For example, arachidonic acid metabolites cause pulmonary venoconstriction, which will raise pulmonary capillary pressure and compound the effect of increased permeability. Accumulation of platelets and neutrophils along with intravascular coagulation will occlude pulmonary vessels, producing pulmonary hypertension and unperfused lung units. It has also been noted that many plasma proteins and nonsurfactant lipids such as cholesterol can antagonize the action of surfactant. Smaller tidal volume is a key part of the protective ventilation strategy described next, but the correct tidal volume to use in an individual patient remains controversial. Second, the hypercapnia that results from the inadequate minute volume may be partially ignored. Known as permissive hypercapnia, arterial Pco2 is allowed to increase until the respiratory acidosis is deemed detrimental. Despite recent evidence in animals that hypercapnia may reduce lung inflammation and cell apoptosis,40 the impact of this strategy in clinical practice remains controversial. Second, there will be areas of lung, usually in dependent regions, with such severe collapse and alveolar flooding that ventilation of these areas will be impossible. Once receiving artificial ventilation a fourth area of lung is commonly described in nondependent regions involving overdistended lung tissue, possibly leading to volutrauma (page 471) and further lung injury. Overdistension of alveoli by application of large tidal volumes is a significant factor in lung damage. Point A indicates the lower inflection of the curve, above which compliance is considerably improved. Application of a positive end-expiratory pressure of approximately 12 cmH2O in this patient will therefore improve tidal volume relative to the ventilatory pressure required. Point B indicates the upper inflection point, above which alveolar overdistension may occur, therefore, in this patient airway pressure should ideally be maintained below 35 cmH2O. In the ventilated patient in the prone position lung perfusion remains broadly unchanged whereas recruitment of dorsal lung units exceeds the derecruitment in ventral areas with consistent improvement in oxygenation. Metaanalyses of prone positioning show improvements in mortality58 but also increased occurrence of pressure ulcers and major airway problems. If plateau airway pressure exceeds 30 cmH2O, or the inspired oxygen level required to obtain acceptable arterial Po2 exceeds 0. Driving pressure appears to be the component of protective ventilation most strongly associated with improved survival. In most cases it has proved difficult to demonstrate their efficacy in the clinical setting. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease. Body position changes redistribute lung computed-tomographic density in patients with acute respiratory failure. Flow and volume dependence of respiratory system flow resistance in patients with adult respiratory distress syndrome. The pulmonary protein C system: preventive or therapeutic target in acute lung injury Lung recruitability is better estimated according to the Berlin definition of acute respiratory distress syndrome at standard 5 cm H2O rather than higher positive end-expiratory pressure: a retrospective cohort study. Biology and pathology of fibroproliferation following the acute respiratory distress syndrome. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. Fluid therapy during acute respiratory distress syndrome: less is more, simplified. Counterpoint: is low tidal volume mechanical ventilation preferred for all patients on ventilation Point: Is low tidal volume mechanical ventilation preferred for all patients on ventilation Effects of acute hypercapnia with and without acidosis on lung inflammation and apoptosis in experimental acute lung injury. The impact of spontaneous ventilation on distribution of lung aeration in patients with acute respiratory distress syndrome: airway pressure release ventilation versus pressure support ventilation. Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome. Positive endexpiratory pressure in acute respiratory distress syndrome: When should we turn up the pressure Applied physiology and process of care for patients with acute respiratory distress syndrome. Compressive forces and computed tomography-derived positive endexpiratory pressure in acute respiratory distress syndrome. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. Ventilation with lower tidal volumes versus traditional tidal volumes in adults for acute lung injury and acute respiratory distress syndrome. Lung protective mechanical ventilation and two year survival in patients with acute lung injury: prospective cohort study. Underuse versus equipoise for low tidal volume ventilation in acute respiratory distress syndrome: is this the right question Prone position in acute respiratory distress syndrome rationale, indications, and limits. The efficacy and safety of prone positional ventilation in acute respiratory distress syndrome: updated study-level meta-analysis of 11 randomized controlled trials. Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: a meta-analysis. Effects of alveolar recruitment maneuvers on clinical outcomes in patients with acute respiratory distress syndrome: a systematic review and meta-analysis. Partial liquid ventilation in adult patients with acute respiratory distress syndrome. In the final stage, when patients are normally receiving artificial ventilation, massive consolidation and a large dead space are seen. The acute phase involves widespread damage to alveolar epithelial cells, intravascular coagulation in the capillaries and severe pulmonary oedema. The fibroproliferative phase occurs a few days later and represents attempted repair of the lung but results in thickening of all components of lung parenchyma followed by remodelling and fibrosis. They are attracted into the lung by cytokines released from epithelial cells or macrophages, and then activated to produce cytokines and lipid-derived mediators, which amplify the inflammation, and protease enzymes and reactive oxygen species which further damage lung tissue. Other strategies for maintaining gas exchange include prone positioning, inverse ratio ventilation, inhaled nitric oxide, and highfrequency ventilation, though of these only prone positioning is proven to improve outcomes. This is more as part of long-term management, for example, in pulmonary rehabilitation programmes (page 399), but is also a useful part of treatment of acute lung problems, such as in ventilated patients1 and in the postoperative period. Despite extensive involvement of physiotherapists in respiratory care throughout the world, the evidence base for improved clinical outcomes as a direct result of physiotherapy interventions is weak. Physiology of Respiratory Interventions the aims of respiratory physiotherapy can be broadly classified into the following three areas. Patient positioning is important for increasing lung volume (page 27) and ventilation perfusion matching, and sitting upright is generally beneficial. Patients with pleural effusions or large, central bronchial tumours usually learn for themselves to lie with the nonaffected lung regions uppermost. Deep breathing exercises have many respiratory benefits, most of which relate to reexpansion and ventilation of dependent lung regions. Ten deep breaths per waking hour are recommended, including an end-inspiratory hold, if possible. This chapter describes the various techniques available to clinicians to improve the gas exchange functions of the respiratory system, including supporting or replacing alveolar ventilation. Autogenic drainage involves performing controlled breaths with slow, large, inspirations, an inspiratory pause and then slow prolonged exhalation through pursed lips to maintain airway patency and prevent flow-related collapse (page 38). A series of these manoeuvres are performed at progressively increasing lung volume. This is normally used in combination with the other breathing techniques described. They aim to improve the clearance of mucus from the airway wall and may work by changing the physical properties of mucus during a cough4 by improving airway-lining fluid and ciliary activity,5 increasing expiratory flow rate6 or freeing adhesive mucus from the airway wall. It may be achieved by either negative pressure ventilation or positive pressure ventilation via a mask or similar device. Negative Pressure Ventilation this requires the application of subatmospheric pressure to the trunk. It was first reported in 19298 and widely used for the next 30 years during polio epidemics. Enthusiasm for the technique has fluctuated since, but there continues to be interest in negative pressure ventilation for a small group of patients. An intermittent negative pressure is then applied in the tank, causing inspiration, with passive expiration as normal. In terms of the airway-toambient pressure gradient cabinet ventilators are identical in principle to positive pressure ventilation, with similar effects on cardiovascular and respiratory physiology. Collapse of the extrathoracic upper airway during inspiration may occur, particularly during sleep. Vomiting or regurgitation of gastric contents exposes the patient to the danger of aspiration during the inspiratory phase. Cuirass and jacket ventilators are a simplified form of cabinet ventilators in which the application of subatmospheric pressure is confined to the trunk or anterior abdominal wall. They are less efficient than cabinet ventilators and suffer from the same disadvantages. However, they are much more convenient to use and may be useful to supplement inadequate spontaneous breathing. Noninvasive Positive Pressure Ventilation11,12 Positive pressure ventilation may be delivered using soft masks that fit over the mouth and nose, the nose only or with a clear plastic helmet over the entire head (sealed around the neck). The high volume in the helmet also results in a time delay when changing the pressure in the helmet to support ventilation or when sensing a spontaneous breath with pressure changes (see later). Ventilator modes that use patient triggering are better tolerated than controlled ventilation, particularly in awake patients, but both techniques are used. In this case benefit occurs simply by displacing the soft palate away from the posterior pharyngeal wall. The inspired gas then flows into the lungs in accord with the resistance and compliance of the respiratory system. If inspiration is slow, the distribution is governed mainly by regional compliance. Expiration is then passive, and differs from expiration during spontaneous breathing in which diaphragm muscle tone is gradually reduced (page 52). In the past, expiration was sometimes accelerated by the application of a subatmospheric pressure, termed negative end-expiratory pressure, though this technique is no longer used. Thus, for example, a sustained inflation pressure of 10 cmH2O with a static compliance of 0. At any instant, the inflation pressure equals the sum of the pressures required to overcome these two forms of impedance. The two components of the inflation pressure vary during the course of inspiration while their sum remains constant. The component overcoming air flow resistance is maximal at first and declines exponentially with air flow as inflation proceeds. The approach of the lung volume to its equilibrium value is according to an exponential function of the wash-in type (see Appendix E). The inflation curve is shown in full with further mathematical detail in Appendix E. It is normal practice for the inspiratory phase to be terminated after 1 or 2 s at which time the lung volume will still be increasing. Inflation pressure is not then the sole arbiter of tidal volume but must be considered in relation to the duration of the inspiratory phase. If expiration is passive and mouth pressure remains at ambient, the driving force is the elevation of alveolar pressure above ambient, which is caused by elastic recoil of lungs and chest wall. Time Course of Inflation and Deflation Equilibration according to the previous equation usually takes several seconds. When the airway pressure is raised during inspiration, it is opposed by the two forms of impedance: the elastic 31 Respiratory Support and Artificial Ventilation 455 Inspiration Inflation or mouth pressure (kPa) 0. Assuming that air flow resistance is constant, it follows that flow rate and pressure gradient required to overcome resistance may be shown on the same graph. Changes in inflation pressure do not alter the time constant of inflation, but directly influence the amount of air introduced into the lungs in a given number of time constants. Effect of Changes in Compliance and Resistance If the compliance is doubled, the equilibrium tidal volume is also doubled. However, the time Pressure gradient required to overcome air flow resistance (kPa) Inspiratory 1 Alveolar pressure (kPa) 0. Conversely, if the compliance is halved, the equilibrium tidal volume is also halved along with the time constant. Changes in resistance have a direct effect on the time constant of inflation but do not affect the equilibrium tidal volume. Thus the effect of an increased resistance on tidal volume is through the reduction in inspiratory flow rate. Within limits, this can be counteracted by prolonging inspiration or by increasing the inflation pressure and the degree of overpressure (explained later). The application of a pressure that, if sustained, would give a tidal volume higher than that which is intended, is 31 A 1.

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Similar, though variable, changes have been obtained over a lower range of Pco2 in human volunteers inhaling carbon dioxide mixtures. This is additional to the general depressant direct effect of carbon dioxide on target organs. Oxygenation of the Blood Quite apart from its effect on ventilation, carbon dioxide exerts three other important effects that influence the oxygenation of the blood. Second, an increase in Pco2 causes a displacement of the oxygen dissociation curve to the right (page 181). This results from changes in pH influencing pulmonary vessels as described in the previous paragraph, as well as causing changes in the size of small-diameter bronchi. Blood Pressure As described earlier, an elevated Pco2 usually causes a small increase in blood pressure, an effect seen in both conscious and anaesthetized patients. However, the response is variable and certainly cannot be relied upon as an infallible diagnostic sign of hypercapnia. Hypotension accompanies an elevation of Pco2 if there is blockade of the sympathetic system by, for example, spinal anaesthesia. Cardiovascular System19 the effects of carbon dioxide on the circulation are complicated by the alternative modes of action on different components of the system. In general, both hypercapnia and acidosis have direct depressant effects on cardiac myocytes and vascular smooth muscle cells, effects that are normally opposed by the increase in catecholamines caused by elevated Pco2. Under different circumstances these opposing effects make the overall effect of carbon dioxide on the cardiovascular system unpredictable. Despite this problem, moderate degrees of hypercapnia have been proposed to have therapeutic potential in treating septic shock when its effects can mimic inotropes such as dobutamine. However, in the intact subject the direct depressant effect of carbon dioxide is overshadowed by the stimulant effect mediated through the sympathetic system. In artificially ventilated humans, increased Pco2 raises cardiac output and slightly reduces total peripheral resistance,14 therefore blood pressure tends to be increased. Awake healthy subjects studied with noninvasive Doppler echocardiography show similar changes. Measurements of left ventricular systolic and diastolic function were unchanged, confirming the dominance of catecholamine stimulation compared with direct depressant effects on the heart. However, at high levels of Pco2 there is constriction of the glomerular afferent arterioles, leading to anuria. Long-term hypercapnia results in increased resorption of bicarbonate by the kidneys, further raising the plasma bicarbonate level, and constituting a compensatory metabolic alkalosis. Long-term hypocapnia decreases renal bicarbonate resorption, resulting in a further fall of plasma bicarbonate and producing a compensatory metabolic acidosis. In each case the arterial pH returns towards the normal value but the bicarbonate ion concentration departs even further from normality. Effect on Blood Electrolyte Levels the acidosis that accompanies hypercapnia causes leakage of potassium ions from the cells into the plasma. Because it takes an appreciable time for the potassium ions to be transported back into the intracellular compartment, repeated bouts of hypercapnia at short intervals result in a stepwise rise in plasma potassium. A reduction in the ionized fraction of the total calcium has, in the past, been thought to be the cause of the tetany that accompanies severe hypocapnia. The muscle spasms probably result from activity in proprioceptive fibres causing reflex muscle contraction. The effects of long-term small elevations in inspired carbon dioxide are described on page 269. A single case report of massive grain aspiration reported survival following a Pco2 of 66. In patients with central failure of respiratory drive, dyspnoea may be entirely absent. On the other hand, when hypoventilation results from mechanical failure in the respiratory system (airway obstruction, pneumothorax, pulmonary fibrosis, etc. Muscle twitching and a characteristic flap of the hands may be observed when coma is imminent. Gross Hypercapnia Few cases of gross hypercapnia are documented, but there are sufficient instances to indicate that complete recovery from gross hypercapnia without hypoxia is possible and may even be the rule. Desflurane and isoflurane have similar effects on cerebral blood flow in patients with intracranial mass lesions. Effects of sevoflurane with and without nitrous oxide on human cerebral circulation. The use of hyperventilation and its impact on cerebral ischaemia in the treatment of traumatic brain injury. Effects of hypercapnia on hemodynamic, inotropic, lusitropic, and electrophysiological indices in humans. Acute hypercapnia improves indices of tissue oxygenation more than dobutamine in septic shock. Hypoventilation from the numerous causes described in Chapter 26 also cause hypercapnia. Finally, a large dead space easily leads to hypercapnia unless the respiratory system is able to increase tidal volume sufficiently to compensate. Cerebral blood flow, and so intracranial pressure, is exquisitely sensitive to Pco2, and hypocapnia and hypercapnia can both affect autoregulation of cerebral blood flow. High levels of Pco2 cause constriction of renal glomerular afferent arterioles and can lead to anuria. Long-term changes in Pco2 lead to compensatory changes in bicarbonate excretion by the kidney. These changes will rapidly block cerebral function, but organs with a lower energy requirement will continue to function for a longer time and are thus more resistant to hypoxia (see later). The implications for production of reactive oxygen species by this pathway are discussed on page 345. All but the simplest forms of life have evolved to exploit the immense advantages of oxidative metabolism. The essential feature of hypoxia is the cessation of oxidative phosphorylation (page 190) when the mitochondrial Po2 falls below a critical level. These trigger a complex series of cellular changes leading first to reduced cellular function and ultimately to cell death. End Products of Metabolism the end products of aerobic metabolism are carbon dioxide and water, both of which are easily diffusible and lost from the body. However, the blood-brain barrier is relatively impermeable to charged ions, therefore hydrogen and lactate ions are retained within the neurones of the hypoxic brain. Recovery of all values, except blood lactate, was complete within 5 minutes of restarting pulmonary ventilation. In severe cerebral hypoxia, a major part of the dysfunction and damage is due to intracellular acidosis rather than simply depletion of highenergy compounds (see later). Gross hypoperfusion is more damaging than total ischaemia, because the latter limits glucose supply and therefore the formation of lactic acid. Similarly, patients who have an episode of cerebral ischaemia whilst hyperglycaemic. There is no subsequent stage in the glycolytic pathway that is significantly rate limited by acidosis. The precise role of each is Brain tissue ratios Blood lactate Arterial blood gas (mmol. Also, the nature of the hypoxic insult has a large effect with differing speed of onset, degree of hypoxia, blood flow, blood glucose concentration and tissue metabolic activity all influencing the resulting tissue dysfunction. Potassium and Sodium Flux Hypoxia has a direct effect on potassium channels (page 100), increasing transmembrane potassium conductance and causing the immediate hyperpolarization. Potassium begins to leak out from the cell, increasing the extracellular potassium concentration, thus tending to depolarize the cell membrane. Following rapid depolarization, sodium and potassium channels probably simply remain open, allowing free passage of ions across the cell membrane leading to cellular destruction. Calcium Intracellular calcium concentration increases shortly after the onset of hypoxia. An altered transmembrane potential is detected within the cell by ryanodine receptors on intracellular organelles leading to release of calcium from the endoplasmic reticulum and mitochondria. At this stage, the cell has probably not been irretrievably damaged by spontaneous depolarization, but derangement of calcium channel function effectively prevents normal synaptic transmission and therefore cellular function. Cells with depleted Immediate Cellular Responses to Hypoxia4 Because of the dramatic clinical consequences of nervous system damage, neuronal cells are the most widely studied and therefore form the basis for the mechanisms described in this section. Once membrane potential reaches zero, cell death is almost inevitable (see text for details). The time between anoxia and rapid depolarization is highly variable, between about 4 minutes with complete ischaemia to almost 1 h with hypoxia and preserved blood flow. Delayed Cellular Responses to Hypoxia Following brain injury in humans, cerebral oedema often continues to develop for some hours after the initial insult. There are several possible explanations for this delayed neuronal damage with activation of many different cellular systems implicated. However, it is a quite different clinical problem that has recently focussed attention on cellular adaptations to hypoxia. The core of many solid malignant tumours has a poor blood supply, caused by the failure of angiogenesis to keep up with the rapid tumour growth. Tumour hypoxia is associated with highly malignant, aggressive tumours, which often respond poorly to treatment. For this reason, much recent research has focussed on understanding the cellular effects of hypoxia, with a view to developing new therapeutic approaches. Some activated genes may accelerate cell proliferation and therefore increase tumour malignancy, whereas other genes are activated that encourage apoptosis and impair tumour growth. Though ischaemic preconditioning has been demonstrated in many tissues the phenomenon has mostly been studied in heart muscle, and three forms are described. Early Protection Reduction in the damage occurring from an ischaemic period begins immediately after the preconditioning has occurred, and lasts for 2 to 3 h. During prolonged hypoxia, fluid and electrolyte imbalances also occur across the mitochondrial membrane impairing the ability of the cell to make the best use of any oxygen remaining in the cell. Late Protection this describes the protection from ischaemia seen about 12 h after the preconditioning and is less effective than early protection. Remote Ischaemic Preconditioning14,15 this phenomenon offers the most potential for future clinical use. The technique involves multiple (usually-three to four) short periods of ischaemia induced in an arm or leg by inflating a blood pressure cuff above systolic blood pressure for 5 minutes. The mechanisms remain largely a mystery, including identifying the messenger system between the tissues and even whether this is humoral, neuronal or immune cell in nature. Venous Po2 approximates to end-capillary Po2 and, though highly variable, is usually in excess of 3 kPa (20 mm Hg) even in maximally working skeletal muscle. Thus when the minimal Po2 in the nearby capillary is approximately 200 times greater than that required by the mitochondria, it is difficult to envisage how cellular hypoxia can occur in all but the most extreme situations. The most widely used technique is applicable only to muscle cells and involves measurement of myoglobin saturation, from which Po2 may be determined. Diffusion of oxygen within cells is believed to be slow because of the proteinaceous nature of the cytoplasm, and therefore large variations in intracellular Po2 are likely to exist. Thus in intact cells, as opposed to isolated mitochondria, critical Po2 is more likely to be of the order of 0. This will depend on many factors besides arterial Po2, including haemoglobin concentration, tissue perfusion and tissue oxygen consumption. This calculation and others under various different conditions are set out in Table 22. Alternatively, there may be favourable factors, such as polycythaemia in chronic hypoxaemia, or reduced cerebral oxygen requirements during hypothermia or anaesthesia. The possible combinations of circumstances are so great that it is not feasible to consider every possible situation. Instead, certain important examples have been selected which illustrate the fundamentals of the problem, and these are shown in Table 22. Uncompensated anaemia is almost equally dangerous, although an increase in cerebral blood flow restores a satisfactory safety margin. Neither abnormality is very serious considered separately, but in combination the arterial Po2 cannot be reduced below its normal value without the risk of cerebral hypoxia. However, it is a general rule that maximal cerebral vasodilatation may be expected to occur in any condition (other than cerebral ischaemia) that threatens cerebral oxygenation. Also, there are circumstances in which the critical organ is not the brain but the heart, liver or kidney. The most important message of this discussion is that there is no simple answer to the question: What is the safe lower limit of arterial Po2 Acclimatized mountaineers have remained conscious at high altitude with arterial Po2 values as low as 3. Patients presenting with severe respiratory disease tend to remain conscious down to similar levels of arterial Po2. However, both acclimatized mountaineers and patients with chronic respiratory disease have compensatory polycythaemia and maximal cerebral vasodilatation. Uncompensated subjects who are acutely exposed to hypoxia are unlikely to remain conscious at such low values for arterial Po2, but considerable individual variation must be expected. Hypoxia presents a serious threat to the body, and compensatory mechanisms usually take priority over other changes. Thus, for example, in hypoxia with concomitant hypocapnia, hyperventilation and an increase in cerebral blood flow occur in spite of the decreased Pco2. Certain compensatory mechanisms will come into play whatever the reason for the hypoxia, although their effectiveness will depend to a large extent on the cause. For example, hyperventilation will be largely ineffective in stagnant or anaemic hypoxia because hyperventilation while breathing air can do little to increase the oxygen content of arterial blood, and usually nothing to increase perfusion. There is little effect until arterial Po2 is reduced to about 7 kPa (52 mm Hg): maximal response is at 4 kPa (30 mm Hg).

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Singlet Oxygen Internal rearrangements of the unpaired electrons of dioxygen result in the formation of two highly reactive species, both known as singlet oxygens (1O2). The superoxide anion is relatively stable in aqueous solution at body pH, but has a rapid biological decay due to the ubiquitous presence of superoxide dismutase (see later). Catalase is a highly specific enzyme active against only hydrogen, methyl and ethyl peroxides. This contrasts with the more familiar single-stage reduction of oxygen to water that occurs in the terminal cytochrome (page 190). The first reaction is a single electron reduction to form the superoxide anion reactive oxygen species. In the second stage the first products of the dismutation reaction are dioxygen and a short-lived intermediate, which then receives two protons to form hydrogen peroxide. This occurs in the phagocytic vesicle of the neutrophil and plays a role in killing bacteria, facilitated by the enzyme myeloperoxidase. The myeloperoxidase reaction also occurs immediately after fertilization of the ovum, and hypochlorous acid thus formed causes polymerization of proteins to form the membrane that prevents further entry of spermatozoa. It is, therefore, hardly surprising that the effect of radiation is increased by high partial pressures of oxygen. As tissue Po2 is reduced below about 2 kPa (15 mm Hg), there is progressively increased resistance to radiation damage until, at zero Po2, resistance is increased threefold. This unfortunate effect promotes resistance to radiotherapy of malignant cells in hypoxic areas of tumours (page 432). This molecule can either rearrange itself into relatively harmless nitrite or nitrate (page 184), or give rise to derivatives with similar biological activity to the hydroxyl radical. Conversely, nitric oxide may act as an antioxidant, binding to ferrous iron molecules and preventing them from contributing to the formation of a superoxide anion (see next) or the Fenton reaction. The first stage reduction of dioxygen to the superoxide anion is therefore critically important in oxygen toxicity. This mechanism is activated during phagocytosis and is accompanied by a transient increase in the oxygen consumption of the cells, a process known to be cyanide resistant. This is the so-called respiratory burst and occurs in all phagocytic cells in response to a wide range of stimuli including bacterial endotoxin, immunoglobulins and interleukins. A similar reaction also occurs during the spontaneous oxidation of haemoglobin to methaemoglobin (page 185). Apart from ferrous iron acting as an electron donor, it is a catalyst in the Fenton reaction (see previous discussion). This accords with the development of clinical oxygen toxicity as discussed in a later section. This process is accelerated at high levels of Po2, and so there is a synergistic effect between paraquat and oxygen. Cellular, and more specifically mitochondrial, redox state is believed to be part of an essential, and poorly understood, cell signalling system6,9 involved, for example, in the sensing of oxygen levels in the carotid body. Breakage of chromosomes in cultures of animal lung fibroblasts by high concentrations of oxygen was first demonstrated in 1978. These potent cellular effects initiate numerous pathological processes including inflammation, malignancy or cell death. Damage to sulphydryl-containing proteins results in formation of disulphide bridges, which inactivates a range of proteins. Interference with these fundamental cellular molecules has widespread physiological implications. Antioxidant Enzymes these enzymes are widely distributed in different organs and different species but are deficient in most obligatory anaerobic bacteria. Animal studies have shown that administration of exogenous surfactant prolongs the duration of oxygen exposure required to cause lung damage. Because ferrous iron is both a potent source of electrons for conversion of oxygen to the superoxide anion and a catalyst in the Fenton reaction, the iron chelating agent desferrioxamine has antioxidant properties in vitro. Endogenous Antioxidants Ascorbic acid is a small molecule with significant antioxidant properties which are particularly important for removal of the hydroxyl free radical. Apart from a direct chemical effect on the cell redox state, ascorbate also has effects on nitric oxide synthesis and may influence cell biochemistry by this mechanism as well. Predictably, its main antioxidant role is in the prevention of lipid peroxidation chain reactions as described earlier. Glutathione is found in high concentrations in the airway lining fluid as part of the glutathione peroxidase system previously described. Clearance of gas loculi in the body may be greatly accelerated by the inhalation of oxygen, which greatly reduces the total partial pressure of the dissolved gases in the venous blood (Table 24. This results in the capillary blood having additional capacity to carry away gas dissolved from the loculi. Total gas partial pressures in venous blood are always slightly less than atmospheric, and this is critically important in preventing the accumulation of air in potential spaces such as the pleural cavity, where the pressure is subatmospheric. Oxygen is therefore useful in the treatment of air embolism (page 415) and pneumothorax (page 434). The most important clinical conditions in which oxygen has been identified as the sole precipitating cause are retrolental fibroplasia and pulmonary oxygen toxicity, though there are many other clinical situations where excess oxygen has adverse effects. Increasing the Inspired Oxygen Concentration23 Many systems exist for increasing the inspired oxygen concentration, and an understanding of these is crucial for effective therapy. Methods may be divided into low-flow (closed) or high-flow (open) delivery systems. Airtight seals may be obtained with cuffed tracheal or tracheostomy tubes or, at low airway pressures, with a tight-fitting facemask or laryngeal mask airway. These devices should give complete control over the composition of the inspired gas. Any closed delivery system requires the use of a breathing system that provides suitable separation of inspired and expired gases to prevent rebreathing and does not present significant resistance to breathing. The popularity of oxygen tents declined because of their large volume and high rate of leakage, which made it difficult to attain and maintain a high oxygen concentration unless the volume was reduced and a high gas flow rate used. These problems are minimized when the patient is an infant, and oxygen control within an incubator is a satisfactory method of administering a precise oxygen concentration. Higher oxygen concentrations require a lower entrainment ratio and therefore a higher oxygen flow to maintain an adequate total delivered flow rate. Numerous studies have indicated that the Venturi mask gives good control over the inspired oxygen concentration that is mostly unaffected by variations in the ventilation of the patient, except at high oxygen concentrations. Referred to as high-flow nasal cannula oxygen therapy the device is very well tolerated by patients and can deliver up to 70 l. The effective inspired oxygen concentration is impossible to predict and may vary between very wide limits. These devices cannot be used for oxygen therapy when the exact inspired oxygen concentration is critical but are useful in many other situations such as recovery from routine anaesthesia. With simple oxygen masks a small inspiratory reservoir will store fresh gas during expiration for use during inspiration, which will tend to increase the inspired oxygen concentration but, again, in a somewhat unpredictable fashion. With a device such as a nasal catheter or prongs, the lower the ventilation, the greater will be the fractional contribution of the fixed flow of oxygen to the inspired gas mixture. There is thus an approximate compensation for hypoventilation, with greater oxygen concentrations delivered at lower levels of ventilation. Arterial Po2 may then be maintained in spite of a progressively falling ventilation, but this will do nothing to prevent the rise in Pco2, which may reach a dangerous level without the development of low oxygen saturations. Oxygen use in neonates was strictly curtailed, but resulted in an increase in morbidity and mortality attributable to hypoxia. In phase 1 there is delayed vascular development of the retina with avascular peripheral areas, and in phase 2 there is vasoproliferation leading to intravitreal angiogenesis. These abnormalities are believed to result from changes in Po2 affecting the activity of hypoxiainducible factor (page 330) and in particular its effect on vascular growth factors at this crucial stage of eye development for humans. In addition, a whole range of other oxidizing substances may be inhaled, including common air pollutants and the constituents of cigarette smoke (Chapter 19). The lung is therefore the organ most vulnerable to oxygen toxicity and a range of defence mechanisms have developed. Overall antioxidant activity from both enzymes and other endogenous antioxidants is very high in the fluid lining of the respiratory tract. Humans seem to be far less sensitive, but there are formidable obstacles to investigation of both human volunteers and patients. Study of oxygen toxicity in the clinical environment is complicated by the presence of the pulmonary pathology that necessitated the use of oxygen. Oxygen exposure beyond this point leads to the widespread structural changes described next, which ultimately give rise to acute lung injury and possibly irreversible changes in lung function. Cellular Changes34 Electron microscopy has shown that, in rats exposed to 1 atm of oxygen, the primary change is in the capillary endothelium, which becomes vacuolated and thin. At a later stage, in monkeys, the epithelial lining is lost over large areas of the alveoli. Most strains of rat will not survive for much more than 3 days in 1 atm of oxygen. Monkeys generally survive oxygen breathing for about 2 weeks, and humans are probably even more resistant. Oxygen tolerance in humans has been investigated,35 but these studies are based on reduction in vital capacity, etc. There is an approximately inverse relationship between Po2 and duration of tolerable exposure. Pulmonary oxygen toxicity seems to be related to Po2 rather than inspired concentration. There is abundant evidence that prolonged exposure to this environment does not result in demonstrable pulmonary oxygen toxicity thus establishing a Po2 of 34 kPa (255 mm Hg) as a safe level. It also confirms that the significant factor is partial pressure and not concentration. In contrast, the concentration of oxygen rather than its partial pressure is the important factor in absorption collapse of the lung (see later). Clinical Studies Some limited information on human pulmonary oxygen toxicity has been obtained from patients in the course of therapeutic administration of oxygen. A similar group of patients ventilated for long periods with high concentrations of oxygen were reviewed in 1980,37 and these authors concluded that adverse effects of oxygen on the alveolar epithelium were rarely of practical importance in hypoxaemic patients. In contrast to these essentially negative findings, a study in 1987 obtained positive findings in a randomized trial involving patients ventilated after cardiac surgery. There are many possible causes for these changes, but the authors concluded that unnecessary elevation of inspired oxygen concentration should be avoided. This is a view from which few would dissent at present, including a recent suggestion that inspired oxygen in artificially ventilated patients should be titrated to a target oxygen saturation, as already advocated in other acutely ill patients as described later. A few minutes of breathing oxygen at residual lung volume results in radiological evidence of collapse, a reduced arterial Po2 and substernal pain on attempting a maximal inspiration. One possible explanation for the lack of clear findings is that hyperoxia simply exacerbates preexisting lung damage, irrespective of whether this is clinically apparent or subclinical, as indicated by reduced pulmonary-diffusing capacity. Oxygen Use in Acute Medicine In clinical practice the administration of oxygen to acutely ill patients has become almost ubiquitous, both in hospital and community settings. Prevention of dangerous hypoxia is always the first priority and hypoxia must be treated in spite of the various hazards associated with the use of oxygen. Uncontrolled use of oxygen is associated with increased mortality in these patients. There is some evidence that hyperoxia causes an increased mortality in patients following severe ischaemic strokes who need artificial ventilation. These adverse clinical outcomes with hyperoxia have led to debate regarding the optimal level of target oxygen saturation or Po2. There are now calls for much more precise control of oxygen levels, particularly in critically ill patients where this is easily achieved, including a suggestion that target levels should be deliberately lower than normal. Nitric oxide inhibitors delay the onset of convulsions in hyperoxia,63 but paradoxically, the same effect is seen with some nitric oxide donors. Hyperbaric oxygenation is the only way arterial Po2 values in excess of 90 kPa (675 mm Hg) may be obtained. However, it is easy to be deluded into thinking that the tissues will be exposed to a similar Po2 as found in the chamber. However, the relationship between arterial and tissue Po2 is highly variable (page 147), and hyperoxia-induced vasoconstriction in the brain and other tissues limits the rise in venous and tissue Po2. It is interesting that the threshold for oxygen convulsions is close to that at which brain tissue Po2 is likely to be sharply increased (Table 24. The relationship to cerebral tissue Po2 is supported by the observation that an elevation of Pco2 lowers the threshold for convulsions. High Pco2 increases cerebral blood flow, therefore raising the tissue Po2 relative to the arterial Po2. An increased haemoglobin saturation of venous blood reduces its buffering power and carbamino carriage of carbon dioxide, possibly resulting in carbon dioxide retention. However, in the brain this might result in a significant increase in cerebral blood flow, causing a secondary rise in tissue Po2. As described earlier, high Po2 causes vasoconstriction, which may be valuable for reduction of oedema in the reperfusion of ischaemic limbs and in burns (see later discussion). However, oxygen will still have a direct toxic effect on microorganisms, particularly on anaerobic bacteria, and relief of hypoxia improves the performance of polymorphs. This effect is additional to that resulting from reduction of the total partial pressure of gases in venous blood (Table 24. Since its first use in 1960 enthusiasm for hyperbaric oxygenation has waxed and waned, and its use is still confined to relatively few centres.

Usage: p.c.

Flow sensing can also detect the end of inspiration and is used in pressure support ventilation (see later). Neurally Adjusted Ventilatory Assist Neurally adjusted ventilatory assist uses an oesophageal probe to measure diaphragm electromyography to coordinate the artificial breath to both the start and finish of the spontaneous breath and adjusts the airway pressure delivered to match the magnitude of diaphragmatic activity. There is also evidence of reduced requirements for sedation and paralysis, less disuse atrophy of respiratory muscles, shorter length of stay in intensive care and improved survival. Many of these are essentially the same but have different nomenclature because of their development by rival ventilator manufacturers. A maximum time delay between breaths is incorporated, following which a breath will be generated by the ventilator if spontaneous triggering has ceased. The second advantage is the facilitation of weaning, which is considered in a later discussion. Flow sensing by the ventilator is also then able to detect when the spontaneous inspiration ends, at which point the pressure support ceases, and expiration occurs. The purpose is not to provide a prescribed tidal volume, but to assist the patient in making an inspiration of a pattern that lies largely within his own control. The amount of pressure support provided does seem to be inversely related to the work of breathing. High-Frequency Ventilation High-frequency ventilation may be classified into the following three categories: 1. Although many conventional ventilators will operate within this frequency range, specially designed ventilators have been used. Inspiration is driven by a high-velocity stream of gas from a jet, which may or may not entrain gas from a secondary supply. A unique advantage is the ability to ventilate through a narrow cannula, for example, through the cricothyroid membrane. At these high frequencies, the respiratory waveform is usually sinusoidal, including active expiration. The relationship between tidal volume and dead space during high-frequency ventilation is crucial to an understanding of the technique. It is useless to infer values for tidal volume and dead space from measurements made under other circumstances, yet it is very difficult to make direct measurements of these variables under the actual conditions of high-frequency ventilation, especially in humans. The actual volume of the physiological dead space decreased with decreasing tidal volume to reach a minimal value of about 90 ml at 1 Hz. However, the normal proportionality between dead space and tidal volume (page 121) was not maintained. One study found that tidal volumes of at least 100 ml were still required at frequencies of 15 Hz, corresponding to an applied minute volume of 90 l. Weaning36 Weaning describes the process by which artificial ventilation is gradually withdrawn and the patient returned to normal respiration. In practice it is useful to think of two stages: the withdrawal of respiratory support and the removal of any artificial airway, usually a tracheal tube or tracheostomy. Predicting Successful Weaning Before weaning can be attempted, the balance between ventilatory load and capacity must be favourable. Extra demands on the respiratory system may originate from increased oxygen consumption, commonly as a result of sepsis, but also occasionally from thyrotoxicosis, convulsions or shivering. Reduced respiratory system compliance or increased airway resistance also impose additional loads on the respiratory system. The capacity of the respiratory system to wean depends on having adequate ventilation perfusion matching and low intrapulmonary shunt and respiratory dead space. Numerous different measurements have been reported to predict successful weaning from ventilatory support, examples of which are shown in Table 31. No single variable is a reliable enough indicator of success, with most having very low predictive values. The sudden reversals of flow direction are likely to set up flow patterns that blur the boundary between dead space and alveolar gas, thus improving the efficiency of ventilation. The techniques have been used mainly for weaning from artificial ventilation in adults and for respiratory support in babies. There is no doubt that effective gas exchange is usually possible with high-frequency ventilation but clinical advantages over conventional artificial ventilation are less clear. It is important to not place excessive reliance on modern ventilator systems to wean patients from ventilatory support. Protocols for weaning are now widely used to ensure all of these aspects are addressed, but some patients will still remain ventilated for many weeks, and specialist units now exist to care for these challenging patients. Biased demand valves may be used but usually result in a pronounced dip in inspiratory pressure, increasing the total work of breathing. If this trial of spontaneous breathing fails, appropriate degrees of ventilatory support should be recommenced, and a further trial of spontaneous breathing performed at 24-h intervals if the predictors of successful weaning remain satisfactory. The simplest is to exhale through a preset depth of water but more convenient methods are spring-loaded valves or diaphragms pressed down by gas, a column of water or a spring. It is also possible to use Venturis and fans opposing the direction of expiratory gas flow. Respiratory Effects48 Artificial ventilation effectively rests the respiratory muscles, and the effect of this on muscle function is described on page 82. Distribution of Ventilation Intermittent positive pressure ventilation results in a spatial pattern of distribution that is determined by inflation pressure, regional compliance and time constants. Based on external measurements, the anatomical pattern of distribution of inspired gas is different from that of spontaneous breathing, and there is a relatively greater expansion of the rib cage. With orotracheal and tracheostomy tubes much of the normal anatomical dead space (page 121) is bypassed, such that overall anatomical dead space may be unchanged or reduced. Although the decline in pressure and flow is normal, there is insufficient time for complete expiration to occur. Expiratory time is normal, but the decline in pressure and flow is retarded to such an extent that expiration is again incomplete. With noninvasive ventilation using facemasks, apparatus dead space may be substantial. In many patients this may be expected to raise the tidal range above the closing capacity (page 38) reducing pulmonary collapse. Pulmonary shunting is decreased, but the accompanying decrease in cardiac output reduces the mixed venous oxygen saturation, which counteracts the effect of a reduction in the shunt, resulting in minimal increase in arterial Po2. Valsalva Effect It has long been known that an increase in intrathoracic pressure has complex circulatory effects, characterized as the Valsalva effect, which is the circulatory response to a subject increasing his airway pressure to about 50 cmH2O against a closed glottis for about 30 s. Initially the raised intrathoracic pressure alters the baseline for circulatory pressures, and the arterial pressure (measured relative to atmosphere) is consequently increased (phase 1). At the same time, ventricular filling is decreased by the adverse pressure gradient from peripheral veins to the ventricle in diastole, and cardiac output therefore decreases. The consequent decline in arterial pressure in phase 2 is normally mitigated by three factors-tachycardia, increased systemic vascular resistance (afterload) and an increase in peripheral venous pressure-which tends to restore the venous return. As a result of these compensations, the arterial pressure normally settles to a value fairly close to the level before starting the Valsalva manoeuvre. However, the arteriolar bed remains constricted temporarily, and there is a transient overshoot of arterial pressure. The initial increase in arterial pressure (phase 1) occurs normally, but the decline in pressure in phase 2 is missing because the output of the congested heart is not usually limited by end-diastolic pressure. Because the cardiac output is unchanged, there is no increase in pulse rate or systemic vascular resistance, and there is no overshoot of pressure when the intrathoracic pressure is restored to normal. Phase 1 is normal, but in phase 2 the decreased cardiac output is not accompanied by an increase in systemic vascular resistance, and the arterial pressure therefore continues to decline. The normal overshoot is replaced by a slow recovery of arterial pressure as the cardiac output returns to control values. There is general agreement that the main cause of reduction in cardiac output is obstruction of filling of the right atrium caused by elevated intrathoracic pressure. Positive intrathoracic pressure abolishes this effect and also imposes a further reduction in driving pressure for flow between extrathoracic and intrathoracic vessels. These changes will clearly be more pronounced with hypovolaemia, and this phenomenon forms the basis of current clinical techniques to assess circulatory volume, such as pulse pressure variation and stroke volume variation. Although there was some increase in systemic vascular resistance, this was only about half that required for maintenance of the arterial pressure in the face of the declining cardiac output. Interpretation of Vascular Pressures Atrial pressures are normally measured relative to atmospheric pressure. With positive pressure ventilation, atrial pressures tend to be increased relative to atmospheric. It is the transmural pressure gradient and not the level relative to atmosphere that is relevant to cardiac filling. With reduced compliance the effect of raised intrathoracic pressure on cardiac output is reduced. Haemodynamic Response in Heart Failure the cardiovascular responses described thus far apply only to patients with normal cardiac function, and, like the Valsalva response, are very different in patients with raised ventricular enddiastolic pressure with or without ventricular failure. The lower unbroken line shows intrapleural pressure in the relaxed healthy subject. The broken line shows values of intrapleural pressure in patients with acute lung injury taken from reference 46. Absolute values of pressure probably reflect experimental technique and cannot be compared between studies. Arterial pressure tends to be reduced as described earlier, whereas central venous pressure is raised. Therefore the pressure gradient between renal artery and vein is reduced which has a direct effect on renal blood flow. Pulmonary Neutrophil Retention Neutrophils have a diameter close to that of a pulmonary capillary, and this is important in 31 Respiratory Support and Artificial Ventilation 471 slowing their transit time through the lung to facilitate margination for pulmonary defence mechanisms (page 423). Artificial ventilation may damage normal lungs only after prolonged ventilation with high airway pressures or large tidal volumes and is rarely a problem in clinical practice. In one of these studies, lung damage with high inflation pressures was attenuated by restricting chest movement to prevent overdistension of the lungs, indicating that alveolar size rather than pressure was responsible for lung injury. There are several possible underlying mechanisms, all of which are closely interrelated. With extreme lung distension in animal studies this occurs quickly and probably results from direct trauma to alveolar structures. Studies using lung cell cultures in vitro reveal some of the mechanisms of this cellular trauma. Stretch frequency is also an important determinant of the damage done, supporting the inclination towards slower respiratory rates in injured lungs. In larger animals and humans, the permeability changes occur slowly (several hours) and are likely to result from the alterations in surfactant and inflammatory mediators described later rather than widespread cellular damage. Atelectrauma Airway trauma occurs with repeated closure and reopening of small airways with each breath, and has been termed atelectrauma. In vitro studies show that physical stresses on epithelial cells as lung reopens are considerable and sufficient to damage tight junction proteins, increasing paracellular permeability. Surfactant function is affected by artificial ventilation exacerbating atelectrauma. Pulmonary barotrauma probably starts as a disruption of the alveolar membrane, with air entering the interstitial space and tracking along the bronchovascular bundles into the mediastinum, from which it can reach the peritoneum, the pleural cavity or the subcutaneous tissues. Radiological demonstration of pulmonary interstitial gas may provide an early warning of barotrauma. The resultant increase in alveolar surface tension will not only affect lung compliance but will also increase local microvascular permeability and encourage alveolar collapse. Termed biotrauma, this includes a proinflammatory response to ventilation that is independent of any infection present, and also includes activation of immune and coagulation systems, and cellular growth and apoptotic pathways. Once activated-for example, by stretching as described previously or by exposure to the alveolar basement membrane-inflammatory mediators will contribute to permeability oedema and further loss of surfactant function. Expired Air Ventilation71 Recognition of the inadequacy of the manual methods of artificial ventilation led directly to a radical new approach to artificial ventilation in an emergency. At first sight, it might appear that expired air would not be a suitable inspired air for the victim. If neither party had any respiratory dead space, the simple relationship shown in Table 31. Expired air ventilation has now displaced the manual methods in all except the most unusual circumstances, and its success depends on the following factors: 1. It is normally possible to achieve adequate ventilation for long periods of time without fatigue, though symptomatic hypocapnia can occur. Plateau pressure is the ventilator measurement that equates most closely to the degree of alveolar distension. It is currently recommended that in patients with normal chest wall compliance the plateau pressure should not be allowed to exceed 30 cmH2O. Methods were based on the rescuer manipulating the trunk and arms of the victim to achieve changes in lung volume which, when performed in sequence, could produce some degree of pulmonary ventilation. These methods, which may have saved many lives in the past, are now largely obsolete. The method seems to come naturally, and many rescuers have achieved success with the minimum of instruction. For the first few minutes after a witnessed cardiac arrest, oxygen stores in the blood and lungs may obviate the need for artificial ventilation until trained personnel and equipment arrive. Extracorporeal gas exchangers were first developed for cardiac surgery to facilitate cardiopulmonary bypass allowing surgery on a motionless heart. Subsequently the use of extracorporeal, and more recently intracorporeal, gas exchange was extended into the treatment of respiratory failure. Therefore a subnormal diffusing capacity does not necessarily result in arterial hypoxaemia.