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JINJ-5209; No. of Pages 10
Injury, Int. J. Care Injured xxx (2012) xxx–xxx

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Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why, when, what and which one?
Carol Hodgson a,b,*, Guillaume Carteaux a,c,d, David V. Tuxen b, Andrew R. Davies a,b, Vin Pellegrino b, Gilles Capellier a, David J. Cooper a,b, Alistair Nichol a,b
a b

Australia and New Zealand Intensive Care Research Centre, Department of Epidemiology & Preventive Medicine, School of Public Health & Preventive Medicine, Monash University, Australia The Alfred Hospital, Melbourne 3181, Australia



Article history: Accepted 20 November 2012 Keywords: Intensive care Acute respiratory distress syndrome Mechanical ventilation

Acute respiratory distress syndrome (ARDS) is an inflammatory condition of the lungs which can result in refractory and life-threatening hypoxaemic respiratory failure. The risk factors for the development of ARDS are many but include trauma, multiple blood transfusions, burns and major surgery, therefore this condition is not uncommon in the severely injured patient. When ARDS is severe, high-inspired oxygen concentrations are frequently required to minimise hypoxaemia. In these situations clinicians commonly utilise interventions termed ‘hypoxaemic rescue therapies’ in an attempt to improve oxygenation, as without these, conventional mechanical ventilation can be associated with high mortality. However, their lack of efficacy on mortality when used prophylactically in generalised ARDS cohorts has resulted in their use being confined to clinical trials and the subset of ARDS patients with refractory hypoxaemia. First line hypoxaemic rescue therapies include inhaled nitric oxide, prone positioning, alveolar recruitment manoeuvres and high frequency oscillatory ventilation, which have all been shown to be effective in improving oxygenation. In situations where these first line rescue therapies are inadequate extra-corporeal membrane oxygenation has emerged as a lifesaving second line rescue therapy. Rescue therapies in critically ill patients with traumatic injuries presents specific challenges and requires careful assessment of both the short and longer term benefits, therapeutic limitations, and specific adverse effects before their use. ß 2012 Elsevier Ltd. All rights reserved.

Contents Is refractory hypoxaemia in acute respiratory distress syndrome (ARDS) a clinical problem? . . . . . . . . ARDS is common and deadly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Classification and mechanism of hypoxaemia and multi-organ failure in ARDS . . . . . . . . . . . . . . . . . . . When to consider using a rescue therapy for severe hypoxia? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Is there a physiological basis for an oxygenation target? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxygen might be part of the problem and not part of the answer-threshold of oxygen toxicity. What is the correct oxygenation target in ARDS patients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . How would an ideal hypoxaemic rescue therapy perform? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . First line hypoxaemic rescue therapy options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inhaled nitric oxide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical use of inhaled nitric oxide in the trauma patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prone positioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical use of prone positioning in trauma patients with ARDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000 000 000 000 000 000 000 000 000 000 000 000 000

* Corresponding author at: ANZIC Research Centre, Department of Epidemiology & Preventive Medicine School of Public Health & Preventive Medicine Monash University, The Alfred Centre 99 Commercial Road, Melbourne, VIC 3004, Australia. Tel.: +61 3 9903 0598; fax: +61 3 9903 0071. E-mail address: (C. Hodgson). c ´ teil, France. Medical Intensive Care Unit, APHP Groupe Hospitalier Albert Chenevier-Henri Mondor, Cre d ´ teil, France. INSERM U955 Team 13, Paris Est University, Cre 0020–1383/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Hodgson C, et al. Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why, when, what and which one? Injury (2012),

. . . . . . . . . . . . . . makes ARDS a significant factor associated not only with mortality and morbidity. . . . . . thoracic injury. . . . . . . . . . . . 000 000 000 000 000 000 000 000 000 Is refractory hypoxaemia in acute respiratory distress syndrome (ARDS) a clinical problem? ARDS is common and deadly Acute respiratory distress syndrome (ARDS) is an inflammatory disorder of the lung parenchyma. . . . . . . . . . . . . . . . . . . . . . . .1016/j. . . Hodgson et al. . . . . Clinical use of ECMO in trauma patients with ARDS. . . . . . . . . . . . . . . . . . . . . . . . . reproduced with permission) showing atelectasis and oedema in the dependent lung regions and (B) supine chest radiograph of a patient with ARDS. . . . . . . . . . These insights also explain the previous findings that strategies which used high intensity mechanical ventilation to maintain adequate systemic oxygenation concentration through the use of high volumes and pressure. 1. . . . . . . . . . . . . . . . . . . . . .1. . but also an increased rate of complications. . . . . . . . . . . . . . . . . . . . . . . . . prolonged duration of mechanical ventilation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2 There are many clinical conditions associated with the development of ARDS in the critically ill including major trauma. .injury. . . . . .8 In this study. . impaired right ventricular performance) may also play a role. . . . with increased length of ICU and hospital stay and an ever growing use of expensive therapies (including hypoxaemic rescue therapies). . . .7. . .21. . . . . . . . . . . . blood transfusions. . . . . . . . . . Clinical use of HFOV trauma of patients. . . . . . . . . . . . . . .9. . . . . . . . despite high positive end expiratory pressure (PEEP) levels. . . . . injury severity. . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . aspiration of gastric contents. . Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why. . . . Extra-corporeal membrane oxygenation (ECMO) . . . . . . . . . . . . . . . ARDS patients who die often succumb to multiple organ failure contributed to by the ongoing ventilator induced injury promoting such biotrauma. . . . . . Conclusion . . . . . . . . when. . .2 ARDS results in impaired gas exchange and hypoxaemic respiratory failure. . . .5. . . . . . . . .15 dependant on gravitational forces. 1). . Clinical use of recruitment manoeuvres and PEEP titration in trauma patients with ARDS . . . . . . . . . High frequency oscillatory ventilation (HFOV) . . / Injury. .e. . . . . . . . . .1. . . . . pneumonia and receiving more than 5 units of fresh frozen plasma were independent predictors of developing ARDS. . . . . . . . . . . . . . . . . . . . . . No. . . . . . . . . . . . . . . . . . .9–13 Classification and mechanism of hypoxaemia and multi-organ failure in ARDS ARDS is a syndrome defined by clinical criteria (acute onset. J. . hypoxaemia (PaO2/FiO2 < 200 mmHg on PEEP > 5 cm H2O). . . .1. .11. . . . . . and are at risk of over-inflation lung injury (volutrauma) by excessive tidal volumes and plateau airway pressures. . . . . . . . . . . . . . resulting in chronic collapse injury. . . . . . . preventing severe hypoxaemia). . . . . . . . . . . . . . . . . . . . . . sepsis. . . . . . . . of Pages 10 2 C. . . . . .0004–7. . . . .20 Interestingly. bilateral infiltrates on chest radiograph without elevation of left atrial pressure). . . . it is important to note that other potential factors (e. . et al. . . . . . . . . . . .G Model JINJ-5209. . . . . . . . . . . .19 These repetitive mechanical insults promote a deleterious pulmonary and systemic inflammatory injury. . http://dx. . . it has the potential to not only worsen pulmonary injury and augment non-pulmonary organ failure and increase mortality. . . . . . . . . . . . . . .23 This is particularly important in Fig. . . . . . . . .17 Alveoli in the least dependent lung regions remain inflated throughout tidal ventilation. . . called biotrauma. . . Alveoli in the most dependent lung region remain collapsed throughout tidal ventilation. . . Conflict of interest statement . . . . Int. . . . poly-trauma. which can be refractory and life threatening. . . . . . . . . . with 3 functionally distinct zones during tidal ventilation (see Fig.13 A better understanding of the pathophysiology of ARDS has established that while mechanical ventilation is a lifesaving intervention. . demonstrated high rates of non-pulmonary associated mortality. . . . . . . .16 An intermediate lung region that collapses and re-expands with each breath results in shear stress-induced injury (atelectrauma). . . . . .22 Therefore clinicians often attempt to minimise the ‘intensity’ of mechanical ventilation. . One large multi-centre trauma cohort in the USA had 5% of patients develop ARDS. . . . . . . . . . . . . . . . . pneumonia. . . . . . burns. . . . .8 The combination of the clinical frequency of ARDS in the trauma intensive care unit (ICU) with an in-hospital mortality rate up to 40%. . . . what and which one? Injury (2012). . . . . . . . . . . . . . . Care Injured xxx (2012) xxx–xxx Recruitment manoeuvres and PEEP titration.017 . . . . . .doi. . . . . . . . . . . . .2012. . . . . . . Computed tomography (CT) images in ARDS demonstrate that the apparently homogeneous lung infiltrate seen on antero–posterior chest X-ray (CXR) is actually heterogeneous. . .g. . . . . The use of rescue therapies requires an assessment that the benefits outweigh the risks for that patient. . . . . . . . an approach that frequently involves the use of rescue therapies to maintain adequate gas exchange (i. . . . . . . . . . . . . . Please cite this article in press as: Hodgson C. . . . . . . . . . . . .org/10. .18. . . . . . . (A) CT of supine ARDS patient (left. . . . . . .3 The incidence of ARDS has been reported in various studies to range from 28 to 82 cases per 100. . . . . . . .14 While the alveolar consolidation and resulting ventilation/perfusion mismatch in ARDS is the predominant mechanism for arterial hypoxaemia. . . . . . .

2012. et al. No.injury. of Pages 10 C. http://dx. HFOV: high frequency oscillatory ventilation. Care Injured xxx (2012) xxx–xxx 3 ARDS + severe hypoxemia Protective lung ventilation applied (Vt ≤ 6 ml/kg and Pplat ≤ 30 cmH2O) Adjust the ventilator settings to achieve: Vt ≤ 6 ml/kg and Pplat ≤ 30 cmH2O No Severe hypoxemia remains No Yes Check the cardiovascular status (at least clinical exam and transthoracic echocardiography) Yes NO REFRACTORY HYPOXEMIA Left heart failure with increase in left atrial pressure Yes Manage diuretics and other heart failure therapies Severe hypoxemia remains No No Yes Low PvO2 Hypovolemia Hypotension Yes Manage with fluid resuscitation and vasoactive drugs Severe hypoxemia remains No No Yes Right heart failure Pulmonary hypertension Intra-cardiac shunt (require transesophageal echocardiography) Yes May guide the choice of a rescue therapy and/or a specific treatment No Sedation Neuromuscular blockades Fever reduction Use of a closed system Avoid useless endotracheal Severe hypoxemia remains No Yes REFRACTORY HYPOXEMIA A rescue therapy is justified Vt = Tidal Volume Pplat = Plateau pressure Fig. iNO: inhaled nitric oxide.doi.11.G Model Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why.017 . / Injury. PEEP: positive end expiratory pressure. Flow chart of suggested optimal patient management for severe ARDS with severe hypoxaemia prior to a rescue therapy being commenced ECMO: extracorporeal membrane oxygenation. Please cite this article in press as: Hodgson C. what and which one? Injury (2012).1016/j. J. when. 2. Int. Hodgson et al.

Animal experiments have clearly demonstrated that exposure to FIO2 of 1. (iii) be inexpensive. N/S: not significant. Rescue therapy Nitric oxide Advantages Management of pulmonary hypertension Disadvantages Expensive Not always available Short term efficacy Requires several staff Pressure sores Needs to be maintained for long periods of time Staff training Transient hypotension/desaturation Risk of increased pulmonary pressure Specific ventilator Training Sputum retention Systemic anticoagulation Expensive Invasive Training Possible mortality benefit N/S Prone positioning Cheap Readily available Cheap Readily available Reduced driving pressure of the lungs Management of air leaks Lung rest and recovery Used when other rescue therapies fail Yes if PaO2/FIO2<10058 RMs and PEEP titration N/S – RMs Yes – PEEP60 Yes77 HFOV ECMO N/S ECMO: extracorporeal membrane oxygenation. First line hypoxaemic rescue therapy options Inhaled nitric oxide Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator. Before the addition of a hypoxaemic rescue therapy to the treatment bundle it is wise to confirm that current care is optimal to minimise lung injury and to maximise outcomes (Fig. However. There is growing interest in permissive hypoxia. a PaO2 as low as 5 mmHg is enough to fuel the reactions in normal individuals. By selectively dilating the pulmonary vasculature of these areas of ventilated lung. Please cite this article in press as: Hodgson C. Many of these injuries may tilt the potential balance more towards risk than benefit for a particular rescue therapy.2012. most studies in a general ARDS population and many clinicians define refractory hypoxia (and suggest the need for hypoxaemic rescue therapies) as either (i) a PaO2/FIO2 ratio < 10035 or (ii) a SaO2 < 88% or (iii) a PaO2 < 60 mmHg with a plateau airway pressure > 30 cm H2O with a FIO2 > 0. chest injuries and brain injuries in the traumatically injured cohort augment the potential for adverse effects of some rescue therapies. The ideal hypoxaemic rescue therapy would (i) have the ability to rapidly and effectively improve oxygenation. hypotension). et al. HFOV: high frequency oscillatory ventilator. Int. when. PaO2/FIO2: ratio of partial pressure of arterial oxygen to fraction of inspired oxygen. this is controversial and needs to be carefully considered in certain patient populations. 2). LicCOx). How would an ideal hypoxaemic rescue therapy perform? It is useful to consider how an ideal hypoxaemic rescue therapy might perform.e. So how low should you go? There are many different opinions regarding the optimal threshold of oxygen saturation and PaO2. termed cytopathic hypoxia. Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why. often with additional cerebral oxygen monitoring (i. Care Injured xxx (2012) xxx–xxx patients with trauma who present with multiple complex injuries.24 This is further highlighted by the finding that at the mitochondrial level.00 induced death in many animal species in 3–5 days.31–34 a tolerance of even lower oxygenation targets to permit less injurious and intensive ventilation strategies. In particular.29 It seems prudent to target the minimally safe PaO2 in our patients as soon as possible.11. (iv) be simple. No. A rescue therapy needs to be considered safe and effective despite the complex issues of the patient. widely available and require minimal staff training to use.6 is higher in ARDS patients with severe airspace enlargement at post mortem. When to consider using a rescue therapy for severe hypoxia? Is there a physiological basis for an oxygenation target? Tissue related hypoxic injury is the result of hypoxaemia. Ideally it should not only increase oxygenation but also improve survival and the quality of life of long-term survivors (see Table 1). Most would agree with targets of 94–98% saturation for healthy subjects30 and between 88 and 92% and a PaO2 > 55–60 mmHg in the context of ARDS. / Injury.24 Oxygen might be part of the problem and not part of the answerthreshold of oxygen toxicity While oxygen is necessary for our the time spent with a FIO2 higher than 0. and (vi) have no short term or longterm adverse effects.017 . http://dx. The question of the minimal safe PaO2 in the context of TBI is less clear.8. RMs: recruitment manoeuvres. what and which one? Injury (2012). it seems reasonable to avoid high FIO2 as oxygenation improves. as this may then provide a ‘yard stick’ by which to compare the pros and cons of current available alternatives. Hodgson et al. therefore care is required in the selection of the most appropriate rescue therapies for traumatically injured ARDS patient with refractory hypoxaemia.1016/j.e.25 In humans. (v) be non-invasive. while others target PaO2 of 60 or lower. of Pages 10 4 C.injury. too much oxygen is toxic. Several recent papers have highlighted the risk of high PaO2 in cardiac arrest patients27 and in traumatic brain injury28 and even in the general population. Interestingly recent evidence suggests that organ dysfunction in the critically ill may be more related to the derailment of the metabolic processes of cells to use available oxygen rather than the lack of available oxygen. J.26 What is the correct oxygenation target in ARDS patients While a high PaO2 is not a major concern in the context of ARDS. iNO improves ventilation perfusion matching and reduces Table 1 Overview of the advantages and disadvantages of each rescue therapy for hypoxia. Its administration via the inhaled route results in delivery to only the alveoli that receive alveolar ventilation and also minimises systemic effects (i.doi. Many clinicians are conservative and tolerate higher FiO2 and PaO2 above 70 mmHg in this context. (ii) facilitate the use of low pressure and low volume protective lung ventilation strategies to minimise additional lung injury. for example acute traumatic brain injury where it is contra-indicated. hypoperfusion and cytokine-mediated mitochondrial dysfunction.G Model JINJ-5209.

decreased alveolar overdistension and reduced ventilator induced lung injury. antibiotics) or even (iii) as an additional rescue therapy (i.doi. resulting in increased dorsal atelectasis.50 The process of prone positioning requires consideration of safety precautions. air is distributed more homogeneously throughout the lungs. / Injury. Prone positioning shifts the gravitational forces and reduces the cardiac compression of the lungs.51 In a recent meta-analysis.G Model JINJ-5209. Future studies are required to assess the response of different doses of iNO and the true effect of iNO in the presence of higher levels of PEEP. it may be an effective short term rescue therapy for patients with very severe refractory hypoxaemia. when. diuretics. 3. most would commence at 5 ppm (parts per million) and titrate up to 40 ppm to achieve optimal effect. and the absence of clear evidence of benefit. Care Injured xxx (2012) xxx–xxx 5 pulmonary shunt. Furthermore.38. particularly if the prone position is maintained for a long period of time49.1016/j.44 Furthermore. PEEP: positive end expiratory pressure.e. J. endotracheal tube obstruction and chest tube removal. hospital costs from enrolment to discharge or in length of hospital stay. Long term outcomes (to one-year) and hospital costs have also been assessed in a RCT of 385 adults with ARDS randomised to 5 ppm iNO or placebo. the inflammatory pulmonary oedema that occurs during ARDS increases lung weight collapsing the dorsal regions of the lungs under the weight of the ventral regions.40 a complication which may aggravate the systemic delivery of oxygen. external fixation or traumatic brain injuries. spine or pelvis.46.48 This protective ventilator effect could potentially minimise the systemic inflammatory response and improve outcomes. Hodgson et al. The ventral regions become dependent and collapse under the weight of the dorsal Individual study findings are supported by two systematic reviews of prophylactic iNO in ARDS that report no difference in survival or ventilator-free days between treatment and placebo groups. 3). Clinical use of inhaled nitric oxide in the trauma patient Given the substantial cost of iNO. No. of Pages 10 C.11.53 There are several additional limitations to the use of prone positioning. Patients with ARDS as a result of severe traumatic injuries may not be suitable for the prone position due to unstable fractures of the face. the limited pharmacokinetic studies in ARDS make it difficult to make firm recommendations about the optimal dose of iNO. the current evidence suggests that while iNO will not improve survival or long term outcomes in patients with ARDS. however the clinical implications of these are as yet uncertain. et al. HFOV: high frequency oscillatory ventilation. Because of their shape. Several randomised controlled trials in ARDS patients have reported that while prophylactic iNO resulted in improvements in oxygenation over a period of 24–48 h (tachphylaxis presumably develops thereafter). Our experience suggests that an optimal effect on oxygenation can usually be achieved with lower doses (5– 10 ppm). and stress and strain are decreased. There may be Fig. this tends to increase atelectasis and consolidation in the gravitational-dependent lung regions. Other potential benefits of prone positioning include enhanced drainage of secretions from the posterior lung segments. Patients treated with iNO therefore require careful monitoring of arterial blood for development of this side effect but this is seldom a clinical problem. a higher percentage of the lungs’ alveolar units are open to ventilation in the prone position than in the supine position. which inflate to a different extent. it may be that the greatest benefit is achieved in the most severe subset of ARDS patients and that this benefit is not detected in studies selecting all ARDS patients. long term clinical outcomes were not improved. Prone positioning Patients with severe trauma and ARDS often spend prolonged time in the supine position. However.36.e. (ii) allowing time for other interventions to take effect (i.39 However.52 One trial found increased risk of unplanned extubation and unplanned removal of venous or arterial catheters.2012. Int. This effect frequently results in both improved oxygenation and decreased pulmonary artery pressure. Flow chart of suggested patient management when a rescue therapy is being considered due to refractory hypoxaemia ECMO: extracorporeal membrane oxygenation. Extra staff are required. prone positioning increased the risk of pressure ulcers. the position of the endotracheal tube and other lines must be securely maintained and the patient must receive constant monitoring for the development of pressure injuries. http://dx. Improved lung recruitment and ventilation-perfusion matching may occur.47 Therefore. the routine use of iNO in ARDS cannot be currently justified.e.43. iNO carries a risk of increased oxidative stress in red blood cells and the development of methaemaglobinaemia.44 however.injury. iNO: inhaled nitric oxide. add iNO to prone45).017 .41. Fig. This may be of clinical value (i) while waiting to establish another longer acting hypoxaemic rescue therapy (i. in the prone position. HFOV or ECMO. whereas optimal effect on pulmonary artery pressure may require higher doses (up to 40 ppm).37 iNO has also been suggested to have anti-inflammatory effects.41 There were no differences between the groups for survival. Please cite this article in press as: Hodgson C. Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why. In addition.46 As the dependent posterior lung segments account for a large proportion of the lungs this may cause significant shunt which contributes to hypoxaemia. what and which one? Injury (2012).

57. multi-centre randomised controlled trials49. No. There were a total of 28 complications.52 The optimal duration of prone positioning is yet to be determined however at least 16 h per day should be used (ref. renal failure. http://dx. PROSEVA). J. Please cite this article in press as: Hodgson C. / Injury. semi-recumbent position.injury. et Clinical use of prone positioning in trauma patients with ARDS Investigation of the survival benefits associated with prone positioning will require future studies to be designed with careful consideration of the use of the technique. At present the evidence suggests that the routine use of this technique is not justified. what and which one? Injury (2012). when. The authors concluded that prone positioning was safe and feasible and may reduce mortality when applied early in the course of ARDS and for prolonged periods of the day. HFOV: high frequency oscillatory ventilator. and hence have a role as a rescue therapy.49. the timing of the intervention and the duration of the intervention. PEEP: positive end expiratory pressure. Hodgson et al.59 However a recent pooled data meta-analysis suggested that patients with severe ARDS (defined as PaO2/FIO2 < 100 mmHg) may have a survival benefit when prone positioning is used. Int. the study population. limitations due to wounds. ICC: intercostal catheter. The use of this therapy in trauma patients could be considered only in the absence of exclusions Difficulties and complications Methaemaglobinaemia. Rescue therapy Nitric oxide Prone positioning Benefit Right ventricular failure by Mancebo et al.63 The oxygenation was improved for up to 10 days in patients with prone positioning. but that it may have a survival benefit in the subset of patients with severe hypoxaemic ARDS. spine. Five randomised controlled trials have shown improved oxygenation with no survival benefit.doi. 4.2012. Schematic diagram of veno-venous extracorporeal membrane oxygenation circuit.54–56 The recent PROSEVA trial (NCT00527813) has reported a 28 day survival benefit with prone positioning for more than 16 h per day in patients with severe ARDS (PaO2/FIO2 < 150) compared to standard protective lung ventilation in the supine. platelet inhibition Unstable or painful fractures (face. RMs: recruitment manoeuvres.49 The investigators randomised 136 patients. investigated the use of prolonged ventilation. Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why. most of which were reversible.58. skin grafts or orthopaedic management. Care Injured xxx (2012) xxx–xxx Fig. of Pages 10 6 C.58 and systematic reviews59–62 had failed to demonstrate that prone positioning leads to a survival benefit in a diverse patient population defined as having ARDS and ALI.53.11. A study Table 2 Clinical considerations for the application of rescue therapies. However.017 . several studies have examined prone ventilation in trauma cohorts and have found that it improves oxygenation without a significant increase in complications in carefully selected patients.1016/j.57. chest) External fixation of fractures Facial injury Internal trauma Pneumothorax or air leaks Chest trauma Right ventricular failure Large amount of sputum Haemorrhage RMs and PEEP titration Immobile patients (unable to turn) HFOV ECMO Pneumothorax or air leaks Presence of ICC When other rescue therapies fail ECMO: extracorporeal membrane oxygenation. 76 patients to receive prone ventilation for 20 h per day and showed prone positioning was used for a mean of 17 h per day for a mean 10 days with a possible trend towards a survival benefit (P = 0. Previously.G Model JINJ-5209.12).

J. These pressure oscillations result in very small tidal volumes (1–4 ml/kg). Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why. No. minimise tidal volume in an attempt to limit airway pressures.78 Furthermore. et al. the oscillator.65 However. / Injury. the very low pressure swings that reach the alveoli may limit volutrauma as well as the repetitive intra-tidal opening and closing of unstable lung units (atelectrauma). The most common RM used in protective ventilation strategies was a static RM of 40 cm H2O pressure for 40 s. potentially providing better alveolar recruitment. concluded that RMs transiently improved oxygenation in patients with ARDS and ALI without adverse effects of barotrauma or hypotension.10. when intracranial pressure monitoring present with controlled pressures. and a round table consensus/discussion was used to publish recent guidelines and protocol for use of HFOV. concurrent ventilator strategies and end PEEP levels. This approach is frequently accompanied by increases in carbon dioxide.69. 3).72–76 Clinical use of recruitment manoeuvres and PEEP titration in trauma patients with ARDS Current evidence suggests that high PEEP regimes may have a survival benefit in patients with severe ARDS but there is insufficient evidence to establish the long term effects of recruitment manoeuvres.64 Importantly this meta-analysis did show an improved survival in the subgroup of patients with ARDS (as opposed to the less severe ALI64) however the best strategy to determine optimal PEEP has not yet been established.e.69 Other recruitment techniques. the pressure oscillations that are imposed into the proximal airways are highly attenuated (damped) by the time they reach the alveoli. defined as 10–16 cm H2O as part of an open ventilation strategy to improve alveolar recruitment in patients with ARDS.G Model JINJ-5209.32. In this case. they may be used for patients with severe refractory hypoxaemia to improve oxygenation.2012. High PEEP aims to maintain functional residual capacity and improve oxygenation. rapid diagnosis of bleeding and minimally invasive management of blood loss is crucial.79 Although head injury is an exclusion criteria in most recruitment trials. Furthermore. time at maximum pressure. have shown reductions in mortality and are now widely accepted. such as a ‘‘staircase’’ recruitment manoeuvre. which incorporate high levels of PEEP. High frequency oscillatory ventilation (HFOV) High-frequency oscillatory ventilation (HFOV) is an alternative mode of ventilation which requires the use of a specific designed ventilator.70 however this may not be the case in patients with fractured ribs or lung contusions.32 A systematic review on the clinical utility of high PEEP in ARDS and acute lung injury (ALI) has suggested that the randomised trials in this area have been underpowered to detect a small but potentially clinically important effect on reducing mortality associated with ARDS. some strategies. so called permissive hypercapnia.32.69 The lack of long term benefit from a static RM in patients with ARDS may have been because the static RM was not performed for an adequate time or with sufficient pressure to open collapsed alveoli this patient While this approach is safe in most ARDS patients.70 Although it is unclear whether recruitment manoeuvres have a long term effect in patients with ARDS.64. Recruitment manoeuvres and PEEP titration are inexpensive.10 A Cochrane review of the effects of RMs.11. which characterise oxygenation and carbon dioxide clearance. To date.77 there is substantial controversy surrounding their use in the trauma patients with ARDS where the use of high PEEP and recruitment manoeuvres may increase barotrauma in the presence of chest injuries. A large randomised controlled trial that included high PEEP and a RM of sustained static lung inflation to pressures of 40 cm H2O for 40 s failed to improve patient survival but reduced the use of rescue therapies and refractory hypoxaemia. including low tidal volume.64 PEEP aims to reverse the pulmonary shunt due to increased lung collapse resulting from pulmonary inflammation in ARDS. recruitment manoeuvres can be done with minimal elevation of intracranial pressure. those who also have a co-existent traumatic brain injury are likely to be at risk of hypercapnia induced increased intracranial pressures.017 . Given this. in our experience. However this RM method can be uncomfortable.71 Protective mechanical ventilation strategies. While some studies demonstrate that recruitment manoeuvres are efficacious post traumatic injury.82 HFOV usually requires heavy sedation and the use of neuromuscular blockers to avoid ventilator asynchrony and these Please cite this article in press as: Hodgson C. that identified seven relevant randomised trials. what and which one? Injury (2012). when. usually smaller than the anatomical dead space. including peak pressure. Two systematic reviews of RMs have shown no substantial increased risk of barotrauma in general ARDS populations69. limitation of plateau pressure and PEEP. of Pages 10 C. HFOV has the potential to reach the goals of an ‘ideal’ protective lung ventilation approach i. in two of these trials there were improvements in important secondary outcomes including the rate of refractory hypoxaemia.66–68 The role of recruitment manoeuvres (RM) in ARDS. around which oscillations of predefined amplitude (DP) are actively superimposed at a high frequency (usually between 3 and 15 Hz) by using a motorised diaphragm. This concept is controversial. is controversial. there is only limited clinical evidence on which to base these assertions. may induce circulatory depression and has not been associated with improved outcomes in patients with ARDS.70 In clinical studies there was substantial heterogeneity in methods used to deliver RMs. readily available and in our experience should be considered prior to other expensive or invasive rescue therapies in patients with refractory hypoxaemia (Fig. Three randomised controlled trials of open lung ventilation strategies that included high PEEP however did not demonstrate an improvement in survival. Int. Recruitment manoeuvres and PEEP titration Clinicians frequently use moderately high positive endexpiratory pressure (PEEP). and novel trials are underway to assess the effect of open ventilation strategies using a combination of staircase recruitment manoeuvres.81 Practically. The principle of HFOV is to deliver a continuous distending mean airway pressure (mPaw). Furthermore. In theory.80. PEEP titration and permissive hypercapnia on survival and duration of mechanical ventilation.69 This and another meta-analysis both concluded that there was no evidence of outcome benefit but that there was insufficient data to exclude a beneficial effect.doi. mean airway pressure can be set at a higher level than the PEEP level during conventional ventilation. Hodgson et al.1016/j. external fixation see Table 2) and only when the treating team are familiar with this intervention in order to minimise the risk of complications. reduce the use of alternate rescue therapies and potentially reduce ventilator free days.32 and the number of ventilator free days. new gas exchange mechanisms have been described during HFOV.injury. usually as part of an open lung ventilation strategy. It is also important to note that high PEEP and RMs can cause systemic hypotension which may be exacerbated in patients with hypovolemia and significant haemorrhage. Care Injured xxx (2012) xxx–xxx 7 (such as unstable spinal fractures. especially if the prior recruitment is optimal.10 use of rescue therapies10. http://dx.69. have been used in pilot randomised controlled trials and been shown to be safe and effective in improving oxygenation and lung compliance. oxygenation can be improved by either increasing the mPaw or the FIO2.

significant barotrauma and air leaks from intercostal catheters. Mean health-care costs per patient were more than twice as high for patients allocated to consideration for treatment by ECMO than for those allocated to conventional management. ECMO was provided at a single highly ECMO-experienced centre while the standard care was conducted at less specialised centres. HFOV was found to be safe in patients with ARDS as a result of trauma to improve oxygenation. intracerebral bleed) or due to inability to surgically correct (i. future studies are required to determine the true clinical place of such a strategy.92 In the 1970s and 1980s. no systemic anti-coagulation.11 This study was conducted in the United Kingdom (UK) and was a pragmatic trial designed to assess the clinical efficacy of the UK model of ECMO provision which included transfer to a specialist ARDS management hospital.87 The potential benefit of the routine use of HFOV as a ventilation strategy during ARDS has not been determined but ongoing clinical trials may provide further information in the future (ISRCTN10416500. the need for specific training in the use of HFOV and circuit set-up. However. or ultra protective lung ventilation facilitated by ECMO delivered by specialised ECMO centres. Only 75% of patients in the treatment arm actually received ECMO.2012. uncontrolled observational reports suggested clinical benefits with the use of extracorporeal support. but improved oxygenation was not. impaired clearance of pulmonary secretions and the need for heavy sedation and neuromuscular blockade. The primary endpoint of the study was survival at 6 months or presence of severe disability. Hodgson et al.03). and sleep quality. when. or barotrauma) as well as hospital or 30 days mortality compared with conventional mechanical ventilation in patients with ARDS. Only 8% of patients in the study had ARDS as a result of traumatic injuries or major surgery. randomised trials that have compared HFOV with protective ventilation strategies have been underpowered to show a difference in mortality. but survival was likely related to the severity of the initial injury and unlikely to be affected by the use of HFOV.97]. of Pages 10 8 C. More data is required about the use of HFOV in combination with other rescue therapies. with 103 referring hospitals and 180 patients randomly assigned to either to be referred for consideration for ECMO or receive conventional mechanical respiratory support.90 Of this cohort 79% had sustained blunt trauma. However this study was designed to demonstrate the equivalence of HFOV to conventional mechanical ventilation with respect to safety and was not powered to detect any difference in mortality. PEEP). J. including patients with blunt trauma. It is possible that synergies exist when other rescue therapies (i.e.017 . Clinical use of ECMO in trauma patients with ARDS The use of ECMO is frequently accompanied by systemic anticoagulation to prevent thrombosis of the extracorporeal circuit. NCT01167621). the largest prospective adult ECMO trial conducted. Int. but these were not realised in subsequent randomised controlled trials (RCTs). prone and iNO) are combined with HFOV. Furthermore the tidal volume in the conventional mechanical ventilation arm was set between 6 and 10 ml/kg of the actual body weight. The ideal timing for the use of HFOV is uncertain. In a retrospective trauma case series in the USA.10). the sample size (smaller than initially planned) appears to have limited the precision of the result.injury. initial Please cite this article in press as: Hodgson C.91 ECMO has been used for over 44 years as a rescue therapy for severe acute respiratory failure that is refractory to mechanical ventilation. http://dx.05– 0. Australian and New Zealand intensive care units have demonstrated a high utilisation and high success with ECMO for severe ARDS associated with H1N1 influenza. the major limitation of the trial was that it was not designed to specifically test the clinical efficacy of ECMO alone for respiratory failure – rather it was an evaluation of a pathway for care of patients with severe respiratory failure.21 To date. the quality of respiratory care in the control arm and the generalisability of the findings outside the UK have been raised. mental and emotional state. The intention-to-treat analysis demonstrated that significantly more patients allocated to consideration for treatment including ECMO survived to 6 months without disability when compared with those allocated to conventional management (relative risk [RR]. P = 0. ECMO is a complex intervention and historically it has been difficult to unequivocally ascertain its true clinical efficacy in the ´ seau Europe ´ en de recherche ´ management of severe ARDS. HFOV was used in 24 patients with ARDS to improve oxygenation. 331 patients with severe ARDS will be randomised to receive either optimal conventional mechanical ventilation. 0. P = 0.83–86 A recent systematic review and meta-analysis has shown that that HFOV improves oxygenation and reduces the risk of treatment failure (refractory hypoxaemia. The Re en Ventilation Artificielle (REVA or Network for Mechanical Ventilation) programme will conduct an international clinical trial titled EOLIA (ECMO to rescue lung injury in severe ARDS) to determine the effectiveness of ECMO support in preventing death from severe ARDS.89 HFOV might be an ideal rescue therapy to be used with chest trauma.86. Though a relatively large treatment effect is evident. which often included ECMO as part of the package. Although there is some evidence that oscillation when prone may also be efficacious.69 [95% CI. to date. 52%. what and which one? Injury (2012). massive GIT bleed). While trauma patients are at excessively high risk of bleeding various strategies have be used (i. Haemorrhage is a major complication of ECMO and can be devastating either due to site (i. RMs. Hypoxaemic rescue therapies in acute respiratory distress syndrome: Why. / Injury. Currently the place of oscillation in the rescue of hypoxaemic ARDS patients is unclear but it is usually commenced after other rescue therapies have been unsuccessful (iNO. The study also evaluated 6 month quality-of-life. Extra-corporeal membrane oxygenation (ECMO) Veno-venous (VV) extracorporeal membrane oxygenation (ECMO) (see Fig. Severity of injury and number of organs failing were predictors of survival. No significant differences were recorded between groups for any of the 6 month follow-up assessments.93 The most recently published ECMO RCT is the CESAR (conventional ventilation or ECMO for severe adult respiratory failure) study. 4) is an alternative form of lung support that can provide non-pulmonary oxygen delivery and carbon dioxide removal and may also facilitate lung protective ventilation in ARDS. CESAR is. The first randomised controlled trial comparing HFOV with conventional ventilation in ARDS found a trend towards less mortality with the use of HFOV (37% vs. a setting that is associated with a poor outcome as compared with a protective ventilation strategy using a low tidal volume (6 ml/kg of the predicted body weight). thereby limiting inferences to this population. hypercapnia.e.e.83. et al.G Model JINJ-5209.84 Both observational and randomised trials have indicated that HFOV is safe and effective in improving oxygenation.doi. No.94 The precise contribution of ECMO to the observed beneficial treatment effect remains debatable in view of possible differences in mechanical ventilation between study groups and the 75% use of ECMO in the treatment arm. In this trial. Clinical use of HFOV trauma of patients Limitations of HFOV include the expense of a separate ventilator to deliver HFOV. Reasonable concerns with regard to the basis of the efficacy. 0.11. Depending on local experience and training many centres would then choose between prone positioning and oscillation as an additional rescue at this point. Care Injured xxx (2012) xxx–xxx are a significant limitation.1016/j.

Journal of the American Medical Association 2010. 27. Jones AE. et al. George L.19(7):383–9.15(January (1)):R4. Falke KJ. 16. Fergusson DA. et al. Bitterman H. Inforsato N. The Acute Respiratory Distress Syndrome Network.97 While there is currently little experience in the use of ECMO in trauma it could be considered in extremis as a useful hypoxaemic rescue therapy in adequately experienced centres. Martin de Lassale E. 8.328(February (6)):399–405. There are a number of potential rescue therapies which the clinician may deploy in an attempt to maintain gas exchange at minimally safe levels. New England Journal of Medicine 1993. arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients. Forel JM. While ECMO is invasive. Edibam C. Lemaire F. et al. / Injury. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. 31. Gacouin A. 17.149(March (3 Pt 1)):818–24. et al. not all of the rescue therapies available for ARDS patients are safe and appropriate for use in patients with traumatic injuries and attention needs to be directed to the contraindications of specific rescue therapies. These first line therapies are often sufficient to prevent critical hypoxia.151(October (8)):566–76. Peelen L. O’Driscoll BR. 7. Care Injured xxx (2012) xxx–xxx 9 heparin free ECMO or low dose anti-coagulation) have been used to facilitate the use of ECMO in this ARDS sub-population. to allow ‘protective’ ventilation and to minimise organ failure. Suter PM. New England Journal of Medicine 2010. J. 5. Wrigge H. Inhaled nitric oxide for the adult respiratory distress syndrome. Steinberg KP. Tiruvoipati R.183(January (1)):59–66. American Journal of Respiratory and Critical Care Medicine 1994. recruitment maneuvers. et al. and clinical trial coordination.165(February (4)):443–8. et al. Putensen C. Maggiore SM. Brower RG. Pressure-controlled ventilation in ARDS: a practical approach. et al. Papazian L. Int.doi. Gauvin D. relevant outcomes.2012. when. Archives of Surgery 2006.G Model JINJ-5209. New England Journal of Medicine 2000. et al. Brigham KL. Pelosi P. and the associated mortality is high. Guyatt GH. Lang JD. Davis DP. Dembinski R. Hess DR. Hudson LD. Peek GJ. No. Jonson B. Caironi P. Salim A. Rubenfeld GD. oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. 6):vi1–68.299(February (6)):646–55. Max M. British Thoracic S. Gangal M. 33. Amato MB. 26. http://dx. Richard JC. 25. Meade MO.95 Despite these high risks some patients have been successfully treated with ECMO as a rescue therapy.83(March (3)):252–8. Pediatric Critical Care Medicine 2009. Brochard L. Vielle B. of Pages 10 C. Neuromuscular blockers in early acute respiratory distress syndrome. 39. 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