Non-ventilatory treatment of acute hypoxic respiratory failure · Acute hypoxic respiratory failure is an uncommon disease, with an incidence of between 1.5 and 5 cases per 100,000

Non-ventilatory treatment of acute hypoxicrespiratory failure

J Duncan YoungNuffield Department of Anaesthetics, Raddiffe Infirmary, Oxford, UK

Severe acute hypoxic respiratory failure is uncommon but often fatal. Standardtreatment involves high inspired oxygen concentrations, mechanical ventilationand positive end-expiratory pressure. Many other interventions have been usedin 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 lunginjury. However, the relationship between oxygenation and survival in acutehypoxaemic respiratory failure is not established, so improved oxygenationcannot be used as a surrogate for survival. Randomised controlled trials are,therefore, needed to assess the effects of these treatments on mortality. In suchtrials, extracorporeal oxygenation and extracorporeal carbon dioxideelimination, surfactant, early methylprednisolone, and prostaglandin E, offer nosurvival advantage over conventional therapy. Prophylactic ketoconazole andpentoxifylline appear to improve mortality in small studies in surgical andoncology patients respectively, and methylprednisolone improves mortality andmorbidity in unresolving disease.

Correspondence to:Dr J D Young, Nuffield

Department ofAnaesthetics, Raddiffe

Infirmary, Woodstock Rd,Oxford OX2 6HE, UK

Acute hypoxic respiratory failure is an uncommon disease, with anincidence of between 1.5 and 5 cases per 100,000 population per year1.Only a limited number of these patients have severe acute hypoxicrespiratory failure in which the hypoxaemia is unresponsive toconventional respiratory support with mechanical ventilation,supplemental oxygen and positive end-expiratory pressure (PEEP).Estimates of the incidence of severe hypoxic respiratory failure aredifficult to find. A cross sectional study in Berlin identified 3.6% of allpatients with acute respiratory failure2. The UK APACHE II databaseshows 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 thesefigures leads to an estimate of 1000-2000 cases of acute severe hypoxicrespiratory failure in the UK per year, spread over about 250 ICUs. Themortality 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

Treatment

Extracorporeal membrane oxygenation

Extracorporeal CO2 removal

Prone position

Intravenous oxygenators

Inhaled nitric oxide

Inhaled prostacychn

Surfactant

Corticosteroids

Ketaconazole

Prostaglandin E,

N-acetylcysteine

Pentoxyifylline

Publishedrandomised

controlled trial?

Yes

Yes

No

No

No

No

Yes

Yes

Yes

Yes

Yes

Yes

Survivalbenefit

demonstrated?

No

No

No

No

No

No

No

Yes#

Yes*

No

No

Yes*

ReferencestoRCTs

57

64

30

67, 68, 71

55

56

75

74

*Prophylactic use; #only in late, unresolving disease.

range of estimates have been published. Acute hypoxic respiratory failureis usually secondary to another condition and it is clear that the majorityof patients die from the underlying disease rather than pulmonaryinsufficiency. Estimates of the number of patients dying of (rather thanwith) acute hypoxic respiratory failure vary between 16% and 40%4r5 ofall patients with acute hypoxic respiratory failure. Thus the populationlikely to derive a survival benefit from advanced methods of respiratorysupport in the UK is between 160 and 800 patients per year, or between0.02% and 0 .1% of all deaths in the UK.

As the patients likely to derive a survival benefit from a new interventionrepresent a small fraction of those with acute respiratory failure, trials ofnovel interventions need to be very large to show a survival benefit. Nearlyall those cited in this review show no benefit but they are mostly small andthe results may merely reflect the limited power of the studies.

The adult (acute) respiratory distress syndrome (ARDS) and acute lunginjury (ALI) are both forms of acute hypoxic respiratory failure. ARDS isdefined as acute hypoxaemic respiratory failure with a PaO2/FiO2 of lessthan 200 mmHg (26.3 kPa) with bilateral pulmonary infiltrates on chestradiograph in the absence of cardiac causes, ALI is the same but thePaO2/nO2 ratio lies between 300 and 200 mmHg (39.5-26.3 kPa)6. Thesedefinitions are of little practical value, essentially dividing all patients withacute hypoxic respiratory failure into two groups based on oxygenation.There is no clear treatment change or mortality change across the oxygen-ation threshold. For these reasons the term acute hypoxic respiratoryfailure will be used in this review.

166 British Medical Bulletin 1999;55 (No. 1)

Non-ventilatory support of respiratory failure

Fig. 1 The effect ofprone position onlung density. This

shows a computer-processed cross-

sectional CT scan ofthe lungs of a patient

with acute hypoxicrespiratory failure in

the supine (upperpanel) and prone

(lower panel) position.The lung density is

high in the black areasand lower in thewhite areas. On

turning prone thedependent collapse

(high density areas) ofthe right lung partially

re-expands whilstsome dependent

collapse begins tooccur in the left lung.

Modified fromGattinoni eta/11.

Supine

Prone

This review covers non-ventilatory treatment options for acute hypoxicrespiratory failure (Table 1), the ventilatory strategies and concomitanttreatments such as nutrition and antibiotics are covered elsewhere.

Prone position

When patients develop acute hypoxic respiratory failure, their lungsincrease in density because of fluid accumulation (non-cardiogenic pul-monary oedema). Lung weight can increase to at least twice normal,whether measured by computerised tomography (CT) or by doubleindicator techniques7'8. The majority of patients are ventilated lyingsupine, and in this position the weight of the upper (ventral or anterior)part of the lung compresses the dependent (dorsal or posterior) parts. Asthe compliance of the dependent part of the lung is effectively reduced, thenon-dependent portion receives more ventilation and the dependent areastend to collapse. The extent of this collapse (as determined by CTscanning) is directly related to the degree of ventilation/perfusionmismatching7 and hence hypoxaemia. A similar, although less severe,effect occurs after the induction of anaesthesia and the associatedreduction in functional residual capacity9 and has been termed'compression atelectasis'.

It has been known since 1977 that the prone position improves oxygen-ation in patients with acute respiratory failure10. This study showed an

British Medical Bulletin 1999;55 (No. 1) 167


initial mean improvement in oxygenation of 9.1 kPa, subsequentinvestigations showed similar improvements attributable to decom-pression and opening of atelectatic regions in the previously dependentareas of the lung, and was elegantly demonstrated by Gattinoni et al usingcomputerised tomography (Fig. I)11.

The re-opening of previously dependent atelectatic areas is accompaniedby a gradual collapse of the now-dependent ventral portion of the lung,which may reduce the benefit of the prone position over time. Regularturning of the patient may be the best way to preserve oxygenation.However, there are also good reasons why the prone position per se, ratherthan positional changes, may maintain better oxygenation. Human lungsare approximately triangular in cross section with considerably more lungtissue dorsally than ventrally. Thus, in the supine position, a greaterfraction of the lung tissue may be at risk from atelectasis. In addition, theweight of the heart and mediastinal structures may contribute to lungcompression in the supine position. In other mammalian species, lungdensity is more evenly distributed in the prone position, even in the slothwhich normally lives supine, implying that the cardiorespiratory systemhas evolved to function optimally in the prone position12713.

Clinical studies have nearly all shown an improvement in oxygenationwith a change from supine to prone position14"18, but those showing asurvival or length of stay advantage have used historical controls andsmall numbers18'19. A large randomised controlled trial underway in Italyis as yet incomplete20. There are obvious practical risks involved in turningcritically ill patients including pressure damage to tissues and dislodge-ment of therapeutic and monitoring catheters, which must be weighedagainst 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 usedprophylactically to reduce both the incidence and severity of IRDS21, orused to treat established IRDS22'23, and is now a standard treatment for thecondition. In 1979, abnormal surfactant function was shown in lavagefluid from the lungs of patients who died from ARDS24, and both func-tional and biochemical surfactant abnormalities have since been des-cribed25. These may be caused by inhibitors present in the alveolar liningfluid, oxidation of the phospholipid or apoprotein moieties of surfactant,or damage to the type II pneumocytes which produce the surfactant26.



The success of trials of surfactant in IRDS and the identification ofabnormal surfactant function in acute respiratory failure led to trials ofsurfactant in adults. Results were conflicting, an improvement inoxygenation being seen in some studies but not all27""29. However, a large(n = 725) randomised controlled trial of aerosolised surfactant to treatadult acute hypoxic respiratory failure failed to show any change in gasexchange or outcome30, and so there is no clear evidence this treatment isof value.

Inhaled nitric oxide

Nitric oxide is an major endogenous mediator of multiple physiologicalprocesses. It is a powerful vasodilator, normally released from vascularendothelium in response to shear stress in order to match vessel calibre toblood flow. Nitric oxide released from the endothelium activates guanyl-ate cyclase in the underlying vascular smooth muscle cells, increasingintracellular cyclic guanosine monophosphate which in turn reducescytosolic calcium concentrations and causes relaxation. Nitric oxide onlyacts locally in the circulation, being rapidly inactivated by combining withoxyhaemoglobin 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 thealveoli and alveolar ducts. Under physiological conditions this has noeffect, as the normal pulmonary vascular tone is very low31, but if there ispulmonary vasoconstriction nitric oxide reduces pulmonary vascularresistance. This was first reported in patients with pulmonary hyper-tension32 where inhaled nitric oxide was as effective as intravenous prosta-cyclin at reducing pulmonary vascular resistance, but with no systemic sideeffects. When inhaled nitric oxide is administered to patients with acutehypoxic respiratory failure, the vasodilator effect is confined to ventilatedareas of the lung, improving ventilation/perfusion matching and therebyoxygenation as well as reducing pulmonary vascular resistance. Bycontrast, intravenously administered vasodilators non-selectively vaso-dilate the lung, reversing hypoxic pulmonary vasoconstriction and wor-sening ventilation/perfusion matching.

The effects of inhaled nitric oxide in patients with acute hypoxicrespiratory failure were first demonstrated by Rossaint and colleagues33

who showed a mean increase in the PaO2/FIO2 ratio of 6.2 kPa and areduction of 7 mmHg in mean pulmonary artery pressure when patientswith acute hypoxic respiratory failure where given 18 ppm (parts permillion) inhaled nitric oxide. This finding has subsequently beenrepeatedly confirmed.

The dose of nitric oxide used appears to be quite important. Increasingthe dose administered to 100 ppm causes increasing vasodilatation, but

British Medial Bulletin 1999;55 (No. 1) 169


between 10 and 100 ppm any improvement in oxygenation begins todiminish34. This is probably because at higher doses pharmacologicallyactive doses of nitric oxide reach relatively underventilated alveoli,increasing blood flow through areas with low ventilation/perfusionratios. This would also explain the limited or paradoxical effect of nitricoxide in patients with chronic obstructive pulmonary disease35-36.

The efficacy of nitric oxide can be increased by simultaneous infusion ofpulmonary vasoconstrictors, which augment vasoconstriction in theunderventilated lung regions but are antagonised in the better ventilatedareas. The most commonly used vasoconstrictor is almitrine37, althoughphenylephrine and the nitric oxide synthase inhibitor L-NMMA(monomethylarginine) have been used clinically or experimentally. Theeffects of nitric oxide, prone positioning and almitrine are all additive15-38.

There have been no definitive randomised controlled trials of nitricoxide in adult acute hypoxic respiratory failure published to date. A phaseII (dose-ranging/efficacy) study involving 177 patients showed a possiblesurvival benefit with 5 ppm nitric oxide in a post hoc analysis39. A pan-European study was stopped prematurely when 268 patients had beenenrolled because of poor recruitment. No survival advantage was seen.The French GENOA study recruited 203 patients and again showed nosurvival advantage. Both the European and GENOA studies remainunpublished.

All the larger studies and case series published to date have shown thatabout 60-70% of patients with acute respiratory failure have a clinicallyuseful increase in their PaO2 after nitric oxide is administered. Althoughwidely used in intensive care units throughout the world, it is not at allcertain that inhaled nitric oxide will eventually be shown to improveoutcome. Fortunately, nitric oxide seems to have few serious side effects,the most important being rebound pulmonary hypertension on abruptwithdrawal40.

As with ECMO, the situation with neonates is different. Neonates withhypoxic respiratory failure treated with nitric oxide require ECMO farless 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 thesystemic circulation and can be nebulised should have an effect similarto inhaled nitric oxide. Nebulised prostacyclin has been most studiedclinically and appears to have similar efficacy to inhaled nitric oxide inimproving oxygenation and reducing pulmonary vascular resistance



with virtually no systemic effects42'43. The pulmonary selectivity ofnebulised prostacyclin is usually attributed to its short half life, drugabsorbed by the lungs being significantly metabolised before it reaches thesystemic circulation. This is probably not the case, because the prostacyclinanalogue iloprost, which has a much longer half life than prostacyclin, hasa similar selectivity for the pulmonary circulation when inhaled. Inaddition, intravenous infusions of prostacyclin cause much greaterreductions in systemic vascular resistance for equivalent pulmonary effectswhen compared with inhaled prostacyclin44. It is probably the high localconcentrations in the lungs which confer the pulmonary selectivity. If thisis correct, most vasodilators should show pulmonary selectivity wheninhaled. Experimental work has shown other prostaglandins and nitro-dilators to also be effective. It is also possible that endogenous pulmonarynitric oxide production is impaired in acute lung injury, and is limited bythe availability of the cofactor for nitric oxide synthase, tetrahydro-biopterin (BH4). If this is the case, nebulised BH4 may improve oxygenationin acute respiratory failure45. There are no randomised controlled trials ofthe effects of any of these treatments on outcome.

Intravenous vasoconstrictors and vasodilators

Pulmonary hypertension is almost universal in acute hypoxic respiratoryfailure46. Some of the increase in pulmonary artery pressure is due toraised intrathoracic and left atrial pressures, but there is also an increasein pulmonary vascular resistance, due to a combination of mechanicaldamage to pulmonary vessels and vasoconstriction. The pulmonaryhypertension increases right ventricular afterload with the potential forright ventricular strain, and may increase lung water. There have beenseveral studies of intravenous pulmonary vasodilators such as nitro-prusside, ketaserin, diltiazem, and acetylcholine47"*9. These all have showna reduction in pulmonary artery pressures, usually accompanied by areduction in systemic pressures. However, the usefulness of these treat-ments is limited, because they all cause a reduction in PaO2 which is theresult 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, whichreduce pulmonary artery pressures and improve oxygenation, there is nowlittle place for intravenous pulmonary vasodilators in the management ofacute hypoxic respiratory failure.

Pulmonary vasoconstrictors tend to increase PaO2 in acute respiratoryfailure. Almitrine is known to augment hypoxic pulmonary vaso-constriction50, 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) 171


Arachidonic acid

Prostaglandin synthase(cyclo-oxygenase)

Fig. 2 The arachidonicacid pathway. Note

that cyclo-oxygenaseinhibitors are highly

non-selective.

most commonly used in combination with nitric oxide rather than as a soleagent.

Drugs acting on the metabolism of arachidonic acid

The products of arachidonic acid metabolism, the thromboxanes,prostaglandins and leukotrienes, have all been implicated in animalmodels studying the pathogenesis of ARDS (Fig. 2). Studying patientsundergoing oesophagectomy, Schilling et al51 were able to demonstratean early increase in pulmonary production of thromboxane A2 inpatients who went on to develop ARDS. Thromboxane is a powerfulpulmonary vasoconstrictor which also promotes neutrophilsequestration in the lung. Neutrophil production of the chemoattractantleukotriene B4 also precedes the onset of respiratory failure53 andprostacyclin levels are reduced in acute respiratory failure54.

Ibuprofen is a non-specific cyclo-oxygenase 1 and 2 inhibitor anddecreases the production of both prostaglandins and thomboxanes.Although not studied directly in patients with acute respiratory failure, alarge randomised controlled study (n = 455) of patients with sepsis treatedwith ibuprofen showed no difference in respiratory complicationsbetween treatment and placebo groups. It may be that any beneficialblockade of thromboxane production was offset by the blockade ofpotentially useful prostaglandins such as prostacyclin and prostaglandin

172 British Medical Bulletin 1999,55 (No 1)


Ej which prevent platelet aggregation, cause vasodilatation and down-regulate neutrophil-induced inflammatory responses.

This problem can be avoided by specifically blocking thromboxanesynthetase, which reduces thromboxane concentrations but leaves prosta-glandin synthesis unchanged. Ketoconazole, an imidazole antifungalagent, is a blocker of thromboxane synthetase and also inhibits leuko-triene biosynthesis. A small randomised controlled trial of oral keto-conazole (n = 54) as a prophylactic measure in high risk surgical patientsshowed a marked reduction in the incidence of ARDS in the treatmentgroup55 from 64% to 15%. This finding remains to be confirmed.

Replacing prostaglandins has also been attempted in patients with acutehypoxic respiratory failure. The use of prostacyclin (prostaglandin IJ hasalready been described under inhaled treatments. Prostaglandin Ej is ananti-inflammatory prostaglandin which inhibits platelet aggregation andvasodilates. It should, therefore, reduce the severity of ARDS. Tworandomised controlled studies have failed to confirm this. The first56

studied 100 patients; no difference between control and treatment groupswere seen. The second study used a liposomal preparation of prosta-glandin Ej (n = 25) because the effects of the liposomes and prostaglandinon neutrophils are additive. This showed a reduction in the time ofmechanical ventilation and a more rapid improvement in oxygenation.No survival benefit was demonstrated, but the control group onlycontained 8 patients so the power of the study was very limited.

Extra corporeal gas exchange

The development of safe cardiopulmonary bypass systems for cardiacsurgery, and especially membrane oxygenators which did not cause thehaemolysis associated with bubble oxygenators, inevitably led to theiruse in the treatment of acute respiratory failure. The first patient whosurvived long term extracorporeal oxygenation was reported in 1972.Two main concepts have evolved since then, extracorporeal membraneoxygenation (ECMO) and extracorporeal CO2 removal (ECCO2R).

ECMO is, in essence, identical to the cardiopulmonary bypass used forcardiac surgery. Blood is removed from the cavae or right atrium, passedthrough a pump and a membrane or hollow fibre oxygenator (artificiallung), and replaced either in the arterial system (veno-arterial ECMO) orback into the venous circulation (veno-venous ECMO). About half totwo-thirds of the patient's cardiac output has to pass through the mem-brane lung to allow adequate oxygen uptake, so in veno-arterial ECMOthe pulmonary blood flow is reduced, whereas in veno-venous ECMO itis maintained.

British Medical Bulletin 1999,55 (No. 1) 173


Following reports of uncontrolled series of 150 and 215 patients treatedwith ECMO with 10-15% survival, the only randomised control ofECMO was reported in 197957. Ninety patients were studied, no survivalbenefit was demonstrated. The study has been criticised because the veno-arterial bypass would have caused pulmonary hypoperfusion, theventilator settings used for the patients on ECMO were not reduced toallow 'lung rest', ECMO was instituted late, and many of the patients hada particularly virulent viral pneumonia. In spite of these objections thestudy has never been repeated. Since 1979, many case series of patientstreated with ECMO have been published58-59 claiming better results thanconventional treatment but all were uncontrolled, or used historicalcontrols. As the mortality of patients with ARDS treated without ECMOis improving60, the interpretation of studies without concurrent controls isalmost impossible, and adult ECMO remains an unproved, speculativetreatment.

This situation only applies to adults with respiratory failure. Neonateswith severe respiratory failure clearly benefit from ECMO, the mortalityfrom the condition is nearly halved61. The use of ECMO in neonates isoutside the scope of this review and has been covered in a previousedition of the British Medical Bulletin62.

A totally different approach to extracorporeal gas exchange waspioneered by Gattinoni in Italy in the early 1980s. They reasoned thatventilation, whilst initially life saving, worsened lung damage in the longterm and that this damage could be reduced by limiting lung movement.To limit ventilator induced lung damage, they employed pressure-limitedventilation at 3-4 breaths/min. In this situation, oxygenation can bemaintained by apnoeic oxygenation. To avoid the otherwise inevitablehypercarbia, CO2 was removed in an extracorporeal circuit. As membranelungs can remove virtually all the CO2 from blood passing through them,the total CO2 production can be removed with extracorporeal blood flowsof only 20-30% of cardiac output. The technique was termed LFPPV-ECCO2R (low frequency positive pressure ventilation - extracorporealCO2 removal). An initial case series of 43 patients showed good survivalrates compared with the ECMO study published 7 years previously63.However, a subsequent randomised controlled trial64, scheduled to recruit60 patients but terminated at 40 patients after interim analysis, showedno survival benefit when compared to conventional treatment.

Two other techniques of non-pulmonary gas exchange have beendescribed. The IVOX (intra vena caval oxygenator or intravenousoxygenator) is a bundle of hollow fibres inserted into the vena cavae viathe femoral vein, through which oxygen is drawn. Gas exchange takesplace between the gas in the lumen of the fibres and the blood aroundthe fibres. The risks of an extra-corporeal circuit can be avoided, but intheir current configuration the devices are inefficient and cannot



exchange enough gas to make them clinically useful65. Carbon dioxidecan also be eliminated as bicarbonate in dialysis systems66, but to datethere are no reported trials of this technique.

Currently there are no data to support the use of extracorporeal gasexchange in acute hypoxic respiratory failure except as part of acontrolled trial.

Modifying the inflammatory response

Steroids

The early stages of acute hypoxic respiratory failure are characterised byneutrophil margination and sequestration in the lungs, with release ofproteases, reactive oxygen species, hypohalites and free radicals. Invitro, at least some of the response of neutrophils to activating stimulican be inhibited by corticosteroids. However, in a clinical setting, acutehypoxic respiratory failure does not respond to early high dosecorticosteroid treatment with methylprednisolone. A randomisedcontrolled trial of 99 patients with acute hypoxic respiratory failure67

failed to show any benefit either in gas exchange parameters or 45 daymortality when given four doses of 30 mg/kg methylprednisolone at thebeginning of their illness. Methylprednisolone also had no value as aprophylactic measure to reduce the risk of acute hypoxic respiratoryfailure in high-risk surgical patients68.

The acute respiratory distress syndrome has three phases, an earlyexudative phase, an inflammatory phase and a later fibroproliferativephase beginning after 7 or more days. Experimental evidence suggeststhe later, fibrotic phase might be attenuated by corticosteroids. There islimited evidence from case series that healing of the lung might beaccelerated 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 advantageand an improvement in morbidity (days on ventilation and other organdysfunction) in patients with acute hypoxic respiratory failure given atapering course of methylprednisolone for 32 days starting 8-9 days intotheir illness. This improvement in outcome was not associated with anincrease in infections. Although statistically sound, the study designresulted in very small numbers (n = 24) with only 8 patients in thecontrol group, so the matching of confounding factors between thecontrol and treatment groups may not have been ideal.

British Medial Bulletin 1999;55 (No. 1) 175


Modulation of neutrophil function

Conclusion

The pulmonary damage that occurs in acute hypoxic respiratory failuremay result from neutrophil sequestration in pulmonary vessels, followedby activation and migration of the neutrophils into the lung. This resultsin the dense neutrophilic infiltration of the interstitium seen onhistological section, neutrophils in lavage fluid and an increasedconcentration of proteolytic enzymes in lavage fluid. The trigger for theneutrophil activation and chemotaxis may be interleukin-8, which ispresent in high concentrations in the blood and lavage fluid of patientswith acute hypoxic respiratory failure72. Neutrophils induce tissuedamage by oxidative damage and proteolysis, leading to the changesseen in the lungs of patients with acute hypoxic respiratory failure.

Pentoxifylline is a phosphodiesterase inhibitor which increases red celldeformability and so improves capillary flow. It has been used to treatperipheral vascular disease, but it also has a major inhibitory effect onneutrophils, reducing their adherence and superoxide and proteolyticenzyme production. In experimental models it reduces the severity ofacute hypoxic respiratory failure73. A study of cancer patients at risk fromacute respiratory failure showed both the severity and mortality of therespiratory 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 byneutrophils. The only compound studied in detail is N-acetylcysteine,commonly used to treat paracetamol poisoning. In a randomisedcontrolled trial of 42 patients, N-acetylcysteine did not alter the severityof acute hypoxic respiratory failure75. Another small study compared N-acetylcysteine, L-2-oxothiazolidine-4-carboxylate (another anti-oxidant), and placebo in a total of 46 patients and found a slight benefitin terms of speed of recovery with both the anti-oxidants, althoughmortality was unchanged76. Superoxide levels can be reduced by givingexogenous superoxide dismutase. Although this has been evaluated inneonatal respiratory failure77 there are no reports in adults.

There are many observational studies of non-ventilatory treatments usingshort-term pathophysiological changes as outcome measures in patientswith acute hypoxic respiratory failure. However, there are very fewrandomised controlled studies using mortality as an endpoint and manyof these may be considerably underpowered because of an overestimationof the population likely to benefit. Extracorporeal oxygenation andextracorporeal CO2 elimination, surfactant, early methylprednisolone,



and prostaglandin Ej provide no major survival advantage overconventional therapy. Prophylactic ketoconazole and pentoxifyllineappear to improve mortality in small studies in surgical and oncologypatients, respectively, and unresolving disease may respond to a longcourse of methylprednisolone. The mainstays of treatment of acutehypoxic respiratory failure are still appropriate treatment of theprecipitating disease and careful ventilatory support.

References

1 Garber BG, Hebert PC, Yelle JD, Hodder RV, McGowan J. Adult respiratory distress syndrome:a systemic overview of incidence and risk factors. Crit Cart Med 1996; 24: 687-95

2 Lewandowski K, Metz J, Deutschmann C et al. Incidence, severity, and mortality of acuterespiratory failure in Berlin, Germany. Am J Respir Crit Care Med 1995; 151: 1121-5

3 Vasilyev S, Schaap RN, Mortensen JD. Hospital survival rates of patients with acute respiratoryfailure in modern respiratory intensive care units. An international, multicentei; prospectivesurvey. Chest 1995; 107: 1083-8

4 Montgomery AB, Stager MA, Carnco CJ, Hudson LD. Causes of mortality in patients with theadult respiratory distress syndrome. Am Rev Respir Dis 1985; 132: 485-9

5 Suchyta MR, Clemmer TP, Elliott CG, Orme Jr JF, Weaver LK. The adult respiratory distresssyndrome. A report of survival and modifying factors. Chest 1992; 101: 1074-9

6 Bernard GR, Artigas A, Brigham KL et al. Report of the American—European consensusconference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination.The Consensus Committee. Intensive Care Med 1994; 20: 225-32

7 Gattinoni L, Pesenn A, Bombino M et al. Relationships between lung computed tomographicdensity, gas exchange, and PEEP in acute respiratory failure. Anesthesiology 1988; 69: 824-32

8 Sibbald WJ, Short AK, Warshawski FJ, Cunningham DG, Cheung H. Thermal dye measurementsof extravascular lung water in critically ill patients. Intravascular Starling forces and extravascularlung water in the adult respiratory distress syndrome. Chest 1985; 87: 585-92

9 Hedenstierna G. Gas exchange during anaesthesia. Ada Anaesthesiol Scand Suppl 1990; 94:27-31

10 Douglas WW, Rehder K, Beynen FM, Sessler AD, Marsh HM. Improved oxygenation in patientswith acute respiratory failure: the prone position. Am Rev Respir Dis 1977; 115: 559-66

11 Gattinoni L, Pelosi P, Vitale G, Pesenti A, D'Andrea L, Mascheroni D. Body position changesredistribute lung computed-tomographic density in patients with acute respiratory failure.Anesthesiology 1991; 74: 15-23

12 Hedenstierna G, Nyman G, Kvart C, Funkquist B. Ventilation-perfusion relationships in thestanding horse: an inert gas elimination study. Equine Vet J 1987; 19: 514-9

13 Hoffman EA, Ritman EL. Effect of body orientation on regional lung expansion in dog and sloth.] Appl Physiol 1985; 59: 481-91

14 Blanch L, Mancebo J, Perez M et al. Short-term effects of prone position in critically ill patientswith acute respiratory distress syndrome. Intensive Care Med 1997; 23: 1033-9

15 Jolliet P, Bulpa P, Ritz M, Ricou B, Lopez J, Chevrolet JC. Additive beneficial effects of the proneposition, nitric oxide, and almitrine bismesylate on gas exchange and oxygen transport in acuterespiratory distress syndrome. Crit Care Med 1997; 25: 786-94

16 Pelosi P, Croci M, Calappi E et al. Prone positioning improves pulmonary function in obesepatients during general anesthesia. Anesth Analg 1996; 83: 578-83

17 Pelosi P, Tubiolo D, Mascheroni D et al. Effects of the prone position on respiratory mechanicsand gas exchange during acute lung injury. Am] Respir Crit Care Med 1998; 157: 387-93

18 Stocker R, Neff T, Stein S, Ecknauer E, Trentz O, Russi E. Prone positioning and low-volumepressure-limited ventilation improve survival in patients with severe ARDS. Chest 1997; 111:1008-17



19 Summer W, Curry P, Haponik E, Nelson F, Elston R. Continuous mechanical turning of intensivecare patients shortens length of stay in some diagnostic-related groups. / Crit Care 1989; 4: 45-53

20 Gattinoni L, Tognoni G, Brazzi L, Latini R. Ventilation in the prone position. The Prone-SupineStudy Collaborative Group. Lancet 1997; 350: 815

21 Merritt TA, Hallman M, Bloom BT et al. Prophylactic treatment of very premature infants withhuman surfactant. N Engl J Med 1986; 315: 785-90

22 Raju TN, Vidyasagar D, Bhat R et al. Double-blind controlled trial of single-dose treatment withbovine surfactant in severe hyaline membrane disease. Lancet 1987; i: 651—6

23 Surfactant replacement therapy for severe neonatal respiratory distress syndrome: aninternational randomized clinical trial. Collaborative European Multicenter Study Group.Pediatrics 1988; 82: 683-91

24 Petty TL, Silvers GW, Paul GW, Stanford RE. Abnormalities in lung elastic properties andsurfactant function in adult respiratory distress syndrome. Chest 1979; 75: 571-4

25 Hallman M, Spragg R, Harrell JH, Moser KM, Gluck L. Evidence of lung surfactant abnormalityin respiratory failure. Study of bronchoalveolar lavage phospholipids, surface activity,phospholipase activity, and plasma myoinositol. / Clin Invest 1982; 70: 673-83

26 Spragg R. Abnormalities of lung surfactant function in patients with acute lung injury. In: ZapolW, Lemaire F (eds) Adult respiratory distress syndrome. New York: Marcel Dekker, 1991;381-95

27 Spragg RG, Gilliard N, Richman P et al. Acute effects of a single dose of porcine surfactant onpatients with the adult respiratory distress syndrome. Chest 1994; 105: 195-202

28 Weg JG, Balk RA, Tharratt RS et al. Safety and potential efficacy of an aerosolized surfactant inhuman sepsis-induced adult respiratory distress syndrome. JAMA 1994; 272: 1433-8

29 Gregory TJ, Steinberg KP, Spragg R et al. Bovine surfactant therapy for patients with acuterespiratory distress syndrome. Am J Respir Crit Care Med 1997; 155: 1309-15

30 Anzueto A, Baughman RP, Guntupalli KK et al. Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. Exosurf Acute Respiratory Distress Syndrome SepsisStudy Group. N Engl J Med 1996; 334: 1417-21

31 Frostell CG, Blomqvist H, Hedenstiema G, Lundberg J, Zapol WM. Inhaled nitric oxideselectively reverses human hypoxic pulmonary vasoconstriction without causing systemicvasodilation. Anesthesiology 1993; 78: 427-35

32 Pepke Zaba J, Higenbottam 1W, Dinh Xuan AT, Stone D, Wallwork J. Inhaled nimc oxide as acause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 1991; 338:1173-4

33 Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adultrespiratory distress syndrome. N Engl] Med 1993; 328: 399-405

34 Gerlach H, Rossaint R, Pappert D, Falke KJ. Time-course and dose-response of nitric oxideinhalation for systemic oxygenanon and pulmonary hypertension in patients with adultrespiratory distress syndrome. Em] Clin Invest 1993; 23: 499-502

35 Barbera JA, Roger N, Roca J, Rovira I, Higenbottam 1W, Rodriguez Roisin R. Worsening ofpulmonary gas exchange with nitric oxide inhalation in chronic obstructive pulmonary disease.Lancet 1996; 347: 436-40

36 Blanch L, Joseph D, Fernandez R et al. Hemodynamic and gas exchange responses to inhalationof nitric oxide in patients with the acute respiratory distress syndrome and in hypoxemic patientswith chronic obstructive pulmonary disease. Intensive Care Med 1997; 23: 51-7

37 Lu Q, Mourgeon E, Law Koune JD et al. Dose-response curves of inhaled nitric oxide with andwithout intravenous almitnne in nitric oxide-responding patients with acute respiratory distresssyndrome. Anesthesiology 1995; 83: 929-43

38 Papazian L, Bregeon F, Gaillat F et al. Respective and combined effects of prone position andinhaled nitric oxide in patients with acute respiratory distress syndrome. Am ] Respir Crit CareMed 1998; 157: 580-5

39 Dellinger RP, Zimmerman JL, Taylor RW et al. Effects of inhaled nitric oxide in patients withacute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxidein ARDS Study Group. Crit Care Med 1998; 26: 15-23

40 Petros AJ. Down-regulation of endogenous nitric oxide production after prolongedadministration. Lancet 1994; 344: 191

178 British Medical Bulletin 1999,55 (No. 1)


41 The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Ertgl J Med 1997; 336: 597-604

42 Zwissler B, Kemming G, Habler O et al. Inhaled prostacyclin (PGI2) versus inhaled nitric oxidein adult respiratory distress syndrome. Am J Respir Crtt Care Med 1996; 154: 1671-7

43 Walmrath D, Schneider T, Schermuly R, Olschewski H, Gnmminger F, Seeger W. Directcomparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distresssyndrome. Am J Respir Cnt Care Med 1996; 153: 991-6

44 Olschewski H, Walmrath D, Schermuly R, Ghofrani A, Grimminger F, Seeger W. Aerosolizedprostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med 1996; 124: 820-4

45 Walter R, Blau N, Schaffner A et al. Inhalation of the nitric oxide synthase cofactortetrahydrobiopterin in healthy volunteers. Am J Resptr Crit Care Med 1997; 156: 2006—10

46 Zapol WM, Snider MT. Pulmonary hypertension in severe acute respiratory failure. N EnglJ Med1977; 296: 476-80

47 Adnot S, Kouyoumdjian C, Defouilloy C et al. Hemodynamic and gas exchange responses toinfusion of acetylcholine and inhalation of nitric oxide in patients with chronic obstructive lungdisease and pulmonary hypertension. Am Rev Respir Dis 1993; 148: 310-6

48 Radermacher P, Huet Y, Pluskwa F et al. Comparison of ketanserin and sodium nitroprusside inpatients with severe ARDS. Anestbesiology 1988; 68: 152-7

49 Melot C, Naeije R, Mols P, Hallemans R, Lejeune P, Jaspar N. Pulmonary vascular tone improvespulmonary gas exchange in the adult respiratory distress syndrome. Am Rev Respir Dis 1987;136: 1232-6

50 Melot C, Dechamps P, Hallemans R, Decroly P, Mols P. Enhancement of hypoxic pulmonaryvasoconstriction by low dose almitrine bismesylate in normal humans. Am Rev Respir Dis 1989;139: 111-9

51 Reyes A, Roca J, Rodriguez Roisin R, Torres A, Usserri P, Wagner PD. Effect of almitrine onvennlation-perfusion distribution in adult respiratory distress syndrome. Am Rev Respir Dis1988; 137: 1062-7

52 Schilling MK, Gassmann N, Sigurdsson GH et al. Role of thromboxane and leukotriene Bt inpatients with acute respiratory distress syndrome after oesophagectomy. Br J Anaestb 1998; 80:36-40

53 Davis JM, Meyer JD, Barie PS et al. Elevated production of neutrophil leukotriene B4 precedespulmonary failure in critically ill surgical patients. Surg Gynecol Obstet 1990; 170: 495-500

54 Slotman GJ, Burchard KW, Gann DS. Thromboxane and prostacyclin in clinical acute respiratoryfailure. / Surg Res 1985; 39: 1-7

55 Yu M, Tomasa G. A double-blind, prospective, randomized trial of ketoconazole, a thromboxanesynthetase inhibitor, in the prophylaxis of the adult respiratory distress syndrome. Crit Care Med1993; 21: 1635-42

56 Bone RC, Slotman G, Maunder R et al. Randomized double-blind, multicenter study of prosta-glandin E, in patients with the adult respiratory distress syndrome. Prostaglandin E, StudyGroup. Chest 1989; 96: 114-9

57 Zapol WM, Snider MT, Hill JD et al. Extracorporeal membrane oxygenation in severe acuterespiratory failure. A randomized prospective study. JAMA 1979; 242: 2193-6

58 Peek GJ, Moore HM, Moore N, Sosnowski AW, Firmin RK. Extracorporeal membraneoxygenation for adult respiratory failure. Chest 1997; 112: 759-64

59 Lewandowski K, Rossaint R, Pappert D et al. High survival rate in 122 ARDS patients managedaccording to a clinical algorithm including extracorporeal membrane oxygenation. Intensive CareMed 1997; 23: 819-35

60 Suchyta MR, Clemmer TP, Orme Jr JF, Morris AH, Elliott CG. Increased survival of ARDSpatients with severe hypoxemia (ECMO criteria). Chest 1991; 99: 951-5

61 UK Collaborative ECMO Trail Group. UK collaborative randomised trial of neonatalextracorporeal membrane oxygenation. Lancet 1996; 348: 75-82

62 Peek GJ, Sosnowski AW. Extra-corporeal membrane oxygenation for paediatric respiratoryfailure. Br Med Bull 1997; 53: 745-56

63 Gattinoni L, Pesenti A, Mascheroni D et al. Low-frequency positive-pressure ventilation withextracorporeal CO2 removal in severe acute respiratory failure. JAMA 1986; 256: 881-6



64 Morris AH, Wallace CJ, Menlove RL et al. Randomized clinical trial of pressure-controlledinverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distresssyndrome. Am } Respir Crit Care Med 1994; 149: 295-305

65 High KM, Snider MT, Richard R et al. Clinical trials of an intravenous oxygenator in patientswith adult respiratory distress syndrome. Anestbesiology 1992; 77: 856—63

66 Chang BS, Garella S. Complete extracorporeal removal of metabolic carbon dioxide by alkaliadministration and dialysis in apnea. Int J Artif Organs 1983; 6: 295-8

67 Bernard GR, Luce JM, Sprung CL et al. High-dose corricosteroids in patients with the adultrespiratory distress syndrome. N Engl J Med 1987; 317: 1565-70

68 Weigelt JA, Norcross JF, Borman KR, Snyder 3rd WH. Early steroid therapy for respiratoryfailure. Arch Surg 1985; 120: 536-40

69 Meduri GU, Chinn AJ, Leeper KV Jr et al. Corticosteroid rescue treatment of progressivefibroproliferation in late ARDS. Patterns of response and predictors of outcome. Chest 1994;105: 1516-27

70 Meduri GU, Belenchia JM, Estes RJ, Wunderink RG, el Torky M, Leeper Jr KV.Fibroproliferative phase of ARDS. Clinical findings and effects of corricosteroids. Chest 1991;100:943-52

71 Meduri GU, Headley AS, Golden E et al. Effect of prolonged methylprednisolone therapy inunresolving acute respiratory distress syndrome. JAMA 1998; 280: 159—65

72 Donnelly SC, Stricter RM, Kunkel SL et al. Interleukin-8 and development of adult respiratorydistress syndrome in at-risk patient groups. Lancet 1993; 341: 643-7

73 Mandell GL. ARDS, neutrophils, and pentoxifylline. Am Rev Respir Dis 1988; 138: 1103-574 Ardizzoia A, Lissoni P, Tancini G et al. Respiratory distress syndrome in patients with advanced

cancer treated with pentoxifylline: a randomized study. Support Care Cancer 1993; 1: 331-375 Domenighetti G, Suter PM, Schaller MD, Ritz R, Perret C. Treatment with N-acetylcysteine

during acute respiratory distress syndrome: a randomized, double-blind, placebo-controlledclinical study. / Cut Care 1997; 12: 177-82

76 Bernard GR, Wheeler AP, Arons MM et al. A trial of anrioxidants N-acetylcysteine andprocysteine in ARDS. The Antioxidant in ARDS Study Group. Chest 1997; 112: 164-72

77 Davis JM, Rosenfeld WN, Richter SE et al. Safety and pharmacokinetics of multiple doses ofrecombinant human CuZn superoxide dismutase administered intratracheally to prematureneonates with respiratory distress syndrome. Pediatrics 1997; 100: 24-30


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Non-ventilatory treatment of acute hypoxic respiratory failure · Acute hypoxic respiratory failure is an uncommon disease, with an incidence of between 1.5 and 5 cases per 100,000