratory muscle endurance is determined by the balance between energy supplies (S) and demands (D). Normally, the supplies meet the demands and a large reserve exists. Whenever this balance weighs in favour of demands, the respiratory muscles ultimately become fatigued, leading to inability to sustain spontaneous breathing. The work of breathing increases proportionally with the mean pressure developed by the inspiratory muscles per breath (mean tidal pressure (PI)), expressed as a fraction of maximum inspiratory pressure (PI,max), V'E, duty cycle (inspiratory time (tI)/total respiratory cycle (ttot)) and mean inspiratory flow rate (VT/tI) 6.
PI is increased if the elastic (stiff lungs, pulmonary oedema) or resistive (airways obstruction, asthma) load imposed on the inspiratory muscles is increased. Roussos et al. 8 directly related PI/PI,max with the time that the diaphragm can sustain the load imposed on it (endurance time). The critical value of PI/PI,max that could be generated indefinitely at functional residual capacity (FRC) was ∼0.60. Greater PI/PI,max were inversely related to the endurance time. The critical value of PI/PI,max increases when end-expiratory lung volume increases. Indeed, when lung volume was increased from FRC to FRC plus 50% inspiratory capacity, the critical value of PI/PI,max and the endurance time were diminished to very low values, 25–30% PI,max. Bellemare and Grassino 9 also found that the maximum pressure that can be sustained indefinitely decreases when tI/ttot increases and suggested that the product of PI/PI,max and tI/ttot defined a useful “tension time index” that is related to the endurance time. Whenever the tension time index is below a critical value (0.15 for the diaphragm), the load can be sustained indefinitely.
A weak muscle requires more energy in relation to its maximum energy consumption to perform a given amount of work. The force developed by a skeletal muscle that is sufficient to produce fatigue is a function of the maximum force that the muscle can develop. Any condition that decreases the maximum force decreases the muscle's strength and predisposes to fatigue. Such conditions include atrophy (a probable result of prolonged mechanical ventilation), immaturity, neuromuscular diseases and performance in an inefficient part of the muscle's length/tension characteristics 10, as in a state of acute hyperinflation, during which both the diaphragm and intercostal muscles work at a shorter length.
Finally, muscle efficiency, the ratio of external work performed to energy consumed, is an important factor in energy demands. Inspiratory muscle efficiency is known to fall in patients with hyperinflation. It has been shown that, for the same work of breathing, the oxygen cost is markedly higher in patients with emphysema than in normal subjects 11. This happens, in emphysematous patients, because either some inspiratory muscles may contract isometrically (they consume energy but do not perform work) or the inspiratory muscles are operating in an inefficient part of their force/length relationship: a more forceful contraction is required to produce a given pressure change, and an even greater degree of excitation is required to develop a given force. Thus both conditions lead to increased energy consumption for a given pressure development 12.
Factors determining the inspiratory muscle energy available are muscle blood flow, the Ca,O2 and the blood substrate concentration as well as the ability of the muscles to extract energy (fig. 3⇑).
Diaphragmatic blood flow is essentially determined by the perfusion pressure, which is a function of cardiac output and peripheral vascular resistance, and the vascular resistance of the muscle, which is a function of the intensity and duration of contraction 13. As has been described in animal models, a reduction in cardiac output accompanying cardiogenic or septic shock is a cause of respiratory fatigue leading to severe alveolar hypoventilation, bradypnoea and respiratory arrest 14, 15. Energy supply to inspiratory muscles also depends on the ability of the muscle to increase blood flow in parallel with the increased work. The diaphragm has a greater capacity to increase blood flow than other skeletal muscles 16. However, the amount that the inspiratory muscle blood flow can be increased may be affected by the intensity and duration of muscle contraction. If the respiratory muscles remain contracted throughout the respiratory cycle, as occurs in asthma 17, the overall blood flow to the muscles may be less than that required. In addition, haemoglobin concentration and oxyhaemoglobin saturation influence the aerobic energy supply to the muscle and hence its endurance.
Conditions characterised by inability of the muscles to extract and use energy, such as sepsis or cyanide poisoning, or diminished energy stores and glycogen depletion, as in extreme inanition, may potentially lead to respiratory muscle fatigue.
It is clear from the above discussion that fatigue may occur in a variety of clinical entities that alone or in combination result in an imbalance between respiratory muscle energy supplies and demands. No matter what the causes are, it is well known that fatigue is characterised by loss of force output 18, leading to inability of the respiratory muscles to develop adequate PI during tidal breathing, with consequent decreases in VT and V'E and hypercapnia.
When the respiratory muscles are extensively loaded, however, it is likely that feedback mechanisms modify the central drive, which, by exerting “central wisdom”, alters the ventilatory pattern and serves in reducing the load and alleviating fatigue, thus protecting the ventilatory pump from exhaustion, which, undoubtedly, is a terminal event.
Although there are no data from patients to substantiate the existence of “central wisdom” in ventilatory failure, there is enough evidence to support this notion. The fact that the reduction in VT that followed resistive breathing in animals could be restored promptly to normal by administration of naloxone 19 or bilateral cervical vagotomy 20, as well as the fact that most hypercapnic patients with COPD can achieve normocapnia by voluntarily increasing their ventilation, implies that, although the subjects could increase their ventilation, they chose not to do so.
Indeed, alterations in the pattern of breathing may occur as a result of loading in animals 19, normal subjects 21 and patients during weaning trials 22.
Patients with acute and chronic respiratory failure as well as normal subjects and animals subjected to fatiguing respiratory loads tend to adopt rapid shallow breathing, consisting of a decrease in VT and increased fR, whereas V'E remains constant or increases slightly. Although this pattern may not be efficient in terms of gas exchange, it may reduce the load on the muscle by decreasing the PI developed, thereby preventing fatigue from occurring 23–26. Moreover, in stable patients with COPD and carbon dioxide retention, this pattern of breathing may be sufficient to keep diaphragm contraction below the fatigue threshold 23, 27.
The neurophysiological mechanisms that cause an altered pattern of breathing are not well elucidated. Chemosensitivity-induced alterations in respiratory activity do not appear to be the explanation. Hypoxia- and hypercapnia-induced reductions in expiratory time (tE) are disproportionately greater than reductions in tI, so that tI/ttot increases. Moreover, VT/tI and VT increase rather than decrease 28.
Rapid shallow breathing may be produced by activation of vagal irritant receptors in the airways 29, or may represent a behavioural response to minimise the sense of dyspnoea 30.
Reflexes originating from mechanoreceptors in the contracting ribcage muscles and diaphragm (tendon organs, spindle organs, and type III and IV endings) probably play a role in shaping the rapid shallow pattern of breathing. In deeply anaesthetised animals, stretch of the intercostal muscles or increase in diaphragm tension may abruptly terminate inspiration 31. Activation of endogenous opioid pathways has also been postulated to alter the pattern of breathing, perhaps as a mechanism by which the sense of dyspnoea might be reduced 19, 32–35.
Small-fibre afferents have been widely implicated in the response of central respiratory output to prolonged stresses such as shock, hypoxia, acidosis and vigorous exercise 15, 36, 37. It is possible that, during loaded breathing, afferents, through the small fibres, modulate endogenous opioids as an adaptive response to minimise breathlessness and avoid or delay the onset of respiratory muscle fatigue 38.
Whatever the mechanisms, however, the limit of this strategy is that with rapid shallow breathing V'ds/VT is increased (see The respiratory equation section) with worsening of hypercapnia.