Ventilatory Strategies For Arterial Hypoxaemia: A Peep Into ...

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Ventilatory Strategies For Arterial Hypoxaemia: A Peep Into The

Future?

The failure of aerobic tissue metabolism (tissue hypoxaemia) inevitably results in organ dysfunction, and

consequently its detection and correction is an important focus for critical care physicians. Of the four

causes of tissue hypoxaemia (Table 1), three were famously described by the Cambridge University

physiologist Joseph Barcroft in August 1920, whilst the fourth, cytopathic hypoxia, has been described

more recently1. Barcroft’s categorisation is memorable because it describes sequentially the barriers to the

transfer of oxygen from inspired gas to mitochondrium. This article addresses the management of the

most proximate of these in patients requiring mechanical ventilation – the impairment of oxygen transfer

from inhaled gas to red blood cell leading to arterial hypoxaemia.

Arterial hypoxaemia

Before we can devise a logical strategy for the management of arterial hypoxaemia we must first

understand what causes it. Of the six possible causes of arterial hypoxaemia (Table 2) not all are either

relevant, or amenable to clinical manipulation. For example, the clinician has little control over barometric

pressure (unless working at high altitude with the option of moving the patient to sea level), and in

mechanically ventilated patients neither a low fractional inspired oxygen concentration (FIO2) nor

hypoventilation are likely to be relevant factors. Furthermore there is little evidence that obstruction to the

diffusion of oxygen from alveolus to pulmonary capillary is ever a significant contributor in clinical practice.

The term ‘shunt’ refers to blood returning to the left ventricle which has not been ‘arterialized’ by contact

with a ventilated alveolus. Even under normal circumstances a small shunt arises from venous blood

returning to the left ventricle from the bronchial veins, which drain the small arterial supply to the

pulmonary parenchyma, and the Thebesian veins, which drain the left ventricular myocardium. A

pathological shunt may be cardiac or pulmonary in origin.

Intra-cardiac shunt is invariably associated with the failure of either the inter-atrial or inter-ventricular

septum, and may be congenital or acquired. In most cases the presence of an intra-cardiac shunt as the

cause for arterial hypoxaemia is obvious, either because the presence of a congenital lesion has previously

Ventilatory Strategies For Arterial Hypoxaemia

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been identified, or because an acquired intra-cardiac shunt is suggested by the clinical circumstances.

Very occasionally a previously ‘silent’ atrial septal defect or patent foramen ovale may suddenly cause

arterial hypoxaemia even in the absence of pulmonary hypertension2, and may be easily overlooked

unless considered as a possible cause. Arterial hypoxaemia arising from an intra-cardiac shunt can only be

reversed by correction of the anatomical defect.

Intra-pulmonary shunt arises from blood that is diverted away from ventilated alveoli through arterio-

venous anastamoses, or that supplies alveoli with no ventilation. However alveolar ventilation that is

anything less than normal (low ratio of ventilation to perfusion, V/Q) also causes arterial hypoxaemia.

Therefore arterial hypoxaemia arising from shunt (zero ventilation) can be seen as a special case of

arterial hypoxaemia arising from alveoli with a reduced ratio of ventilation to perfusion (V/Q). Together

these are the predominant contributors to arterial hypoxaemia, with a small additional contribution, in

some cases, from venous desaturation. So the questions then arises, what are the causes of low V/Q and

shunt, and what can we do about them?

Low V/Q

Hypoventilation of lung units may occur with proximal airway obstruction (Table 3), loss of the alveolar

lumen by occupation of the air space by cellular material (consolidation) or fluid (alveolar flooding), or as

a result of alveolar atelectasis.

Obstruction of the proximal airway does not usually present a diagnostic problem, either because of a

suggestive history (of aspiration) or because of the clinical context in which it has occurred (e.g.

pulmonary haemorrhage in a patient with pulmonary-renal syndrome). It may occasionally occur

unexpectedly as a sudden deterioration in oxygenation in a patient receiving mechanical ventilation, and

in this case the most common cause is mucus plugging of a bronchus (Figure 1). In most cases, some

form of physical intervention is required, either to directly relieve the obstruction by rigid or flexible

bronchoscopy, or to isolate healthy lung by passage of a double-lumen endotracheal tube.

Loss of alveolar airspace by the influx of inflammatory cells, fibrin and cellular debris resulting in

pulmonary consolidation is not amenable to any form of physical intervention and depends on the

resolution of the underlying condition. In contrast, alveolar flooding may respond to a variety of

therapeutic manoeuvres. The passage of fluid from capillary to interstitium, and then from the interstitium


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to alveolar lumen, is determined by the balance between the hydrostatic and colloid osmotic pressures in

the three compartments (capillary, interstitium and alveolus), the reflection co-efficients of the interceding

endothelium (capillary/interstitium interface) or epithelium (interstitial/alveolar interface), and the

function of the drainage mechanisms (pneumocyte abluminal Na+/K+-ATPase and pulmonary lymphatics).

Currently nothing can be done to alter the pulmonary capillary endothelial reflection co-efficient which falls

as a result of the relaxation of inter-endothelial tight junctions mediated by inflammatory mediators. The

alveolar epithelial reflection co-efficient has two components; the first being the inter-epithelial tight

junctions (similar to the pulmonary capillary endothelium), the second arising from the effect of alveolar

surfactant. As with the capillary endothelium, relaxation of inter-epithelial tight junctions is currently not

amenable to intervention. Loss of alveolar surfactant occurs by a number of mechanisms which include the

degradation of alveolar surfactant by plasma proteins that have leaked into the alveolar lumen and the

loss of alveolar type II pneumocytes which synthesize surfactant. The administration of exogenous

surfactant (either synthetic or of animal origin) has been shown to improve lung mechanics, oxygenation

and outcome in neonates with hyaline membrane disease3, but has yet to be shown to be of benefit in

adults. Capillary fluid efflux may be reduced, or indeed reversed, by minimising the pulmonary capillary

filtration pressure, which in disease may not equate to the pulmonary artery occlusion pressure because of

the presence of significant pulmonary venous flow restriction, and in patients with ARDS the resultant

reduction of extra-vascular lung water has been shown to be associated with a better outcome4. Alveolar

fluid reabsorption (but not interstitial fluid absorption5) may be promoted by positive end-expiratory

pressure and results in improved oxygenation. Alveolar fluid reabsorption is promoted in animal models of

pulmonary oedema by activation of the abluminal pneumocyte Na+/K+-ATPase by b-adrenoreceptor

agonists6,7, suggesting that these agents may be helpful in promoting the resolution of pulmonary oedema

in patients8. Interstitial fluid drainage through the pulmonary lymphatics may be encouraged by

minimising central venous pressures. There is no evidence that manipulation of the plasma colloid oncotic

pressure with either natural (human albumin solution, fresh frozen plasma) or synthetic products has any

effect on reducing either alveolar or interstitial fluid.

Atelectasis

Atelectasis (alveolar collapse) in mechanically ventilated patients occurs as a consequence of (1)

surfactant depletion/degradation, (2) gravitational compression from increased interstitial fluid in


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overlying lung9,10, (3) absorption of oxygen from alveoli with long time constants11,12 (4) reversal of the

normal ventilation gradient13 and (5) low tidal volumes. For the sake of clarity atelectasis can be described

as taking two forms depending on its behaviour during the respiratory cycle; type A, in which the alveolus

is collapsed at end-expiration but opens during inspiration (i.e. tidal recruitment), and type B, which is

collapsed at both end-expiration and end-inspiration but may be recruited if sufficient pressure is used

(Figure 2). The factors determining the proportion of type A and type B atelectasis in any given patient are

currently unknown, but may include amongst other things patient morphology and aetiology of the lung

disease. The extent to which type A atelectasis contributes to alveolar hypoventilation will depend on the

frequency distribution of the ‘opening times’ of these alveoli over the inspiratory cycle, which is likely to

vary depending on local factors (such as the position of the alveolus in the antero-posterior axis of the

chest, Figure 3). Nevertheless there is evidence that tidal recruitment of collapsed alveoli (type A

atelectasis) contributes to ventilator-associated lung injury 14,15 and may have a role in the genesis of

multiple organ failure16,17. Although the factors tending to precipitate atelectasis may be addressed (Table

4), direct intervention involves the application of positive end-expiratory pressure (PEEP) and, possibly

volume recruitment manoeuvres and sighs.

PEEP

The effect of PEEP in improving oxygenation was originally described in the mid to late 1960’s18,19, and

PEEP has remained an important component of the ventilatory strategies for improving oxygenation.

However, the question of how much PEEP to use has never been conclusively settled, and is now an issue

of renewed interest because of recent evidence suggesting reduced mortality in patients ventilated with

lower tidal volumes and airway pressures20,21.

One of the earliest suggested techniques for determining optimum PEEP was to examine the relationship

between PEEP and oxygen delivery22, as increasing levels of PEEP were noted to have opposite effects on

arterial haemoglobin saturation on the one hand, and cardiac output on the other. Suter’s ‘best PEEP’ was

therefore defined as the level of PEEP that was associated with the maximum oxygen delivery. Subsequent

work, originally suggested in the 1980’s23-25, focused on examination of lung mechanics for determining

optimum PEEP. This method depends on examination of a plot of lung volume change from functional

residual capacity against inflating pressure under conditions of zero flow (Figure 4). This can be seen to

have a sigmoidal shape in which the slope of the line at any point represents total thoraco-pulmonary


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compliance, and has three distinct segments; an initial segment of low but increasing compliance, a

straight middle section where compliance is constant, and an upper section where compliance falls as total

lung capacity is approached. If, as was originally thought, the initial low-compliance section of this curve is

due to alveolar recruitment being completed at the lower inflection point (LIP), optimum PEEP would lie at

a pressure just above the LIP. Setting PEEP in this way has been shown to be associated with a significant

reduction in mortality in patients with ARDS20, and has been shown to reduce the production of

inflammatory cytokines by the lung26, but the practical limitations of this technique in a non-research

setting have prevented its widespread adoption27,28.

More recently investigators have questioned the validity of selecting PEEP based on the LIP of the inflation

pressure/volume curve29,30. Firstly, PEEP has its effect in the expiratory limb of the pressure/volume loop

which is normally quite different from the inspiratory limb (Figure 5). The difference between the two

limbs is partly ascribed to the effect of Laplace’s law which predicts that considerably more pressure is

required to open collapsed alveoli than is needed to keep these recruited alveoli open, a phenomenon that

has been convincingly demonstrated in an animal model31 and patients with ARDS30. Secondly,

mathematical modelling predicts that alveolar recruitment continues above the LIP32, and this has now

been demonstrated in animal models of ARDS33 and in patients with ALI34,35 or ARDS30. Taken together

these two observations suggest that PEEP should be set after fully recruiting all available alveoli (i.e. both

type A and type B atelectasis, see above) with a volume recruitment manoeuvre (VRM), as originally

proposed by Lachman36, followed by examination of the deflation limb of the pressure/volume curve to

identify the critical closing volume30,37. In practical terms this technique would still appear to require the

construction of a volume/pressure curve, albeit during deflation rather than inflation, and in one study in

patients with ALI no discrete critical closing pressure could be detected35. An alternative technique

suggested by mathematical modelling would be to select optimal PEEP during down-titration from total

lung capacity by selecting the PEEP value associated with the maximum compliance38, which in clinical

practice is considerably easier to perform. Details of the optimum techniques for performing a VRM remain

unspecified, even though VRM has been recommended in the management of ARDS39. In this context VRM

would primarily being used to safely aerate as much lung as possible (to total available lung capacity) in

order to set optimum PEEP. Improvements in oxygenation and compliance achieved by a VRM will depend

on the ratio of recruitable atelectasis (types A and B) to un-recruitable consolidation that is responsible for


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the arterial hypoxaemia in that patient, at that time. There is evidence from both animal models of acute

lung injury40 and patients with ARDS41,42 that this may differ, depending on the mechanism of injury, and

that some patients may be ‘unresponsive’ to VRM.

Another important issue that needs to be addressed is the frequency with which a VRM and PEEP titration

should be performed. Significant alveolar collapse occurs in patients with ALI simply by the loss of PEEP34,

and further alveolar collapse is caused by endotracheal suction43,44. In patients with severe arterial

hypoxaemia it would therefore seem prudent to avoid the loss of PEEP at any time by using closed suction

circuits and self-sealing nebuliser ports, and to perform a VRM after endotracheal suction. Even in the

absence of nursing intervention the benefits accrued by a VRM fade over time, with some investigators

reporting a return to baseline oxygenation in as little as five minutes45. One contributing factor in the rapid

loss of benefit following a VRM is an inappropriately low PEEP setting42, but another contributing factor

may be a high fractional inspired oxygen concentration (FIO2). Absorption atelectasis was described by

Nunn46 and accounts for the increase in pulmonary shunt that occurs in patients breathing high

concentrations of oxygen11,12. In anaesthetised subjects the effects of a VRM lasted at least 40 minutes in

those breathing 40% oxygen, but only 5 minutes in those breathing 100% oxygen47. This data suggests

that the interval between VRM’s should be inversely proportional to the FIO2, and that advantage should

be taken of any improvement in oxygenation following a VRM by immediate reduction in the FIO2.

Other strategies

Prolonging the ratio of inspiratory to expiratory time results in an increase in the mean intra-pulmonary

pressure, which is the principle determinant of the alveolar gas-exchange surface, and therefore

oxygenation. But despite initially promising results48-50, comparison of ‘inverse-ratio’ ventilation with

conventional ventilation with equivalent values of PEEP has failed to demonstrate an indiscriminate

oxygenation advantage51-53. However in any given individual inverse ratio ventilation may improve

oxygenation, and thereby allow a reduction in FIO2.

Improved oxygenation in ventilated patients turned prone was originally advocated in 197454, and has

been shown to cause rapid and sustained improvements in oxygenation in some patients with ARDS55,56.

In a recent prospective study in patients with ARDS prone ventilation did not improve survival57, but this


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study has been criticised on a number of grounds58,59, in particular that the technique was applied ‘too

little, too late’. Other studies have suggested that early prone ventilation may be of benefit60.

Inhaled nitric oxide has been shown to significantly improve oxygenation and reduce pulmonary

hypertension in some adults with ARDS61, but in randomised controlled trials in adults these effects have

not translated into a reduction in mortality62-65. None of the studies were powered to examine mortality as

a primary outcome and a recent meta-analysis66 has concluded that the full potential of inhaled nitric

oxide in the treatment of ARDS is yet to be established.

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57. Gattinoni L, Tognoni G, Pesenti A, Taccone P, Mascheroni D, Labarta V, Malacrida R, Latini R, for the Prone-Supine Study Group: Effect of prone positioning on the survival of patients with acute respiratory failure. NewEngland Journal of Medicine 2001; 345: 568-73

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62. Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K, Hyers TM, Papadakos P,and the Inhaled Nitric Oxide in ARDS Study Group: Effects of inhaled nitric oxide in patients with acuterespiratory distress syndrome: results of a randomized phase II trial. Critical Care Medicine 1998; 26: 15-23

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Tables

Table 1 Barcroft’s classification of ‘anoxaemia’ (1 to 3), or the causes of the failure of aerobic

cellular metabolism, with the addition of cytopathic hypoxia.

1) Anoxic – partial pressure of oxygen in arterial blood reduced (may also be called arterial hypoxaemia)

2) Anaemic – Arterial oxygen content reduced, either by an absolute (anaemia) or functional(carboxyhaemoglobin, methaemoglobin) deficit of haemoglobin.

3) Stagnant – Failure of arterial blood flow to tissues, either globally (cardiac failure, haemorrhage), orlocally (arterio-venous shunt, thrombo-embolism).

4) Cytopathic – Inability of tissue to utilise supplied oxygen (e.g. cyanide poisoning).

Table 2 Causes of arterial hypoxaemia

1) Low partial pressure of inspired oxygen: barometric pressure and FIO2

2) Hypoventilation

3) Diffusion barrier

4) Shunt

5) Low V/Q

a. Proximal airway obstruction (Table 3)

b. Loss of alveolar lumen with cellular material (consolidation) or fluid\

c. Atelectasis

6) Venous desaturation


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Table 3 Causes of proximal airway obstruction leading to alveolar hypoventilation

1) Plugging of airway

a) Mucous plug

b) Blood

c) Inhaled foreign body

d) Shed airway epithelium

e) Froth

2) Compression from outside the airway

a) Enlarged lymph nodes

b) Haematoma

3) Lesions arising from the airway wall

a) Mucosal oedema

4) Other

a) Airway transection and displacement

Table 4 Causes of alveolar hypoventilation and their immediate treatment

Cause of low V/Q Immediate solution to improve oxygenation

Proximal airway obstruction Mechanical relief

Occupation of alveolar air space, cellular None

Occupation of alveolar air space, liquid:

- ↑ capillary filtration pressure

- low plasma oncotic pressure

- Ø endothelial reflection coefficient

- Ø lymphatic drainage

- Ø endothelial reflection coefficient

- loss of surfactant

- Ø alveolar fluid reabsorption

Reduce pulmonary venous hypertension Ædiuretics, arterial vasodilators (to reduce left-ventricular end-diastolic pressure) and pulmonaryvenodilators

None

None

Reduce CVP Æ diuretics & venodilators

None

Replacement therapy?

b-adrenoreceptor agonists, PEEP

Atelectasis

- loss of surfactant

- compression

- absorption

- reversed ventilation gradient

Recruitment & PEEP, ± sigh?

Replacement therapy?

Minimise alveolar & interstitial oedema, prone

Minimise FIO2

Spontaneous ventilation, prone


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Figures

Figure 1 Collapse of the left lung due to mucus plugging of a bronchus.

Figure 2 Left: Computerised tomography of the chest in a patient with the Acute Respiratory Distress

Syndrome. Right: Diagram illustrating three distinct lung regions9—A, normally aerated and ventilated

lung; B, atelectatic lung, and C, consolidated lung. Atelectatic lung (B) divides into two sub-regions—B1,

tidally recruited lung (type A atelectasis), and B2, recruitable lung (type B atelectasis).


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Figure 3 Theoretical frequency distibution of alveolar (Type A)opening times during theinspiratory cycle


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Figure 4 Diagram of the static inflation pressure/volume curve. Three distinct segments are

recognized during inflation; an initial phase of low compliance terminating at the lower

inflection point (sometimes called Pflex), a segment of higher compliance which is constant and

which ends at the upper inflection point, and a final segment of diminishing compliance

starting at the upper inflection point and ending at total lung capacity.


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Figure 5 Diagram of the static inflation (blue) and deflation (green) pressure/volume curve.

Inflation and deflation traces are distinct, a phenomenon termed ‘hysteresis’, which is

explained by the effects of alveolar recruitment and the visco-elastic properties of the lung.

Ventilatory Strategies For Arterial Hypoxaemia: A Peep Into ...

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