Non-ventilatory treatment of acute hypoxic
respiratory failure
J Duncan Young
Nuffield Department of Anaesthetics, Raddiffe Infirmary, Oxford, UK
Severe acute hypoxic respiratory failure is uncommon but often fatal. Standard
treatment involves high inspired oxygen concentrations, mechanical ventilation
and positive end-expiratory pressure. Many other interventions have been used
in parallel with conventional treatment or as rescue therapy when it fails,
including extracorporeal gas exchange, prone positioning, inhaled vasodilators,
exogenous surfactants and drugs which modify the inflammatory process.
Nearly all these treatments improve arterial oxygenation or markers of lung
injury. However, the relationship between oxygenation and survival in acute
hypoxaemic respiratory failure is not established, so improved oxygenation
cannot be used as a surrogate for survival. Randomised controlled trials are,
therefore, needed to assess the effects of these treatments on mortality. In such
trials, extracorporeal oxygenation and extracorporeal carbon dioxide
elimination, surfactant, early methylprednisolone, and prostaglandin E, offer no
survival advantage over conventional therapy. Prophylactic ketoconazole and
pentoxifylline appear to improve mortality in small studies in surgical and
oncology patients respectively, and methylprednisolone improves mortality and
morbidity in unresolving disease.
Correspondence to:
Dr J D Young, Nuffield
Department of
Anaesthetics, Raddiffe
Infirmary, Woodstock Rd,
Oxford OX2 6HE, UK
Acute hypoxic respiratory failure is an uncommon disease, with an
incidence of between 1.5 and 5 cases per 100,000 population per year1.
Only a limited number of these patients have severe acute hypoxic
respiratory failure in which the hypoxaemia is unresponsive to
conventional respiratory support with mechanical ventilation,
supplemental oxygen and positive end-expiratory pressure (PEEP).
Estimates of the incidence of severe hypoxic respiratory failure are
difficult to find. A cross sectional study in Berlin identified 3.6% of all
patients with acute respiratory failure2. The UK APACHE II database
shows that only 1% of all intensive care unit (ICU) admissions had a PaO2
of less than 50 mmHg (6.7 kPa) in the first 24 h of admission. Using these
figures leads to an estimate of 1000-2000 cases of acute severe hypoxic
respiratory failure in the UK per year, spread over about 250 ICUs. The
mortality for this group of patients is probably 40-60 %3, although a wide
Bnthh Medical Bulletin 1999;55 (No. 1): 165-180
C The British Council 1999
Intensive care medicine
Table 1 The commonest non-ventilatory treatments for acute hypoxic respiratory failure,
and the level of evidence supporting their use
Published
randomised
controlled trial?
Survival
benefit
demonstrated?
Extracorporeal membrane oxygenation
Yes
No
57
Extracorporeal CO2 removal
Yes
No
64
Prone position
No
No
Intravenous oxygenators
No
No
Inhaled nitric oxide
No
No
Inhaled prostacychn
No
No
Surfactant
Yes
No
30
Corticosteroids
Yes
Yes#
67, 68, 71
55
Treatment
References
toRCTs
Ketaconazole
Yes
Yes*
Prostaglandin E,
Yes
No
56
N-acetylcysteine
Yes
No
75
Pentoxyifylline
Yes
Yes*
74
*Prophylactic use; #only in late, unresolving disease.
range of estimates have been published. Acute hypoxic respiratory failure
is usually secondary to another condition and it is clear that the majority
of patients die from the underlying disease rather than pulmonary
insufficiency. Estimates of the number of patients dying of (rather than
with) acute hypoxic respiratory failure vary between 16% and 40% 4r5 of
all patients with acute hypoxic respiratory failure. Thus the population
likely to derive a survival benefit from advanced methods of respiratory
support in the UK is between 160 and 800 patients per year, or between
0.02% and 0 . 1 % of all deaths in the UK.
As the patients likely to derive a survival benefit from a new intervention
represent a small fraction of those with acute respiratory failure, trials of
novel interventions need to be very large to show a survival benefit. Nearly
all those cited in this review show no benefit but they are mostly small and
the results may merely reflect the limited power of the studies.
The adult (acute) respiratory distress syndrome (ARDS) and acute lung
injury (ALI) are both forms of acute hypoxic respiratory failure. ARDS is
defined as acute hypoxaemic respiratory failure with a PaO2/FiO2 of less
than 200 mmHg (26.3 kPa) with bilateral pulmonary infiltrates on chest
radiograph in the absence of cardiac causes, ALI is the same but the
PaO 2 /nO 2 ratio lies between 300 and 200 mmHg (39.5-26.3 kPa)6. These
definitions are of little practical value, essentially dividing all patients with
acute hypoxic respiratory failure into two groups based on oxygenation.
There is no clear treatment change or mortality change across the oxygenation threshold. For these reasons the term acute hypoxic respiratory
failure will be used in this review.
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Non-ventilatory support of respiratory failure
Fig. 1 The effect of
prone position on
lung density. This
shows a computerprocessed crosssectional CT scan of
the lungs of a patient
with acute hypoxic
respiratory failure in
the supine (upper
panel) and prone
(lower panel) position.
The lung density is
high in the black areas
and lower in the
white areas. On
turning prone the
dependent collapse
(high density areas) of
the right lung partially
re-expands whilst
some dependent
collapse begins to
occur in the left lung.
Modified from
Gattinoni eta/11.
Supine
Prone
This review covers non-ventilatory treatment options for acute hypoxic
respiratory failure (Table 1), the ventilatory strategies and concomitant
treatments such as nutrition and antibiotics are covered elsewhere.
Prone position
When patients develop acute hypoxic respiratory failure, their lungs
increase in density because of fluid accumulation (non-cardiogenic pulmonary oedema). Lung weight can increase to at least twice normal,
whether measured by computerised tomography (CT) or by double
indicator techniques7'8. The majority of patients are ventilated lying
supine, and in this position the weight of the upper (ventral or anterior)
part of the lung compresses the dependent (dorsal or posterior) parts. As
the compliance of the dependent part of the lung is effectively reduced, the
non-dependent portion receives more ventilation and the dependent areas
tend to collapse. The extent of this collapse (as determined by CT
scanning) is directly related to the degree of ventilation/perfusion
mismatching7 and hence hypoxaemia. A similar, although less severe,
effect occurs after the induction of anaesthesia and the associated
reduction in functional residual capacity9 and has been termed
'compression atelectasis'.
It has been known since 1977 that the prone position improves oxygenation in patients with acute respiratory failure10. This study showed an
British Medical Bulletin 1999;55 (No. 1)
167
Intensive care medicine
initial mean improvement in oxygenation of 9.1 kPa, subsequent
investigations showed similar improvements attributable to decompression and opening of atelectatic regions in the previously dependent
areas of the lung, and was elegantly demonstrated by Gattinoni et al using
computerised tomography (Fig. I) 11 .
The re-opening of previously dependent atelectatic areas is accompanied
by a gradual collapse of the now-dependent ventral portion of the lung,
which may reduce the benefit of the prone position over time. Regular
turning of the patient may be the best way to preserve oxygenation.
However, there are also good reasons why the prone position per se, rather
than positional changes, may maintain better oxygenation. Human lungs
are approximately triangular in cross section with considerably more lung
tissue dorsally than ventrally. Thus, in the supine position, a greater
fraction of the lung tissue may be at risk from atelectasis. In addition, the
weight of the heart and mediastinal structures may contribute to lung
compression in the supine position. In other mammalian species, lung
density is more evenly distributed in the prone position, even in the sloth
which normally lives supine, implying that the cardiorespiratory system
has evolved to function optimally in the prone position12713.
Clinical studies have nearly all shown an improvement in oxygenation
with a change from supine to prone position14"18, but those showing a
survival or length of stay advantage have used historical controls and
small numbers18'19. A large randomised controlled trial underway in Italy
is as yet incomplete20. There are obvious practical risks involved in turning
critically ill patients including pressure damage to tissues and dislodgement of therapeutic and monitoring catheters, which must be weighed
against the unproved benefit of the prone position.
Inhaled treatments
Surfactant
Premature infants are unable to produce functionally active surfactant,
leading to a condition known as infant respiratory distress syndrome
(IRDS) or hyaline membrane disease. Exogenous surfactant can be used
prophylactically to reduce both the incidence and severity of IRDS21, or
used to treat established IRDS22'23, and is now a standard treatment for the
condition. In 1979, abnormal surfactant function was shown in lavage
fluid from the lungs of patients who died from ARDS24, and both functional and biochemical surfactant abnormalities have since been described25. These may be caused by inhibitors present in the alveolar lining
fluid, oxidation of the phospholipid or apoprotein moieties of surfactant,
or damage to the type II pneumocytes which produce the surfactant26.
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Non-ventilatory support of respiratory failure
The success of trials of surfactant in IRDS and the identification of
abnormal surfactant function in acute respiratory failure led to trials of
surfactant in adults. Results were conflicting, an improvement in
oxygenation being seen in some studies but not all27""29. However, a large
(n = 725) randomised controlled trial of aerosolised surfactant to treat
adult acute hypoxic respiratory failure failed to show any change in gas
exchange or outcome30, and so there is no clear evidence this treatment is
of value.
Inhaled nitric oxide
Nitric oxide is an major endogenous mediator of multiple physiological
processes. It is a powerful vasodilator, normally released from vascular
endothelium in response to shear stress in order to match vessel calibre to
blood flow. Nitric oxide released from the endothelium activates guanylate cyclase in the underlying vascular smooth muscle cells, increasing
intracellular cyclic guanosine monophosphate which in turn reduces
cytosolic calcium concentrations and causes relaxation. Nitric oxide only
acts locally in the circulation, being rapidly inactivated by combining with
oxyhaemoglobin to form inorganic nitrates and methaemoglobin.
When exogenous gaseous nitric oxide is inhaled, it diffuses into the outer
(ablumenal) surface of pulmonary blood vessels, which are adjacent to the
alveoli and alveolar ducts. Under physiological conditions this has no
effect, as the normal pulmonary vascular tone is very low31, but if there is
pulmonary vasoconstriction nitric oxide reduces pulmonary vascular
resistance. This was first reported in patients with pulmonary hypertension32 where inhaled nitric oxide was as effective as intravenous prostacyclin at reducing pulmonary vascular resistance, but with no systemic side
effects. When inhaled nitric oxide is administered to patients with acute
hypoxic respiratory failure, the vasodilator effect is confined to ventilated
areas of the lung, improving ventilation/perfusion matching and thereby
oxygenation as well as reducing pulmonary vascular resistance. By
contrast, intravenously administered vasodilators non-selectively vasodilate the lung, reversing hypoxic pulmonary vasoconstriction and worsening ventilation/perfusion matching.
The effects of inhaled nitric oxide in patients with acute hypoxic
respiratory failure were first demonstrated by Rossaint and colleagues33
who showed a mean increase in the PaO2/FIO2 ratio of 6.2 kPa and a
reduction of 7 mmHg in mean pulmonary artery pressure when patients
with acute hypoxic respiratory failure where given 18 ppm (parts per
million) inhaled nitric oxide. This finding has subsequently been
repeatedly confirmed.
The dose of nitric oxide used appears to be quite important. Increasing
the dose administered to 100 ppm causes increasing vasodilatation, but
British Medial Bulletin 1999;55 (No. 1)
169
Intensive care medicine
between 10 and 100 ppm any improvement in oxygenation begins to
diminish34. This is probably because at higher doses pharmacologically
active doses of nitric oxide reach relatively underventilated alveoli,
increasing blood flow through areas with low ventilation/perfusion
ratios. This would also explain the limited or paradoxical effect of nitric
oxide in patients with chronic obstructive pulmonary disease35-36.
The efficacy of nitric oxide can be increased by simultaneous infusion of
pulmonary vasoconstrictors, which augment vasoconstriction in the
underventilated lung regions but are antagonised in the better ventilated
areas. The most commonly used vasoconstrictor is almitrine37, although
phenylephrine and the nitric oxide synthase inhibitor L-NMMA
(monomethylarginine) have been used clinically or experimentally. The
effects of nitric oxide, prone positioning and almitrine are all additive15-38.
There have been no definitive randomised controlled trials of nitric
oxide in adult acute hypoxic respiratory failure published to date. A phase
II (dose-ranging/efficacy) study involving 177 patients showed a possible
survival benefit with 5 ppm nitric oxide in a post hoc analysis39. A panEuropean study was stopped prematurely when 268 patients had been
enrolled because of poor recruitment. No survival advantage was seen.
The French GENOA study recruited 203 patients and again showed no
survival advantage. Both the European and GENOA studies remain
unpublished.
All the larger studies and case series published to date have shown that
about 60-70% of patients with acute respiratory failure have a clinically
useful increase in their PaO2 after nitric oxide is administered. Although
widely used in intensive care units throughout the world, it is not at all
certain that inhaled nitric oxide will eventually be shown to improve
outcome. Fortunately, nitric oxide seems to have few serious side effects,
the most important being rebound pulmonary hypertension on abrupt
withdrawal40.
As with ECMO, the situation with neonates is different. Neonates with
hypoxic respiratory failure treated with nitric oxide require ECMO far
less frequently than control infants41 and, thereby, avoid an expensive,
invasive therapy that carries with it the potential for neurological damage.
Nitric oxide will probably be licensed first for neonatal use.
Other inhaled therapies
Any drug that is a pulmonary vasodilator, has a short half life in the
systemic circulation and can be nebulised should have an effect similar
to inhaled nitric oxide. Nebulised prostacyclin has been most studied
clinically and appears to have similar efficacy to inhaled nitric oxide in
improving oxygenation and reducing pulmonary vascular resistance
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British Medical Bulletin 1999;55 (No. 1)
Non-ventilatory support of respiratory failure
with virtually no systemic effects42'43. The pulmonary selectivity of
nebulised prostacyclin is usually attributed to its short half life, drug
absorbed by the lungs being significantly metabolised before it reaches the
systemic circulation. This is probably not the case, because the prostacyclin
analogue iloprost, which has a much longer half life than prostacyclin, has
a similar selectivity for the pulmonary circulation when inhaled. In
addition, intravenous infusions of prostacyclin cause much greater
reductions in systemic vascular resistance for equivalent pulmonary effects
when compared with inhaled prostacyclin44. It is probably the high local
concentrations in the lungs which confer the pulmonary selectivity. If this
is correct, most vasodilators should show pulmonary selectivity when
inhaled. Experimental work has shown other prostaglandins and nitrodilators to also be effective. It is also possible that endogenous pulmonary
nitric oxide production is impaired in acute lung injury, and is limited by
the availability of the cofactor for nitric oxide synthase, tetrahydrobiopterin (BH4). If this is the case, nebulised BH4 may improve oxygenation
in acute respiratory failure45. There are no randomised controlled trials of
the effects of any of these treatments on outcome.
Intravenous vasoconstrictors and vasodilators
Pulmonary hypertension is almost universal in acute hypoxic respiratory
failure46. Some of the increase in pulmonary artery pressure is due to
raised intrathoracic and left atrial pressures, but there is also an increase
in pulmonary vascular resistance, due to a combination of mechanical
damage to pulmonary vessels and vasoconstriction. The pulmonary
hypertension increases right ventricular afterload with the potential for
right ventricular strain, and may increase lung water. There have been
several studies of intravenous pulmonary vasodilators such as nitroprusside, ketaserin, diltiazem, and acetylcholine47"*9. These all have shown
a reduction in pulmonary artery pressures, usually accompanied by a
reduction in systemic pressures. However, the usefulness of these treatments is limited, because they all cause a reduction in PaO 2 which is the
result of worsening ventilation/perfusion matching in the lung48-49
probably because of reversal of hypoxic pulmonary vasoconstriction.
With the increasing use of inhaled nitric oxide and prostacyclin, which
reduce pulmonary artery pressures and improve oxygenation, there is now
little place for intravenous pulmonary vasodilators in the management of
acute hypoxic respiratory failure.
Pulmonary vasoconstrictors tend to increase PaO 2 in acute respiratory
failure. Almitrine is known to augment hypoxic pulmonary vasoconstriction 50 , and improves ventilation/perfusion matching in ARDS51,
but at the cost of increased pulmonary artery pressure. Almitrine is now
Britlih Medical Bulletin 1999;55 (No. 1)
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Intensive care medicine
Arachidonic acid
Prostaglandin synthase
(cyclo-oxygenase)
Fig. 2 The arachidonic
acid pathway. Note
that cyclo-oxygenase
inhibitors are highly
non-selective.
most commonly used in combination with nitric oxide rather than as a sole
agent.
Drugs acting on the metabolism of arachidonic acid
The products of arachidonic acid metabolism, the thromboxanes,
prostaglandins and leukotrienes, have all been implicated in animal
models studying the pathogenesis of ARDS (Fig. 2). Studying patients
undergoing oesophagectomy, Schilling et al51 were able to demonstrate
an early increase in pulmonary production of thromboxane A2 in
patients who went on to develop ARDS. Thromboxane is a powerful
pulmonary vasoconstrictor which also promotes neutrophil
sequestration in the lung. Neutrophil production of the chemoattractant
leukotriene B4 also precedes the onset of respiratory failure53 and
prostacyclin levels are reduced in acute respiratory failure54.
Ibuprofen is a non-specific cyclo-oxygenase 1 and 2 inhibitor and
decreases the production of both prostaglandins and thomboxanes.
Although not studied directly in patients with acute respiratory failure, a
large randomised controlled study (n = 455) of patients with sepsis treated
with ibuprofen showed no difference in respiratory complications
between treatment and placebo groups. It may be that any beneficial
blockade of thromboxane production was offset by the blockade of
potentially useful prostaglandins such as prostacyclin and prostaglandin
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Non-ventilatory support of respiratory failure
Ej which prevent platelet aggregation, cause vasodilatation and downregulate neutrophil-induced inflammatory responses.
This problem can be avoided by specifically blocking thromboxane
synthetase, which reduces thromboxane concentrations but leaves prostaglandin synthesis unchanged. Ketoconazole, an imidazole antifungal
agent, is a blocker of thromboxane synthetase and also inhibits leukotriene biosynthesis. A small randomised controlled trial of oral ketoconazole (n = 54) as a prophylactic measure in high risk surgical patients
showed a marked reduction in the incidence of ARDS in the treatment
group55 from 64% to 15%. This finding remains to be confirmed.
Replacing prostaglandins has also been attempted in patients with acute
hypoxic respiratory failure. The use of prostacyclin (prostaglandin IJ has
already been described under inhaled treatments. Prostaglandin Ej is an
anti-inflammatory prostaglandin which inhibits platelet aggregation and
vasodilates. It should, therefore, reduce the severity of ARDS. Two
randomised controlled studies have failed to confirm this. The first56
studied 100 patients; no difference between control and treatment groups
were seen. The second study used a liposomal preparation of prostaglandin Ej (n = 25) because the effects of the liposomes and prostaglandin
on neutrophils are additive. This showed a reduction in the time of
mechanical ventilation and a more rapid improvement in oxygenation.
No survival benefit was demonstrated, but the control group only
contained 8 patients so the power of the study was very limited.
Extra corporeal gas exchange
The development of safe cardiopulmonary bypass systems for cardiac
surgery, and especially membrane oxygenators which did not cause the
haemolysis associated with bubble oxygenators, inevitably led to their
use in the treatment of acute respiratory failure. The first patient who
survived long term extracorporeal oxygenation was reported in 1972.
Two main concepts have evolved since then, extracorporeal membrane
oxygenation (ECMO) and extracorporeal CO2 removal (ECCO2R).
ECMO is, in essence, identical to the cardiopulmonary bypass used for
cardiac surgery. Blood is removed from the cavae or right atrium, passed
through a pump and a membrane or hollow fibre oxygenator (artificial
lung), and replaced either in the arterial system (veno-arterial ECMO) or
back into the venous circulation (veno-venous ECMO). About half to
two-thirds of the patient's cardiac output has to pass through the membrane lung to allow adequate oxygen uptake, so in veno-arterial ECMO
the pulmonary blood flow is reduced, whereas in veno-venous ECMO it
is maintained.
British Medical Bulletin 1999,55 (No. 1)
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Intensive care medicine
Following reports of uncontrolled series of 150 and 215 patients treated
with ECMO with 10-15% survival, the only randomised control of
ECMO was reported in 197957. Ninety patients were studied, no survival
benefit was demonstrated. The study has been criticised because the venoarterial bypass would have caused pulmonary hypoperfusion, the
ventilator settings used for the patients on ECMO were not reduced to
allow 'lung rest', ECMO was instituted late, and many of the patients had
a particularly virulent viral pneumonia. In spite of these objections the
study has never been repeated. Since 1979, many case series of patients
treated with ECMO have been published58-59 claiming better results than
conventional treatment but all were uncontrolled, or used historical
controls. As the mortality of patients with ARDS treated without ECMO
is improving60, the interpretation of studies without concurrent controls is
almost impossible, and adult ECMO remains an unproved, speculative
treatment.
This situation only applies to adults with respiratory failure. Neonates
with severe respiratory failure clearly benefit from ECMO, the mortality
from the condition is nearly halved61. The use of ECMO in neonates is
outside the scope of this review and has been covered in a previous
edition of the British Medical Bulletin62.
A totally different approach to extracorporeal gas exchange was
pioneered by Gattinoni in Italy in the early 1980s. They reasoned that
ventilation, whilst initially life saving, worsened lung damage in the long
term and that this damage could be reduced by limiting lung movement.
To limit ventilator induced lung damage, they employed pressure-limited
ventilation at 3-4 breaths/min. In this situation, oxygenation can be
maintained by apnoeic oxygenation. To avoid the otherwise inevitable
hypercarbia, CO2 was removed in an extracorporeal circuit. As membrane
lungs can remove virtually all the CO2 from blood passing through them,
the total CO2 production can be removed with extracorporeal blood flows
of only 20-30% of cardiac output. The technique was termed LFPPVECCO2R (low frequency positive pressure ventilation - extracorporeal
CO2 removal). An initial case series of 43 patients showed good survival
rates compared with the ECMO study published 7 years previously63.
However, a subsequent randomised controlled trial64, scheduled to recruit
60 patients but terminated at 40 patients after interim analysis, showed
no survival benefit when compared to conventional treatment.
Two other techniques of non-pulmonary gas exchange have been
described. The IVOX (intra vena caval oxygenator or intravenous
oxygenator) is a bundle of hollow fibres inserted into the vena cavae via
the femoral vein, through which oxygen is drawn. Gas exchange takes
place between the gas in the lumen of the fibres and the blood around
the fibres. The risks of an extra-corporeal circuit can be avoided, but in
their current configuration the devices are inefficient and cannot
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Non-ventilatory support of respiratory failure
exchange enough gas to make them clinically useful65. Carbon dioxide
can also be eliminated as bicarbonate in dialysis systems66, but to date
there are no reported trials of this technique.
Currently there are no data to support the use of extracorporeal gas
exchange in acute hypoxic respiratory failure except as part of a
controlled trial.
Modifying the inflammatory response
Steroids
The early stages of acute hypoxic respiratory failure are characterised by
neutrophil margination and sequestration in the lungs, with release of
proteases, reactive oxygen species, hypohalites and free radicals. In
vitro, at least some of the response of neutrophils to activating stimuli
can be inhibited by corticosteroids. However, in a clinical setting, acute
hypoxic respiratory failure does not respond to early high dose
corticosteroid treatment with methylprednisolone. A randomised
controlled trial of 99 patients with acute hypoxic respiratory failure67
failed to show any benefit either in gas exchange parameters or 45 day
mortality when given four doses of 30 mg/kg methylprednisolone at the
beginning of their illness. Methylprednisolone also had no value as a
prophylactic measure to reduce the risk of acute hypoxic respiratory
failure in high-risk surgical patients68.
The acute respiratory distress syndrome has three phases, an early
exudative phase, an inflammatory phase and a later fibroproliferative
phase beginning after 7 or more days. Experimental evidence suggests
the later, fibrotic phase might be attenuated by corticosteroids. There is
limited evidence from case series that healing of the lung might be
accelerated by corticosteroids in the later phase of the disease69-70,
although the mortality from these series are within the expected range.
A recent randomised controlled trial71 showed both a survival advantage
and an improvement in morbidity (days on ventilation and other organ
dysfunction) in patients with acute hypoxic respiratory failure given a
tapering course of methylprednisolone for 32 days starting 8-9 days into
their illness. This improvement in outcome was not associated with an
increase in infections. Although statistically sound, the study design
resulted in very small numbers (n = 24) with only 8 patients in the
control group, so the matching of confounding factors between the
control and treatment groups may not have been ideal.
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Intensive care medicine
Modulation of neutrophil function
The pulmonary damage that occurs in acute hypoxic respiratory failure
may result from neutrophil sequestration in pulmonary vessels, followed
by activation and migration of the neutrophils into the lung. This results
in the dense neutrophilic infiltration of the interstitium seen on
histological section, neutrophils in lavage fluid and an increased
concentration of proteolytic enzymes in lavage fluid. The trigger for the
neutrophil activation and chemotaxis may be interleukin-8, which is
present in high concentrations in the blood and lavage fluid of patients
with acute hypoxic respiratory failure72. Neutrophils induce tissue
damage by oxidative damage and proteolysis, leading to the changes
seen in the lungs of patients with acute hypoxic respiratory failure.
Pentoxifylline is a phosphodiesterase inhibitor which increases red cell
deformability and so improves capillary flow. It has been used to treat
peripheral vascular disease, but it also has a major inhibitory effect on
neutrophils, reducing their adherence and superoxide and proteolytic
enzyme production. In experimental models it reduces the severity of
acute hypoxic respiratory failure73. A study of cancer patients at risk from
acute respiratory failure showed both the severity and mortality of the
respiratory failure was reduced by prophylactic use of pentoxifylline74,
there are no data available on its efficacy in established respiratory failure.
Antioxidants can be given to reduce the oxidative damage done by
neutrophils. The only compound studied in detail is N-acetylcysteine,
commonly used to treat paracetamol poisoning. In a randomised
controlled trial of 42 patients, N-acetylcysteine did not alter the severity
of acute hypoxic respiratory failure75. Another small study compared Nacetylcysteine, L-2-oxothiazolidine-4-carboxylate (another antioxidant), and placebo in a total of 46 patients and found a slight benefit
in terms of speed of recovery with both the anti-oxidants, although
mortality was unchanged76. Superoxide levels can be reduced by giving
exogenous superoxide dismutase. Although this has been evaluated in
neonatal respiratory failure77 there are no reports in adults.
Conclusion
There are many observational studies of non-ventilatory treatments using
short-term pathophysiological changes as outcome measures in patients
with acute hypoxic respiratory failure. However, there are very few
randomised controlled studies using mortality as an endpoint and many
of these may be considerably underpowered because of an overestimation
of the population likely to benefit. Extracorporeal oxygenation and
extracorporeal CO2 elimination, surfactant, early methylprednisolone,
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Non-ventilatory support of respiratory failure
and prostaglandin Ej provide no major survival advantage over
conventional therapy. Prophylactic ketoconazole and pentoxifylline
appear to improve mortality in small studies in surgical and oncology
patients, respectively, and unresolving disease may respond to a long
course of methylprednisolone. The mainstays of treatment of acute
hypoxic respiratory failure are still appropriate treatment of the
precipitating disease and careful ventilatory support.
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